A thiourea-oxazoline library with axial chirality: Ligand synthesis and studies of the palladium-catalyzed enantioselective bis(methoxycarbonylation) of terminal olefins

Article abstract of DOI:10.1002/adsc.201000070

We report herein the synthesis of novel chiral S,N-heterobidentate thiourea-oxazoline ligands and their application to palladium-catalyzed enantioselective bis(methoxycarbonylation)s of terminal olefins under mild conditions. Copper salts were found to play multiple roles in this reaction. Substituted 2- phenylsuccinates were obtained in >90% yield and up to 84% ee under optimized conditions.

Full text of DOI:10.1002/adsc.201000070

FULL PAPERS
DOI: 10.1002/adsc.201000070
A Thiourea-Oxazoline Library with Axial Chirality: Ligand Syn-
thesis and Studies of the Palladium-Catalyzed Enantioselective
Bis(methoxycarbonylation) of Terminal Olefins
Ying-Xiang Gao,a Le Chang,a Hang Shi,a Bo Liang,a Kittiya Wongkhan,b
Duangduan Chaiyaveij,b Andrei S. Batsanov,b Todd B. Marder,b,*
Chuang-Chuang Li,a,* Zhen Yang,a,* and Yong Huanga,*
a
Laboratory of Chemical Genomics, Shenzhen Graduate School of Peking University, Shenzhen 518055, Peopleꢀs Republic
of China, and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education and Beijing
National Laboratory for Molecular Science (BNLMS), College of Chemistry, Peking University, Beijing 100871, Peopleꢀs
Republic of China
Fax : (+86)-755-2603-5326; e-mail: huangyong@szpku.edu.cn, zyang@pku.edu.cn, chuangli@pku.edu.cn
Department of Chemistry, Durham University, South Road, Durham DH1 3 LE, United Kingdom
b
Fax : (+44)-191-384-4737; e-mail: todd.marder@durham.ac.uk
Received: January 28, 2010; Published online: August 16, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000070.
Abstract: We report herein the synthesis of novel phenylsuccinates were obtained in >90% yield and
chiral S,N-heterobidentate thiourea-oxazoline ligands up to 84% ee under optimized conditions.
and their application to palladium-catalyzed enantio-
selective bis(methoxycarbonylation)s of terminal ole- Keywords: asymmetric catalysis; catalyst design;
fins under mild conditions. Copper salts were found enantioselectivity; palladium; thiourea-oxazoline li-
to play multiple roles in this reaction. Substituted 2- brary
Introduction
catalysis. In fact, styrenes and CO can be co-polymer-
ized using Pd catalysts containing nitrogen ligands
Thioureas have emerged as an important class of li- such as 2,2’-bipyridyl and 1,10-phenanthroline.[7a,8] Di-
gands for transition metal-catalyzed reactions in phosphine ligands were reported to catalyze mono-
recent years.[1–5] A number of coupling reactions cata- methoxycarbonylations with various degrees of regio-
lyzed by palladium-thiourea complexes have been re- selectivity (linear vs. branched), depending on the
ported. Their advantages over traditional phosphine electronic nature of the ligand.[7i]
ligands include robust air stability and resistance to
We recently reported[4h] that a chiral thiourea-oxa-
oxidation, which is important in oxidative catalytic zoline 1 (Figure 1) was a highly efficient ligand for
processes, easy electronic tuning and sometimes or- palladium-catalyzed bis(methoxycarbonylation) of
thogonal chemoselectivities. Bis(methoxycarbonyla-
tion) reactions have long been an efficient method to
install two ester groups across a carbon-carbon
double bond. Since the initial discovery by Heck in
1972,[6] several palladium-catalyzed asymmetric pro-
cesses have been reported.[7] However, this reaction
has had limited applications in the synthesis of com-
plex scaffolds, partially due to poor mechanistic un-
derstanding and few reliable methodologies to ensure
high yields and enantioselectivities. Styrenes are
among the most challenging substrates due to their in-
clination to polymerize rapidly under transition metal Figure 1. Thiourea-oxazoline ligands.
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their application in palladium-catalyzed asymmetric
bis(methoxycarbonylation) reactions of terminal ole-
fins. We describe herein the synthesis of the chiral
ligand library, single-crystal studies of a palladium-
ligand complex and a detailed investigation of opti-
mized reaction conditions. A more robust anthracene-
substituted bidentate thiourea-oxazoline was devel-
oped in accord with the hypothesis that increased
Scheme 1. Palladium-catalyzed bis(methoxycarbonylation)
of styrene.
styrenes (Scheme 1). High yields and moderate ees bulk near the palladium center would enhance ees.
were observed with various styrenes under ambient Using this ligand, reactions could be carried out at
temperature and pressure of CO. Of particular inter- 08C in the presence of commercial CuCl and a silver
est was our observation that atropoisomerism at the salt, giving up to quantitative yield of the desired
À
N Caryl bond appeared to be more important in deter- product and up to 84% ee using styrene as substrate.
mining enantioselectivity than the chiral oxazoline
moiety. Importantly, both experimental and theoreti-
cal studies indicated that the barrier to rotation Results and Discussion
À
around the N Caryl bond was quite large, and thus the
two diastereomers were readily separated and were Synthesis of the Ligand Library and Initial Screening
configurationally stable even at temperatures over Results
1008C With this in mind, we turned our attention to
the design of alternative ligands which would also The general synthetic route to prepare the ligand li-
possess atropoismers, and in which a group larger brary is shown in Scheme 2. Thus, 1-bromo-2-nitro-
than the ortho-isopropyl moiety would protrude into benzene 2 was coupled with the appropriate primary
the coordination sphere of the palladium center, with amines under Buchwald–Hartwig conditions,[4h,9] and
the idea that this would improve enantioselectivity in the nitro group was hydrogenated to give the corre-
the catalytic reaction. We also wished to confirm our sponding diamine 3. Alkylation using ethyl bromoace-
theory by examining a larger library of ligands with tate resulted in ester 4. Thiourea formation was ac-
and without the atropoisomerisation issue.
complished using previously described conditions with
In addition, our recent studies showed that rigorous thiophosgene[4d,h] in the presence of NaHCO3. Thiour-
purification of CuCl was required in order to main- ea-ester 5 could undergo stepwise mono- or bismethy-
tain decent enantioselectivities using ligand 1. Com- lation using LiHMDS/MeI by controlling the reaction
mercial CuCl from various source consistently pro- temperature and reagent stoichiometry. Attempts to
duced 10–20% lower ees. In this paper, we report the access the gem-dimethyl analogue through direct al-
synthesis of a small library of novel chiral S,N-hetero- kylation using ethyl 2-bromo-2-methylpropanoate
bidentate thiourea-oxazoline ligands (Figure 1) and gave unsatisfactory results. Hydrolysis,[10,4h] amide cou-
Scheme 2. General route for the synthesis of thiourea-oxazoline ligands.
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A Thiourea-Oxazoline Library with Axial Chirality: Ligand Synthesis
Table 1. Ligands varying left N-substitution and their catalytic activities.
pling, followed by oxazoline ring closure using the facial selectivity (ligand L2–L6). For ortho-substituted
Burgess reagent[11,4h] proceeded smoothly to give li- phenyl rings, two separable atropoisomers exist as a
À
gands L.
result of restricted C N bond rotation. The effect of
The ligands containing varying “left side” aromatic the two independent stereocenters was examined.
(or, in one case, cyclohexyl) N-substitution and the Bulky ortho-substituents were among the best in
catalytic results derived therefrom are summarized in terms of enantioselectivity. Using an ortho-9-anthra-
Table 1. Using 1.5 mol% [PdACHTNUGRTNEUNG
(h3-C3H5)Cl]2 as the Pd cenyl substituted ligand S-L9-up, 97% yield and 76%
source, ligand L, and CuCl (20 mol%), most reactions ee were obtained. Noticeably, this ligand was proven
proceeded smoothly at room temperature, under at- to be more robust than the previous S-L1-up ligand,
mospheric pressure of oxygen and CO (1/4 ratio), al- which required freshly purified CuCl. Various com-
though they normally took 2 days to reach comple- mercial samples of CuCl gave very consistent results,
tion. It was evident that N-aryl substitution was re- together with S-L9-up. It is especially interesting that
quired to maintain catalytic reactivity and enantiose- the seemingly more remote atropic chirality overruled
lectivity. Thus, the cyclohexyl substituted ligand S-L5 that of the oxazoline moiety in a mis-matched case,
gave sluggish, and non-selective reactions, resulting in generating enantioselectivities merely 18% and 6%
only 15% isolated yield, with 18% ee. The stereogenic lower for S-L1-down and S-L9-down, respectively.
center of the oxazoline generated approximately 50% The absolute configuration of the newly generated
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Scheme 3. Synthesis of unsubstituted oxazoline ligands.
stereocenter in the product was the opposite to those Table 2. Impact of chiral centers on the oxazoline moiety.
generated using S-L1-up and S-L9-up.
The chiral center on the oxazoline moiety was also
modified in an attempt to find a synergetic/additive
effect in a matched scenario. The simple unsubstituted
oxazoline ligand was prepared using the route shown
in Scheme 3, following separation of the atropoisomers.
Other analogues bearing various chiral centers on the
oxazoline were also synthesized. Cleavage of the oxa-
zoline ring under acid conditions resulted in the forma-
tion of the gem-dimethyl amino acid.[12] Standard pep-
tide coupling using HOBt/EDC with ethanolamine af-
forded the hydroxylamide. Treatment with the Burgess
reagent led to the final thiourea-oxazoline ligand.
Generally, the size of the R group on the oxazoline
moiety did not have a significant effect on the enan-
tioselectivity of the bis(methoxycarbonylation). This
is consistent with the atropic chirality being the main
element dictating asymmetric induction. Nevertheless,
bulky i-Pr and t-Bu ligands consistently led to superi-
or yields and ees (Table 2).
The bidentate nature of these thiourea-oxazoline li-
gands necessitates a quick survey of the bite angle be-
tween thiourea and oxazoline lone pairs. One way to
modify this angle is to remove methyl groups from
the side chain. L10 was obtained as two diastereoiso-
mers, assigned as S-L10-R and S-L10-S. Theoretically,
there are four stereoisomers for S-L11 (S-L11-R-up,
Unfortunately, the mono-methylated ligands per-
S-L11-S-up, S-L11-R-down and S-L11-S-down, respec- formed worse than the gem-dimethyl scaffolds, and
tively), however, only two (S-L11-R-up and S-L11-S- the reactions were very slow. In fact, the bis(methoxy-
down) were separated by silica gel chromatography. carbonylation) did not occur using the standard 1:2
The other two decomposed readily during work-up Pd/L ratio. A Pd/L ratio of 1:1 generated partial con-
and purification, probably due to the presence of an version and poor enantioselectivity. This suggested
imine a-proton that leads to decomposition or epime- that mono-methylated oxazolines were poor chelating
rization.
ligands for palladium and that a significant portion of
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A Thiourea-Oxazoline Library with Axial Chirality: Ligand Synthesis
Table 3. Bis(methoxycarbonylation) using mono-methylated
ligands.
steps beyond 9) was prepared according to Scheme 4.
S-L9 was obtained as a 1:1 mixture of atropic isomers,
which was resolved via silica gel column chromatogra-
phy to give S-L9-up and S-L9-down. S-L9-up turned
out to be the matched combination of the atropic
chirality and the stereogenic center on the oxazoline.
In CH2Cl2 at room temperature, it forms very cleanly
a monomeric complex with PdCl2, which was charac-
terized by X-ray diffraction.
Various alcohols and mixed solvents were screened
and the results are listed in Table 4. Bulkier alcohols
resulted in slow (Table 4, entry 2) or even no (en-
tries 3 and 4) reaction. No product was detected when
diethylamine was used as the nucleophile (Table 4,
entry 5). MeOH proved to be the most reactive nucle-
ophile, and the effect of co-solvents was also exam-
ined. Although addition of chloroform improved
enantioselectivity slightly, the reaction rate dropped
significantly.
[a]
Isolated yield after silica gel chromatography. Number in
parathesis is ee, determined by chiral HPLC (Daicel
Chiralcel OD-H).
Presumably, the function of CuCl was to regenerate
Pd(II) through oxidation, similar to that of CuCl2 in
the traditional Wacker oxidation.[13] The use of molec-
ular oxygen avoided the need for a stoichiometric
the bis(methoxycarbonylation) may proceeded via a amount of CuCl, thanks to its facile oxidation of
ligand-free Pd(II) species (Table 3).
Cu(I) to Cu(II). However, to our surprise, CuCl2 itself
did not promote bis(methoxycarbonylation) in our
system. Furthermore, a stoichiometric amount of
Pd(II), as both in situ generated or pre-formed thiour-
ea-oxazoline complexes, failed to promote bis(me-
Reaction Condition Studies using S-L9-up
The quick ligand library survey helped us to locate thoxycarbonylation) in the absence of CuCl and
the most promising ligand, S-L9-up. The correspond- oxygen (Scheme 5).
ing synthetic starting material N-1-(2-(anthracen-9-
This is very strong evidence that copper did not
yl)phenyl)benzene-1,2-diamine 9 (see Scheme 2 for simply act as an oxidant. It is our hypothesis that
Scheme 4. Synthesis of thiourea-oxazoline ligand S-L9.
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Table 4. Pd-catalyzed carbonylation in different solvents.
[a]
Isolated yield after silica gel chromatography. Number in parathesis is ee, determined by
chiral HPLC (Daicel Chiralcel OD-H).[a] Isolated yield after silica gel chromatography.
Determined by HPLC analysis (Daicel Chiralcel OD-H).
Incomplete conversion after 2 d.
[b]
[c]
[d]
[e]
Conversion determined by GC-MS with biphenyl as external reference after 2 d.
Incomplete conversion after 64 h.
Table 5. Effect of various “oxidants.”
Scheme 5. Bis(methoxycarbonylation) reaction with a stoi-
chiometric amount of Pd(II).
CuCl participates in carbon-metal bond forming and
breaking processes during the catalytic cycle. To un-
derstand better the role of copper, various “oxidants”
were examined in lieu of CuCl. The results are listed
in Table 5. None of the metal and organic oxidants we
examined catalyzed the bis(methoxycarbonylation) of
styrene, except for Cu(I) salts.
Although chloride counter ion was not required, we
did observe a mild “Cl” effect (Table 6). CuACTHNUTRGENUG(N OTf) was
as effective for bis(methoxycarbonylation) under stan-
dard conditions. It was later found that palladium cat-
alysts bearing Cl were required in order to perform
[a]
[b]
Isolated yield after silica gel chromatography.
Determined by chiral HPLC (Daicel Chiralcel OD-H).
efficiently. No reaction was observed using Pd
On the other hand, the reaction employing CuCl/
Pd(OAc)2 in combination proceeded smoothly. Addi- the reaction. The reaction rate correlated strongly
tion of various inert chloride sources did not improve with the amount of CuCl used. The reactions acceler-
ACHTUNGERTN(NUNG OAc)2.
ACHTUNGTRENNUNG
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A Thiourea-Oxazoline Library with Axial Chirality: Ligand Synthesis
Table 6. Effect of chloride ion.
Table 7. Pd-catalyzed carbonylation using different palladi-
um precursors with or without ligand S-L9-up.
[a]
Isolated yield after silica gel chromatography.
[b]
Determined by chiral HPLC (Daicel Chiralcel OD-H).[a]
Isolated yield after silica gel chromatography.
Determined by HPLC analysis (Daicel Chiralcel OD-H).
[b]
ated significantly with 20 mol% or more of CuCl. The
reaction using CuCl alone, in the absence of any pal-
ladium catalyst did not proceed.
[a]
A: S-L9-up was added. B: Blank reaction without ligand.
Determined by GC-MS using biphenyl as external refer-
ence.
Determined by HPLC analysis (Phenomenex Lux 5u
Cellulose-2).
Bis(methoxycarbonylation) is normally a Pd(II)-
catalyzed reaction. The electronic nature of palladium
should play a very important role in catalyst reactivi-
ty. We discovered at quite an early stage that the
[b]
[c]
background reaction, using [Pd
any ligand, proceeded almost as fast as the “cata-
(h3-C3H5)Cl]2 without
ACHTUNGTRENNUNG
lyzed” version (Table 7, entries 1A and 1B). This the reaction rate dropped significantly when the ratio
made it very difficult to develop a highly enantiose- of (Pd+Cu)/L was less than 1/1 (Table 8, entries 1–4).
lective reaction. In order to find a distinct rate gap The reaction did not proceed when the ratio of (Pd+
between the background and ligand-assisted path- Cu)/L was 1/2 or less (Table 8, entry 4). On the other
ways, various Pd species were examined and reaction hand, with a large excess of copper, the ligand/Pd
progress was closely monitored.
ratio alone did not affect the reaction to any extent
Bis(methoxycarbonylation) did not occur under Pd- (Table 8, entries 5–8). This is a strong indication that
free conditions, indicating that both palladium and thiourea-oxazolines are actually a poison to copper.
copper are required. Cationic Pd(II) generally gave a Presumably, by complexing with copper, the ligand ef-
faster reaction, compared with [PdACTHNUTRGNEUNG
(h3-C3H5)Cl]2, ac- fectively shuts down the activity of copper. Unfortu-
companied by suppressed background ligand-free nately, attempts to isolate a copper-ligand complex
competition. In particular, reactions using 3 mol% have as yet been unsuccessful. Further studies are cur-
PdCl
sion within 8 h, and thus this was chosen as the stan-
dard palladium catalyst precursor for the following anol. A small amount of water did not affect the bis-
studies. We note that Pd(0), in the form of Pd2A(dba)3 (methoxycarbonylation) to a great extent. When the
(Table 7, entry 4A), was also an effective catalyst pre- water concentration was increased to 10 equivalents
cursor in the presence of ligand S-L9-up. with respect to substrates, the reaction became slower
(CH3CN)2 were able to reach complete conver- rently under way.
The standard reaction conditions employ dry meth-
C
ACHTUNGTRENNUNG
An interesting observation was made when the (Table 9). Any amount of water beyond 10 equiva-
ligand/catalyst ratio was altered. As shown in Table 8, lents significantly inhibited the bis(methoxycarbonyla-
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Table 8. Efferct of the metal ligand ratio.
Table 10. Reaction at lower temperatures.
[a]
[b]
Determined by GC-MS.
Determined by HPLC analysis (Phenomenex Lux 5u
Cellulose-2).
N-containing bases TMEDA and pyridine were
tested, and they shut down the bis(methoxycarbonyla-
tion) almost completely, possibly due to strong coor-
dination to palladium. Addition of Brønsted acids did
not lead to noticeable improvement either. After we
improved the reaction rate from ca. 48 h to within
8 h, a logical solution to the moderate enantioselectiv-
ity would be carrying out the reactions at low temper-
atures. To our surprise, 208C below room temperature
led to an extremely slow reaction, not consistent with
the kinetics law expected (Table 10). Several factors
could potentially contribute to this loss of reactivity
at low temperature, such as poor solubility of metal
complexes, inefficient absorption of CO by copper,
etc.
[a]
Determined by HPLC analysis (Daicel Chiralcel OD-H).
[b]
[PdACHTUNGTRENNUNG
(h3-C3H5)Cl]2 was used.
[c]
[d]
PdCl2ACHTUNGTRENNUNG(CH3CN)2 was used.
Reaction time over 4 days. Isolated yield after silic gel
chromatography.
Less than 10% yield.
Reaction time is 16 h. Conversion determined by GC-
MS.
[e]
[f]
Table 9. Effect of water.
Fortunately, addition of another metal salt, espe-
cially silver salts, with moderate redox potential
helped to resurrect the bis(methoxycarbonylation) at
08C (Table 11). It is not clear what the role of the
silver salt is. Control experiments under chloride-free
conditions yielded trace amounts of product. This sug-
gested that silver did not simply act as a chloride
scavenger, as it often does in other reactions[15]. After
screening a variety of metal salts, we found that silver
triflate was able to promote bis(methoxy-carbonyla-
tion) at 08C with good conversion and over 80% ee.
Various substituted styrenes were examined using
S-L9-up under the optimized protocol (Table 12). For
most of the substituted styrenes, yields were good to
excellent. The substrates bearing electron-donating
groups on the phenyl rings resulted in faster reactions
[a]
Conversion determined by GC-MS.
Determined by HPLC analysis (Daicel Chiralcel OD-H).
[b]
tion). These results confirmed that commercial grade and generally higher ee values than those containing
methanol can be used without distillation. electron-withdrawing groups. It was noticed that elec-
We have shown that CuCl plays an additional role tron-deficient styrenes were particularly sensitive to
beyond simply that of an oxidant for these reactions. polymerization under the reaction conditions. The re-
It has been reported that CuCl can absorb CO in or- actions were generally much slower. S-L9-up failed to
ganic solvents.[14] It may also act as a CO shuttle to fa- induce appreciable level of enantioselectivities using
cilitate CO transfer to palladium, and ultimately to non-styrene type alkene substrates.
substrates. N,N,N’,N’-Tetramethylethylenediamine is
S-L9-up forms clean monomeric complex with
known to stabilize copper-carbonyl complexes. The PdCl2 in methylene chloride (see Figure 2 for crystal
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A Thiourea-Oxazoline Library with Axial Chirality: Ligand Synthesis
Table 11. Effect of metal salts on reaction at 08C.
[a]
Determined by GC-MS with biphenyl as external reference.
Determined by HPLC analysis (Phenomenex Lux 5u Cellulose-2).
The ee was not determined.
[b]
[c]
[d]
(1R,2R)-(À)-1,2-Cyclohexanediamino-N,N’-bis(3,5-di-tert-butylsalicylidene)co-
AHCTUNGTRENNbGUN alt(II).
structure). The Pd complex adopts a square planar ge- ture-reactivity relationships (SRR) led to a more
ometry with a severely biased steric environment. The robust and more selective ligand, namely S-L9-up.
bulky anthracene substituent overwhelmingly blocks a Chemically labile styrenes were bis(methoxycarbony-
significant portion of the space above the palladium lated) under very mild conditions in high yields and
square planar. At the same time, one of the gem- respectable enantioselectivities. The delicate catalytic
methyl groups is pointing inwards to the palladium system required an additional metal salt, AgOTf, to
center. This combination may block the left pathway work properly at low temperatures. Further studies
in Figure 3. The bottom half of the left aniline aro- on more reactive and selective ligands, and to obtain
matic ring and i-Pr group on the oxazoline, effectively a deeper mechanistic understanding of the bis(me-
shield the lower part of the palladium square plane. thoxycarbonylation) catalytic cycle, are currently
Since the oxazoline ring is noticeably bent downward under way and will be reported in due course.
in the X-ray structure of the palladium-thiourea com-
plex, we speculate that this only leaves an open chan-
nel between the axial gem-methyl and i-Pr group on
the oxazoline to accommodate the steric demands of
Experimental Section
the phenyl moiety of the incoming styrene (Figure 3,
pathway on the right).
This hypothesis predicts an S absolute stereochem-
istry, which is consistent with the experimental obser-
vations.[16] However, we note that the mechanism of
the carboxylation process including the role of copper
and other additives is not yet well understood, and it
General Remarks
All reactions were carried out under a nitrogen atmosphere
with dry solvents under anhydrous conditions, unless other-
wise noted. Unless otherwise indicated, chemicals were pur-
chased commercially, and used without further purification.
Anhydrous THF was distilled from sodium-benzophenone,
and dichloromethane was distilled from calcium hydride.
is clear that more detailed mechanistic studies are Reactions were monitored by thin-layer chromatography
(TLC) carried out on 0.25 mm Tsingdao silica gel plates
(60F-254) using UV light as visualizing agent and an etha-
nolic solution of phosphomolybdic acid and cerium sulfate,
and heat as developing agents. Tsingdao silica gel (60, parti-
cle size 0.040–0.063 mm) was used for flash column chroma-
tography. NMR spectra were recorded on Brꢂker Advance
300 (1H: 300 MHz, 13C: 75.5 MHz), Brꢂker Advance 500
(1H: 500 MHz, 13C: 125 MHz), Varian Inova 300 (1H:
300 MHz, 13C: 75.5 MHz), Varian Inova 500 (1H: 500 MHz,
13C: 125 MHz), or Varian Inova 700 (1H: 700 MHz, 13C:
needed to understand fully the rather complex facial
differentiation process.
Conclusions
Systematic studies revealed several interesting fea-
tures of the palladium thiourea-oxazoline-catalyzed
asymmetric bis(methoxycarbonylation) of styrenes.
Structure-selectivity relationships (SSR) and struc- 175 MHz) spectrometers and calibrated using residual un-
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Table 12. Ligand S-L9-up-based Pd-catalyzed bis(methoxycarbonylation) of terminal alkenes.
[a]
[b]
[c]
Isolated yield after silic gel chromatography.
Determined by HPLC analysis (Phenomenex Lux 5u Cellulose-2).
The reaction was run at room temperature.
deuterated solvent as an internal reference. Assignments of
the NMR spectroscopic data were based on a series of 2D
NMR studies. Mass spectrometric data were obtained using
ABI QSTAR Elite mass spectrometer using ESI (electro-
spray ionization), ZAB-HS (EI, 70 eV) spectrometer or
Thermo LTQFT mass spectrometer (for ESI/HR-MS-ESI).
Melting points were obtained using a Sanyo Gallenkamp ap-
paratus, and are uncorrected. The enantiomeric excesses of
the products were determined by HPLC analysis on an Agi-
lent 1100 HPLC or Agilent 1200 HPLC using a Diacel Chir-
alcel OD-H (Daicel, 4.6ꢃ250 mm) or OJ-H (Daicel, 4.6ꢃ
250 mm) column or Phenomenex Lux 5u Cellulose-2
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A Thiourea-Oxazoline Library with Axial Chirality: Ligand Synthesis
General Procedure for the Pd-Catalyzed Asymmetric
Bis(methoxycarbonylation)s of Terminal Olefins
(Table 12)
A mixture of PdCl2ACTHNUGTRNEUNG(CH3CN)2 (13 mg, 0.050 mmol), ligand S-
L9-up (42 mg, 0.075 mmol), CuCl (30 mg, 0.30 mmol) and
8 mL MeOH was stirred at room temperature under a bal-
loon pressure of CO and O2 (ca 4:1) until a clear solution
was formed. Then, AgOTf (77 mg, 0.30 mmol) was added at
08C, followed by substrate (1.0 mmol). The reaction mixture
was stirred at 08C (Table 12, entries 1–5, 6, 7, 9, 10) or at
room temperature (Table 12, entries 8, 11) for the indicated
time. The solvent was evaporated and the residue was puri-
fied by flash chromatography (silica gel, hexanes/EtOAc=
10/1) to give the product (see the Supporting Information
for the syntheses of products 13b–22b).
Compound 12b: Product 12b was obtained in 85% yield
1
with 84% ee; H NMR (300 MHz, CDCl3): d=7.25–7.34 (m,
5H), 4.08–4.13 (m, 1H), 3.68 (s, 3H), 3.64 (s, 3H), 3.17–3.26
(m, 1H), 2.64–2.71 (m, 1H); 13C NMR (75 MHz, CDCl3):
d=173.3, 171.9, 137.6, 128.8, 127.6, 127.6, 52.3, 51.8, 46.9,
37.5; HR-MS (EI): m/z=222.0894, calcd for C12H14O4 [M+]:
222.0892; HPLC (Phenomenex Lux 5u Cellulose-2, hexane/
i-PrOH=80/20, 0.6 mLminÀ1, 230 nm, 308C): tr (major)=
10.0 min, tr (minor)=12.1 min.
Figure 2. X-ray molecular structure of PdCl2/S-L9-up (ther-
mal ellipsoids at 50% probability). The Pd atom has a dis-
torted square-planar coordination. Selected bond distances:
À
À
À
Pd Cl(1) 2.3090(6), Pd Cl(2) 2.3039(6), Pd S 2.2833(6) and
Acknowledgements
À
Pd N(13) 2.007(7) ꢄ. Dihedral angles between planes: ben-
zothiourea (T)/benzene (B) 728, B/anthracenyl 738, T/Pd-co-
ordination plane (M) 408, M/oxazoline 548. The asymmetric
unit also contains 4 molecules of CDCl3. Crystallographic
data (excluding structure factors) for PdCl2/S-L9-up·4CDCl3
have been deposited with the Cambridge Crystallographic
Data Centre as CCDC 766369. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif or on appli-
cation to the CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK [fax: (+44)-1223-336-033; E-mail: deposit@ccdc.cam.
ac.uk].
This work was supported by grants of the National Science
and Technology Major Project “Development of key technol-
ogies for the combinatorial synthesis of privileged scaffolds”
(2009ZX09501-012), the National Science Foundation of
China (20325208 and 20521202) and Nanshan Science &
Technology (NANKEPING2007005). T.B.M. and Z.Y. thank
the Royal Society for an International Joint Project Grant.
T.B.M. thanks the EPSRC (UK) for an Overseas Research
Travel Grant and the Royal Society of Chemistry for a Jour-
nals Grant for International Authors. K.W. and D.C. thank
the Royal Thai Government for postgraduate scholarships.
column (4.6ꢃ250 mm) and UV/CD detectors. The following
abbreviations were used to explain the multiplicities: s=sin-
glet, d=doublet, t=triplet, q=quartet, m=multiplet, brs=
broad singlet.
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Adv. Synth. Catal. 2010, 352, 1955 – 1966