Non-covalent immobilization of rare earth heterobimetallic frameworks and their reactivity in an asymmetric Michael addition

Article abstract of DOI:10.1002/adsc.201400087

Heterobimetallic Lewis acid catalysts are broadly useful and methods to recycle them have immediate applications. However, their immobilization through covalent binding can be challenging. Non-covalent immobilization of supported asymmetric catalysts is attractive due to ease of preparation and potential for reversible binding. We report a novel non-covalent binding strategy for Shibasaki's REMB framework {RE=rare earth metal; M=Li, Na, K; B=BINOL; RE:M:B=1:3:3, [M₃(sol)_n][(BINOLate)₃RE]} and explore the reactivity of the supported catalyst.

Full text of DOI:10.1002/adsc.201400087

FULL PAPERS
DOI: 10.1002/adsc.201400087
Non-Covalent Immobilization of Rare Earth Heterobimetallic
Frameworks and their Reactivity in an Asymmetric Michael
Addition
a
b
b
a
Jerome R. Robinson, Jagjit Yadav, Xinyuan Fan, Gretchen R. Stanton,
a,
b,c,
a,
Eric J. Schelter, * Miquel A. Pericꢀs, * and Patrick J. Walsh *
P. Roy and Diana T. Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104,
USA
a
E-mail: schelter@sas.upenn.edu or pwalsh@sas.upenn.edu
Institute of Chemical Research of Catalonia (ICIQ), Av. Paꢁsos Catalans 16, 43007 Tarragona, Spain
Fax : (+34)-9-7792-0222; e-mail: mapericas@iciq.es
b
c
Departament de Quꢂmica Orgꢀnica, Universitat de Barcelona (UB), 08028 Barcelona, Spain
Received: January 23, 2014; Published online: April 2, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400087.
Abstract: Heterobimetallic Lewis acid catalysts are framework {RE=rare earth metal; M=Li, Na, K;
broadly useful and methods to recycle them have im- B=BINOL;
RE:M:B=1:3:3,
[M ACHTUNGTRENNUG( sol) ]-
3 n
mediate applications. However, their immobilization [(BINOLate) RE]} and explore the reactivity of the
AHCTUNGTRENNUNG
3
through covalent binding can be challenging. Non- supported catalyst.
covalent immobilization of supported asymmetric
catalysts is attractive due to ease of preparation and Keywords: asymmetric catalysis; heterobimetallic
potential for reversible binding. We report a novel complexes; Michael addition; rare earths; supported
non-covalent binding strategy for Shibasakiꢃs REMB catalysts
Introduction
tallic and multifunctional RE catalysts often display
superior activity due to cooperativity between proxi-
[
6c,8]
Asymmetric catalysis is an attractive and green mate functionalities.
However, the immobilization
method for obtaining enantiomerically enriched or- of RE catalysts is also challenging. For example, Shi-
[
1]
ganic compounds. However, widespread application, basakiꢃs REMB frameworks {RE=rare earth metal;
including industrial use, has been limited due to the M=Li, Na, K; B=BINOLate; RE:M:B=1:3:3,
high costs of transition metal-based enantioenriched [M ACHTUNGTRENNNUG( sol) ] ACHTUNRTGNEG[NU (BINOLate) RE]} are highly enantioselec-
3 n 3
catalysts and the difficulty of separation of the final tive catalysts for the formation of CÀC and CÀE (E=
products from trace metals. Immobilization of ho- N, O, P, S) bonds, yet there has been only
[
2]
[6a,c,8a,9]
mogeneous catalysts addresses some of these issues; a single report of a supported system. Bhatt and co-
the catalyst can be easily recycled through physical workers immobilized LaLB through the formation of
separation, which increases ultimate turnover num- a covalent bond between the axially chiral ligand,
[
7i]
bers (TONs), while reducing the cost and E-factor of BINOL, and the heterogeneous support, MCM-41.
[2,3]
the process. Progress has been made in immobiliz- Their synthesis of the supported catalyst required
ing catalysts through formation of covalent bonds be- nine steps and an overall yield was not disclosed.
[
2a,4]
tween enantioenriched ligands and solid sup
In contrast, immobilization through ensembles of immobilize heterobimetallic catalysts such as REMB.
non-covalent interactions has received less attention, Previous binding studies by one of us have demon-
despite their ease of preparation and potential for re- strated N,N’-dimethylethylenediamine (DMEDA)
A
H
U
G
E
N
N
ports.
There is a clear need for new strategies to effectively
[
2b,5]
+
versible binding toward catalyst recovery.
binds tightly to Li cations in the REMB framework,
The rare earth metals (REs; La–Lu, Sc, Y) com- even in the presence of a neat coordinating solvent
[
10]
prise successful catalysts for a number of diverse such as THF. Notably, it was shown that the pres-
[
6]
asymmetric transformations, where catalyst recy- ence of diamine does not affect the catalytic per-
[
7]
cling has been possible in some cases. Heterobime- formance of LaLB in Diels–Alder, Henry, or hydro-
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MRs are attractive candidates as supports due to the
ease in their chemical modification, low cost, and
[
12]
availability.
A series of functionalized MRs (MR-
X) was conveniently prepared by the two complemen-
tary pathways in Scheme 1.
One synthetic strategy involved the straightforward
1
S 2 substitution (Scheme 1A, L ) of commercially
N
À1
available MR-Cl (1% DVB, f=0.530 mmolg ) and
amine nucleophiles. Progress of reactions was moni-
tored using Raman spectroscopy following the disap-
À1
pearance of the resin CÀCl stretch (679 cm ). Func-
À1
tionalization values, f (mmolg ), ranged from 0.345
Figure 1. Possible methods for supporting REMB catalysts
to 0.488 (68–100% yield; see Supporting Information
for further details), and were determined based on ni-
trogen content obtained from combustion analysis of
phosphonylation reactions. In light of these observa- MR-Xa (X=1, 2, 4, and 6). Commercially available
tions, we envisioned a strategy for immobilizing MR, amine nucleophile, and base (2 equiv.; NEt , or
3
REMB catalysts through functionalized achiral solid K CO ) were combined in toluene or CH CN and re-
2
3
3
+
supports as ligands to remotely bind M cations fluxed for 24–72 h to furnish MR-Xa (X=1, 2, and 6).
(
Figure 1). This strategy would represent a non-cova- For the synthesis of the linear triamine MR-4a, the
lent approach, and would enable the expedient syn- SN2 substitution reaction was performed with nucleo-
theses of supported catalysts from achiral materials philic resin MR-6a and electrophilic monomer (2-
with minimal perturbation of the chiral environment. bromoethyl) ACHTUGNTERNN(UNG methyl)carbamate in CH CN. Subse-
3
Herein, we report the synthesis and characterization quent deprotection of the BOC group provided MR-
À1
of a novel family of diverse functionalized Merrifield 4a (f=0.345 mmolg ) in 68% yield overall starting
resins (MRs), demonstrate their ability to reversibly from MR-Cl.
bind LaNaB presumably at the sodium cations, and
The second strategy to prepare the functionalized
investigate their reactivity in an asymmetric Michael resins utilized the copper(I)-catalyzed azide–alkyne
[
13]
addition between cyclohexenone and dibenzyl malo- cycloaddition (CuAAC) reaction,
between readily
nate.
synthesized alkyne functionalized monomers and
[
14]
azide-substituted MR, MR-N ,
to form MR-Xb
3
2
(
Scheme 1B, L ). This approach has been used by
[
14,15]
[16]
Results and Discussion
some of us
and others
with a broad range of
supported catalysts, including an example of an RE-
[
7d]
Synthesis and Characterization of Functionalized
Merrifield Resins
pybox catalyst.
In the CuAAC the reaction prog-
ress was monitored using IR spectroscopy following
À1
the disappearance of the azide stretch (2100 cm ).
Insoluble organic polymers are used broadly in the Support functionalization values were determined in
immobilization of chiral metal catalysts because they an analogous manner as for MR-Xa, and ranged from
À1
have advantages as solid supports including flexibility 0.289–0.471 mmolg .
[1b,11]
and ductility.
Among the insoluble polymers,
Scheme 1. General strategy for functionalized Merrifield resin (MR) synthesis. (A) S 2 pathway between commercially avail-
N
1
2
able MR and amine nucleophile (L ). (B) CuAAC pathway between alkyne functionalized monomers (L ) and azide-substi-
tuted MR (MR-N ).
3
2
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Non-Covalent Immobilization of Rare Earth Heterobimetallic Frameworks
Scheme 2. Synthesis of triazole-linked cyclen-terminated resin, MR-3b.
À1
Reaction of propargyl bromide with 1-aza-15- MR-5b (f=0.471 mmolg ) was obtained in 81%
crown-5 provided the alkyne-functionalized monomer overall yield.
2
a
0
a in 86% yield. Compound 2a smoothly underwent
A variety of functionalized MRs was accessible in
CuAAC reaction to furnish MR-2b (f= a few steps from commercially available starting ma-
À1
.380 mmolg ) in 86% yield and 72% overall yield terials, highlighting the synthetic utility of the two
starting from MR-Cl.
complementary synthetic strategies. With a diverse set
The synthesis of cyclic polyamine, MR-3b of well-characterized MR-X in hand we investigated
Scheme 2), required the selective protection of three their ability to bind REMB catalysts.
(
NH groups in cyclen with Boc anhydride to furnish
[
17]
intermediate 3a in 68% yield.
SN2 reaction of 3a
with propargyl bromide produced alkyne-functional- Catalyst Immobilization Studies and Reversible
ized 3b in 82% yield (see the Supporting Informa- Binding Properties
tion). Compound 3b was subjected to CuAAC condi-
tions to provide intermediate 3c, which was immedi- Initial immobilization studies were performed using
ately deprotected with TFA to furnish MR-3b (f= tetrahydrofuran (THF) as a solvent with [M3
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(sol) ]-
n
À1
0.288 mmolg ) in 34% overall yield over 5 steps
A
H
U
G
R
N
N
[(BINOLate) RE] (REMB; RE=La and Eu; M=Li,
3
starting from MR-Cl.
Na, and K). Stirring solutions of REMB with the
The synthesis of secondary diamine containing MR-X (X=1–7) supports in THF resulted in quanti-
resin, MR-5b, was achieved in 5 synthetic steps as tative recovery of the free catalysts from the filtrate,
1
outlined in Scheme 3. Protection of commercially as determined by H NMR integration against mesity-
available sarcosine (N-methylglycine) with Boc anhy- lene as an internal standard. We hypothesized that
[
18]
[19]
dride produced 5a in 91% yield. Amide coupling
the neat coordinating solvent, THF, outcompeted
+
of 5a with propargylamine formed 5b in 94% yield. MR-X for binding at the M sites. This result was not
Alkyne-functionalized 5b was anchored through anticipated based on our earlier studies, wherein
CuAAC to provide resin 5c. Following Boc deprotec- DMEDA preferentially bound the M cations even in
tion of 5c with TFA and performing a subsequent neat THF.
amide reduction of 5d with BH ·THF, the product may be due to the increased steric hindrance upon
+
[
10]
We rationalized that the weak binding
[20]
3
Scheme 3. Synthesis of triazole-linked secondary diamine-terminated polystyrene resin, MR-5b.
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Table 1. Functionalized Merrifield resins (MR-X) including
functionalization values and wash efficiencies.
Scheme 4. Reversible immobilization and release of LaNaB
through choice of solvent.
+
tethering the M binding site to the solid support,
rather than limited exposure of the dative ligand sites
to react with the REMB catalysts. It should be men-
tioned that THF displays excellent swelling properties
[
21]
for Merrifield resins.
To favor catalyst binding at the support, we em-
ployed CH Cl also as a solvent. As a non-coordinat-
2
2
[
[
a]
b]
ing solvent a competitive binding scenario would be
eliminated; CH Cl exhibits similar swelling proper-
Determined by CHN and ICP-AES analysis of MR-X-
(LaNaB).
Determined by ICP-AES analysis of THF washed MR-
(LaNaB) after drying under reduced pressure.
2
2
AHCTUNGTRENNUNG
ties to THF, ensuring maximum exposure of the
ligand sites (Scheme 4). Upon stirring the support and
REMB complexes together for 1 day, complete immo-
bilization was observed for all MR-X, furnishing the
XACHTUNGTRENNUNG
polymer supported catalysts, MR-X ACHUTNRGNENUG( REMB). As quired incorporation of a pyridyl group, controls con-
LaNaB catalysts are more effective asymmetric cata- taining non-coordinating phenyl groups in place of
lysts than RELB catalysts in non-coordinating sol- pyridyl provided similar levels of initial immobiliza-
[
9b,d,22]
vents,
MR-X
Characterization of the immobilized catalysts, MR- resin was a major contributor to immobilizing the dir-
(LaNaB), was accomplished using FT-IR, combus- hodium catalyst and that pyridine coordination was
tion analysis (% CHN), and ICP-AES (% La) tech- not a necessary prerequisite.
we focused on characterization of the tion and reactivity. Their observations suggested that
ACHTUNGTRENNUNG( LaNaB) system. the environment provided by the substituted Wang
XACHTUNGTRENNUNG
niques after thorough washing of the impregnated
To differentiate and validate our proposed binding
resin with CH Cl and drying under reduced pressure. scheme, we performed the control reaction between
2
2
FT-IR of MR-X ACHUTNGRNENGU( LaNaB) revealed characteristic the chloro-functionalized MR starting material and
peaks for both MR-X and LaNaB, supporting that the LaNaB. After 48 h of stirring in DCM the resin was
resin and catalyst do not experience gross structural isolated following identical conditions used for MR-
changes upon binding (Supporting Information, Fig-
X AHCTUNGTERNNUN(G LaNaB); the FT-IR of the isolated resin remained
ures S24–S31). High functionalization values (f; unchanged from MR-Cl (Figure S32, Supporting In-
À1
mmolg , Table 1) ranging from 0.235 to 0.514 were formation), with quantitative recovery of LaNaB in
1
obtained, and were determined independently from the filtrate, as determined by H NMR analysis. Ac-
the techniques described above (Supporting Informa- cordingly, we propose that binding of the heterobime-
tion).
To the best of our knowledge, this is the first exam- exchange events and not supramolecular encapsula-
tallic catalyst to the resin occurs through labile ligand
[
23i]
ple of an RE or heterobimetallic catalyst immobilized tion.
using an achiral support as a ligand. Few systems
To demonstrate the utility and reversible nature of
have been investigated using achiral supports as li- this attachment strategy, the binding and release of
[
23]
gands for enantioselective transition metal catalysts.
A homobimetallic example comes from Davies and
co-workers, where they immobilized several chiral di- (wash efficiency, Table 1), which was verified through
rhodium catalysts employing pyridine functionalized independent characterization of the resin [FT-IR,
LaNaB to MR-X was investigated. Treatment of MR-
X ACHTUNGTR(EUNNNG LaNaB) with THF released LaNaB into solution
ACHTUNGTRENNUNG
[
23h–j]
1
polystyrene-based polymers.
While the highest ICP-AES (%La)] and the filtrate ( H NMR). Methyl-
levels of reactivity and catalyst immobilization re- ene-linked MR-Xa quantitatively released LaNaB
4
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Non-Covalent Immobilization of Rare Earth Heterobimetallic Frameworks
[
21]
upon exposure to THF, however, the triazole-linked catalyst. All the catalysts investigated provided ex-
resins, MR-Xb, only released 50–80% of LaNaB. FT- cellent levels of conversion at room temperature over
IR of washed MR-Xb ACHUTNGRENNUG( LaNaB) contained characteris- 12 h, however, we observed that the identity of the
tic peaks for LaNaB, which confirmed the presence of achiral support and linker had a significant impact on
residual LaNaB (Supporting Information, Figures S26, the enantioselectivity for the reaction. While the
S27, and S29). The physical origin for the increased choice of achiral ligand can be used in homogeneous
[
9h,25]
binding of LaNaB with the triazole-linked resins is catalysis to amplify stereoselectivity,
still unclear, however, our preliminary studies indicat- has seen limited application in supported catalysis.
ed that the choice of linker, rather than increased From the results in Table 2, it can be seen that cata-
ligand denticity, imparted significantly different bind- lysts with linear amine tethers performed more selec-
ing properties. tively than those wirh pyridyl or cyclic tethering li-
this concept
Notably, the binding and release of LaNaB did not gands (entries 5–7 and 11 versus entries 1–4), suggest-
affect catalytic activity. Use of the THF wash of MR- ing that the remote coordination of MR-X influenced
6a ACHTUNGTRENNUNG( LaNaB) as a catalyst (10 mol%) in the asymmetric the chiral environment at the catalytic centers. Higher
Michael addition of cyclohexenone and dibenzyl mal- selectivities were observed at room temperature for
onate matched levels of selectivity observed in the higher denticity linear amines (entry 7 versus 11 and
original report by Shibasaki and co-workers using ho- entry 5 versus 6), however, denticity and donor type
mogeneous LaNaB and furnishing the Michael adduct (N versus O) had a minimal impact on selectivity in
[
9b,24]
in 91% yield and 87% ee.
the cyclic tethering ligands (entries 3 and 4). Under
homogeneous conditions, the presence of macrocyclic
chelating agents, such as crown ethers, have resulted
in essentially racemic product using the REMB cata-
Investigation of Catalytic Reactivity in an
Asymmetric Michael Addition
[
22]
lyst framework. However, moderate levels of selec-
tivity were observed for MR-2 and MR-3 in this study
Encouraged by the facile and reversible binding of (entries 2–4). The choice of linker affected the extent
LaNaB to MR-X, we investigated the catalytic activi- of reversible release of LaNaB from MR-X(LaNaB)
ty of MR-X(LaNaB) in the Michael addition of di- with THF (Table 1), though levels of enantioselectivi-
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
benzyl malonate to cyclohexenone (Table 2). Of the ty were comparable between the methylene-linked
non-coordinating solvents investigated (Table S4, Sup- and triazole-linked crown-ether analogues (entries 2
porting Information), CH Cl provided the highest and 3).
2
2
levels of reactivity and selectivity, which we attribute
The size of the central RE has been demonstrated
to the solventꢃs ability to swell the Merrifield resins, to be critical to enantioselectivity across a broad
increasing the exposed surface area of the supported array of asymmetric reaction with the REMB cata-
[
9a,b,g,26]
lysts.
Smaller ionic radii of the central RE
cation resulted in diminished stereoselectivities (en-
tries 7, 9, and 10), which is consistent with the results
Table 2. Catalytic reactivity of MR-X ACHUTNGRNENUG( RENaB) in an asym-
metric Michael addition.
[
9b]
of the homogeneous Michael addition.
Lowering
the temperature to À358C improved enantioselectivi-
ty to 80%, while maintaining high levels of reactivity
(
entry 8). Shibasakiꢃs original report used hydrated
LaNaB in the Michael addition, which provided high
levels of enantioselectivity in coordinating and non-
coordinating solvents. Surprisingly, our use of the an-
hydrous LaNaB catalyst resulted in much lower selec-
tivities (entry 12), and further demonstrates that the
achiral polymer support dramatically affects the chiral
environment of the catalyst.
[a]
Entry Catalyst
Temp. [8C] Yield [%] ee [%]
1
2
3
4
5
6
7
8
9
1
1
1
MR-1a
MR-2a
MR-2b
MR-3b
MR-4a
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(LaNaB) 25
(LaNaB) 25
(LaNaB) 25
(LaNaB) 25
(LaNaB) 25
MR-5b(LaNaB) 25
(LaNaB) 25
(LaNaB) À35
(EuNaB) 25
(YbNaB) 25
(LaNaB) 25
25
89
95
93
96
91
98
98
97
94
90
97
95
33
48
44
47
72
51
66
80
49
28
59
35
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
ACHTUNGTRENNUNG
Initial attempts to recycle the catalyst from MR-6a-
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
A
H
U
G
R
N
N
(LaNaB) in CH Cl at À358C resulted in complete
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
2
2
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
erosion of enantioselectivity after three runs, suggest-
ing that significant catalyst leaching was occurring
during the reaction (see Supporting Information). Fil-
tration of the resin from the reaction mixture immedi-
ately after mixing still resulted in product formation
in the filtrate, albeit in lower conversion (84% after
MR-6a
MR-6a
MR-6a
MR-6a
MR-7a
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
0
1
2
ACHTUNGTRENNUNG
LaNaB
24 h at room temperature) and selectivity (41% ee)
[
a]
Determined by HPLC.
versus 100% conversion and 66% ee in the presence
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of the heterogenized MR-6aACHTNUGRTNEUNG
(LaNaB) catalyst. These spectively. All spectra were measured at 300 K unless other-
wise specified. Chemical shifts were recorded in units of
parts per million downfield from residual proteo solvent
results were consistent with some catalyst leaching to
the homogeneous phase, and provided further evi-
dence that resin-catalyst interaction formed a more
selective catalyst.
To better understand the nature of the resin-cata-
lyst interaction, we investigated the catalytic activity
of LaNaB with the homogeneous analogue of MR-6a,
1
13
1
peaks ( H) or characteristic solvent peaks ( C{ H}). All cou-
pling constants are reported in hertz. The infrared spectra
À1
were obtained from 400–4000 cm using either a Perkin–
Elmer 1600 series infrared spectrometer or a Bruker Optics
FTIR Alpha spectrometer equipped with a DTGS detector.
Elemental analyses (C; H; N) for MR-X ACHUTNGRNEUNG( REMB) and MR-
N-benzylethylenediamine. Addition of 10 mol% of N- X were performed at the University of California, Berkeley
benzylethylenediamine to 10 mol% LaNaB restored Microanalytical Facility using a Perkin–Elmer Series II 2400
the selectivity of the Michael addition from 35% in CHNS analyzer, and at the Universidad Complutense de
Madrid using a LECO CHNS 932 micro-analyzer, respec-
its absence to 63% ee (Table S7, Supporting Informa-
tively. Thin-layer chromatography was carried out on EMD
tion). This result offers further support that MR-X
pre-coated silica gel 60 F254 plates and visualized by ultra-
can act as ligand to LaNaB, and can significantly alter
violet light or by staining with potassium permanganate.
the chiral environment of the catalyst. While improve-
Silica gel (230–400 mesh, EMD) was used for air-flashed
ments in the resinꢃs ability to bind the catalyst are
column chromatography. Analysis of enantiomeric excess
necessary for the practical application of this strategy,
our results offer proof-of-principle that functionalized
was performed by HPLC using a Hewlett–Packard 1100
series with an AS-H column at 210 nm. Rare earth metal
organic polymers can act as ligands for heterobimetal- analysis (%RE) measurements were performed by Gal-
lic catalysts.
braith Laboratories, Inc. using a Perkin–Elmer ICP-OES
Optima 5300.
Tetrahydrofuran, diethyl ether, dichloromethane, hexanes,
and pentane were purchased from Fisher Scientific. The sol-
Conclusions
vents were sparged for 20 min with dry N and dried using
2
a commercial two-column solvent purification system com-
prising columns packed with Q5 reactant and neutral alumi-
na, respectively (for hexanes and pentane), or two columns
of neutral alumina (for THF, Et O and CH Cl ). The follow-
In summary, we have readily synthesized a diverse
family of functionalized Merrifield resins (MR-X)
through either S 2 or CuAAC reactions. In dichloro-
N
2
2
2
methane, MR-X effectively binds the asymmetric het-
ing liquid reagents were purchased from their respective
erobimetallic catalyst, LaNaB, while maintaining cata- companies, degassed using freeze-pump-thaw cycles, and
lystꢃs overall structure. To the best of our knowledge, store for 24 h over 4ꢅ molecular sieves in an N atmosphere
2
these results are the only examples of using dative glovebox prior to use: deuterated pyridine (Cambridge Iso-
tope Laboratories, Inc.), N-benzylethylenediamine (Oak-
achiral ligand-exchange to bind an enantioenriched
ridge Chemicals), cyclohexenone (TCI), and dibenzyl malo-
RE or heterobimetallic catalyst. Preliminary investi-
nate (TCI). The following anhydrous solvents were pur-
gation of catalytic activity in the Michael addition of
chased from Sigma–Aldrich and used without further purifi-
dibenzyl malonate to cyclohexenone indicated that
the identity of the achiral ligand impacted enantiose-
lectivity, while recycling and phase-separation studies
supported significant catalyst leaching. Further studies
cation: cyclopentyl methyl ether (CPME), 1,2-dichloroben-
zene, methyl tert-butyl ether (MTBE), and dichloroethane
[10b,27]
DCE). Synthesis of [M ACTHNGUTRENNUG( THF) ] ACHUTNGTRNENGU[ (BINOLate) RE],
3 n 3
[28]
(
and tert-butyl (2-bromoethyl) ACHTUNGRNENUG( methyl)carbamate (4a)
to improve the binding ability of non-covalently im- were synthesized following literature procedures. All other
mobilized frameworks and application of “catch and chemicals were purchased from commercial suppliers and
release” strategies for supported catalysis are current- used without further purification.
ly underway.
Synthesis of MR-1a
Bis(pyridin-2-ylmethyl)amine
(0.540 mL,
3.00 mmol,
Experimental Section
3
equiv.; FW: 199.26) was added to a 50-mL flask charged
with Merrifield resin (MR, 1.89 g, 1.00 mmol; f=
General
À1
0
.530 mmolg , 100–200 mesh, Novabiochem), anhydrous
À1
When specified, reactions and manipulations were per-
K CO (6 mmol, 0.83 g; FW: 138.21 gmol ), toluene
2
3
formed under an inert atmosphere (N ) using standard
(12 mL), and a Teflon-coated stir bar. The mixture was
heated to reflux, and gently stirred. After disappearance of
2
Schlenk techniques or in a Vacuum Atmospheres, Inc.
Nexus II drybox equipped with a molecular sieves 13X/Q5
Cu-0226S catalyst purifier system. Glassware was oven-dried
À1
the CÀCl bond (679 cm , ~36 h) was observed by Raman
spectroscopy, the mixture was filtered and the solid phase
was washed with water (2ꢆ30 mL), MeOH (2ꢆ20 mL),
THF (2ꢆ20 mL) and CH Cl (2ꢆ20 mL). The off-white
1
overnight at 1508C prior to use. H NMR spectra were ob-
tained on a Bruker DMX-300, Bruker Advance 300, Bruker
AM-500, or Bruker Advance 500 Ultrashield Fourier trans-
form NMR spectrometer at 300 and 500 MHz, respectively.
2
2
resin MR-1a was dried under reduced pressure at 408C for
24 h, then weighing 1.72 g. The functionalization was deter-
mined by elemental analysis based on %N (fmax =
13
1
C{ H} NMR spectra were collected at 75 or 126 MHz, re-
6
asc.wiley-vch.de
ꢄ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

FULL PAPERS
Non-Covalent Immobilization of Rare Earth Heterobimetallic Frameworks
À1
À1
0
7
.488 mmolg ; f=0.488 mmolg , 100% yield; 89.27% C,
72.73 (CCH), 71.13 (CH ), 70.65 (CH ), 70.41 (CH ), 69.73
2 2 2
+
.57% H, 2.10% N).
(CH ), 53.86 (NCH ), 45.11 (CH CCH); HR-MS (ESI ):
2 2 2
m/z= 258.1700, calculated for C H NO : 258.1697; IR
1
3
24
4
(
5
ATR): n=2962, 1608, 1561, 1437, 1257, 1010, 789, 684,
01 cm .
Synthesis of MR-2a
À1
1
2
-Aza-15-crown-5 (0.400 g, 1.82 mmol, 2.3 equiv.; FW=
19.28 gmol ) was added to a 30-mL glass tube charged
À1
Synthesis of MR-2b
À1
with MR (1.50 g, 0.795 mmol, f=0.530 mmolg ), anhydrous
À1
K CO3 (0.520 g, 4.7 mmol, 5 equiv.; FW: 138.21 gmol ),
A 50-mL Schlenk tube was charged with azide-substituted
resin (MR-N , 2.00 g, 1.02 mmol; f=0.510 mmolg ), CuI
(24.2 mg, 0.127 mmol, 0.12 equiv.; FW: 190.45 gmol ), N,N-
diisopropylethylamine (DIPEA, 2.40 mL, 13.8 mmol,
13 equiv.; FW: 129.24 gmol ), and a Teflon-coated stir bar
under an N flow. DMF (12.5 mL) and THF (12.5 mL) were
2
À1
À1
CH CN (10 mL), and a Teflon-coated stir bar. The tube was
3
3
sealed, the content stirred and heated to 608C. After disap-
À1
pearance of the CÀCl band (679 cm , ~72 h) was observed
À1
by Raman spectroscopy, the mixture was filtered and the
solid phase was washed with water (5ꢆ500 mL), MeOH (1ꢆ
2
5
00 mL), THF (1ꢆ200 mL) and CH Cl (1ꢆ200 mL). The
added to the reaction mixture, gently stirred, and heated at
2
2
light-yellow resin MR-2a was dried under reduced pressure
at 408C for 24 h, then weighing 1.34 g. The functionalization
408C for 12 h. After disappearance of the characteristic
azide peak (2100 cm ) the resultant mixture was cooled to
À1
was determined by elemental analysis based on % N (f
=
room temperature, filtered, and the solid was washed with
water (500 mL) and MeOH (500 mL). The following steps
were performed three times: 1) a 100-mL round-bottom
flask was charged with the resin, THF (50 mL), and ethy-
max
À1
À1
0
7
.483 mmolg ; f=0.442 mmolg , 92% yield; 87.19% C,
.77% H, 0.62% N).
AHCTUNGTRENNUNGl enediamine (1 mL), 2) shaken (orbital shaker) at room tem-
perature for 20 min, 3) filtered, and 4) washed with THF
(50 mL) and MeOH (50 mL). Finally the solid was washed
Synthesis of MR-N3
A 1-L round-bottom flask was charged with MR (20.0 g,
À1
10.6 mmol, 1 equiv., f=0.530 mmolg ), and DMF (200 mL).
with water (500 mL), 50% H O:MeOH (500 mL), 50%
2
Sodium azide (6.90 g, 106 mmol, 10 equiv.; FW:
THF:MeOH (500 mL), THF (500 mL), and CH Cl2
2
À1
6
5.00 gmol ) was added to the suspension. The reaction
(500 mL). The light-yellow resin MR-2b was dried under re-
duced pressure at 408C for 24 h, then weighing 1.91 g. The
functionalization was determined by elemental analysis
flask was sealed and shaken (orbital shaker) at 608C over-
À1
night. After disappearance of the CÀCl band (679 cm ,
À1
À1
~
12 h) was observed by Raman spectroscopy, the mixture
was cooled to room temperature and filtered. The resin was
based on % N [fmax =0.442 mmolg ; f=0.380 mmolg ,
86% yield, 72% overall yield (starting from MR); 86.99%
C, 7.52% H, 2.10% N].
washed with water (500 mL), 50% H O:MeOH (500 mL),
MeOH (500 mL), 50% THF:MeOH (500 mL), THF
2
(
500 mL), and CH Cl (500 mL), and dried under reduced
2 2
Synthesis of 3a
pressure at 408C for 48 h, then weighing 19.01 g. The func-
tionalization value was determined by elemental analysis
based on % N (fmax =0.528 mmolg ; f=0.510 mmolg ,
A 1-L round-bottom flask was charged with cyclen (5.50 g,
À1
À1
À1
31.90 mmol; FW: 172.27 gmol ), CHCl (300 mL), and
3
9
2
7% yield; 86.21% C, 6.62% H, 2.14% N); IR
A
H
U
G
R
N
U
(ATR): n=
a Teflon-coated stir bar. Triethylamine (13.3 mL, 95.6 mmol,
5.7 equiv.; FW: 101.19 gmol ) was added to the stirring so-
lution. A 500-mL addition funnel was fitted to the 1-L
À1
À1
096 cm (N stretch). Procedure and characterization data
3
[14b]
are similar to those in the previous report.
round-bottom flask and was charged with di-tert-butyl dicar-
bonate
(20.52 mL,
88.0 mmol,
2.77 equiv.;
FW:
Synthesis of 2a
À1
2
18.25 gmol ) and CHCl (250 mL). The contents of the ad-
3
A 100-mL round-bottom flask was charged with 1-aza-15-
crown-5 (2.00 g, 9.13 mmol; FW: 219.28 gmol ), THF
dition funnel were added dropwise over 1 h. The reaction
was further stirred for 24 h at room temperature until com-
plete as judged by TLC. The reaction mixture was concen-
trated under reduced pressure and purified by column chro-
matography (SiO ,50% ethyl acetate:n-hexane) to obtain 3a
as a white solid; yield: 10.25 g (21.68 mmol, 68%; FW:
À1
(
ACHTUNGTRENNUNG
1
25 mL), toluene (25 mL), and a Teflon-coated stir bar. Tri-
ethylamine (6.36 mL, 45.7 mmol, 5 equiv.; FW:
01.19 gmol ) was added and the stirring mixture was
À1
2
heated at 608C for 15 min. Propargyl bromide (80% in tolu-
ene, 2.95 mL, 27.3 mmol, 3 equiv., FW: 118.96 gmol ) was
À1
À1
1
13
1
472.63 gmol ). H and C{ H}-NMR spectra of 3a match
[17]
added and the mixture was heated at 708C for 12 h. The
mixture was then allowed to cool to room temperature and
the white precipitate was separated by filtration, washed
with THF (2ꢆ30 mL), and the filtrate was evaporated to
dryness. The residue was suspended water and extracted
the previously reported spectra.
Synthesis of 3b
A 250-mL round-bottom flask was purged under an N flow
and charged with 3a (8.15 g, 17.2 mmol; FW: 472.63 gmol ),
2
À1
with CH Cl2 (2ꢆ100 mL). The combined organic layers
2
were dried with MgSO and evaporated to dryness to afford
CH CN (160 mL), anhydrous K CO (4.75 g, 34.4 mmol,
4
3
2
3
À1
the product as a yellow oil which was used without any fur-
ther purification; yield: 2.02 g (7.84 mmol, 86%; FW:
2 equiv.; FW: 138.21 gmol ), and a Teflon-coated stir bar.
Propargyl bromide (80% in toluene, 4.46 mL, 41.4 mmol,
À1
1
À1
2
57.33 gmol ). H NMR (500 MHz, CDCl ): d=3.69–3.64
2.4 equiv., FW: 118.96 gmol ) was added to the reaction
3
(
2
m, 16H, OCH CH O), 3.46–3.45 (m, 2H, CH CCH),
mixture at room temperature. The reaction mixture was
stirred for ~12 h at reflux until complete as judged by TLC.
The contents of the flask were cooled to room temperature,
2
2
2
.83(td, J=5.9, 1.4 Hz, 4H, NCH ), 2.19 (t, J=2.3 Hz, 1H,
2
13 1
CCH); C{ H} NMR(126 MHz, CDCl ): d=79.55 (CCH),
3
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢄ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
7
ÞÞ
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Jerome R. Robinson et al.
FULL PAPERS
filtered, and washed with CH Cl (2ꢆ100 mL). The com-
bined filtrate was evaporated under reduced pressure. The
residue was treated with water (1ꢆ200 mL) and extracted
alyzed by elemental analysis based on N: fmax =
0.461 mmolg ; f=0.290 mmolg , 63% yield, 34% overall
yield (starting from MR); 84.42% C, 7.36% H, 2.83% N.
2
2
À1
À1
with CH Cl2 (2ꢆ100 mL). The combined organic layers
2
were dried over MgSO , and concentrated under reduced
pressure. The resulting residue was purified by column chro-
4
Synthesis of 4b
matography (SiO , 30% ethyl acetate:n-hexane) to obtain
A
10-mL flask was charged with MR-6a (0.510 g,
2
À1
3
b as a white solid; yield: 7.25 g (14.2 mmol, 82%; FW:
0.250 mmol; f=0.493 mmolg ), anhydrous K
0.5 mmol, 2 equiv.; FW: 138.21 gmol ), and CH
tert-butyl (2-bromoethyl) AHCTUNGRETNNUN(G methyl)carbamate (4a, 119 mg,
0.5 mmol, 2 equiv.; FW: 238.21 gmol ) was added, and the
flask was sealed and the mixture shaken (orbital shaker) for
3 days. The mixture was filtered and the solid phase was
washed with water (2ꢆ10 mL), MeOH (2ꢆ10 mL), THF
(2ꢆ10 mL), and CH Cl (2ꢆ10 mL). The off-white resin 4b
was dried under vacuum at 408C for 24 h, then weighing
2
CO
3
(68.8 mg,
À1
1
À1
510.68 gmol ). H NMR (500 MHz, CDCl ): d=3.56–3.30
CN (3 mL).
3
3
(
m, 14H, CHCCH2 and NCH CO), 2.80–2.73 (m, 4H,
2
À1
CHCCH NCH ), 2.18 (t, J=2.2 Hz, 1H, CCH), 1.47 [br s,
2
2
1
3
1
9
(
H, C ACHTUNGTRENNUNG( CH ) ], 1.45 [br s, 18H, C ACHTUNGTRENNUGN( CH ) ]; C{ H} NMR
126 MHz, CDCl ): d=156.20 [COOC ACHTUNGTRNEGNU( CH ) ], 155.89
3 3
3
3
3
3
3
[
COOC ACHTUNGTRENNUNG( CH ) ], 155.44 [COOC ACHTNUGTERNNUNG( CH ) ], 79.90 [C CATHUNGTRENUNGN( CH ) ],
3 3 3 3 3 3
79.67 [C
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(CH ) ], 79.46 [C
A
H
U
G
R
N
U
G
2 2
3
3
3
3
2
(
CHCCH ), 54.56 (NCH ), 53.40 (NCH ), 50.16 (NCH ),
2
2
2
2
5
4
0.01 (NCH ), 48.08 (NCH ), 47.89 (NCH ), 46.74 (NCH ),
0.500 g. The functionalization was determined by elemental
2
2
2
2
À1
7.28 (NCH ), 39.36 (CHCCH ), 28.94 [C
A
H
U
G
R
N
U
G
analysis based on
%
N: (fmax =0.457 mmolg ; f=
2
2
3 3
+
À1
A( CH ) ], 28.68 [C
C
H
T
U
N
G
T
R
E
N
N
U
N
G
A( CH ) ]; HR-MS (ESI ): m/z=511.3490,
C
H
T
U
N
G
T
R
E
N
N
U
N
G
0.359 mmolg , 78% yield; 88.67% C, 7.62% H, 1.51% N).
3
3
3 3
calculated for C H N O : 511.3494; IR (ATR): n=3249,
26
47
4
6
2
1
1
974, 2927, 1671, 1453, 1412, 1363, 1309, 1246, 1149, 1100,
030, 978, 945, 905, 856, 771, 681, 558, 503, 451 cm ; mp
23.6–125.48C.
Synthesis of MR-4a
À1
A 15-mL flask was charged with 4b (0.500 g, 0.180 mmol;
À1
f=0.359 mmolg ), CH Cl (5 mL), and TFA (2 mL,
2
2
À1
2
6.1 mmol, 145 equiv.; FW: 114.02 gmol ). The flask was
Synthesis of 3c
sealed and the mixture shaken (orbital shaker) for 3 h. The
mixture was filtered and CH Cl (5 mL) and ethylenedia-
mine (5 mL) were added to the solid phase and shaken for
1 h. The product was filtered and washed with water (2ꢆ
A 50-mL Schlenk tube was charged with MR-N3 (2.00 g,
2
2
À1
À1
À1
1
0
1
.02 mmol; f=0.510 mmolg ), CuI (24.2 mg, 0.127 mmol,
.12 equiv.; FW: 190.45 gmol ), and 3b (0.76 g, 1.49 mmol,
.4 equiv.; FW: 510.68 gmol ), and a Teflon-coated stir bar
10 mL), MeOH (2ꢆ10 mL), THF (2ꢆ10 mL), and CH Cl2
2
under an N2 flow. DIPEA (2.40 mL, 13.7 mmol, 13 equiv.;
FW: 129.24 gmol ), DMF (12.5 mL) and THF (12.5 mL)
were added to the reaction mixture, gently stirred, and
(2ꢆ10 mL). The off-white resin MR-4a was dried under
vacuum at 408C for 24 h, then weighing 0.450 g. The func-
tionalization was determined by elemental analysis based on
N: fmax =0.372 mmolg ; f=0.345 mmolg , 93% yield, 68%
overall yield (starting from MR); 88.85% C, 7.78% H,
1.45% N.
À1
À1
À1
heated at 408C for 12 h. After disappearance of the charac-
À1
teristic azide peak (2100 cm ) the resultant mixture was
cooled to room temperature, filtered, and the solid was
washed with water (500 mL) and MeOH (500 mL). The fol-
lowing steps were performed three times: 1) a 100-mL
round-bottom flask was charged with the resin, THF
Synthesis of 5a
(
50 mL), and ethylenediamine (1 mL), 2) shaken (orbital
A 250-mL round-bottom flask was charged with sarcosine
À1
shaker) at RT for 20 min, 3) filtered, and 4) washed with
THF (50 mL) and MeOH (50 mL). Finally the solid was
(0.900 g, 10.0 mmol; FW: 89.09 gmol ), a water solution
(100 mL) containing triethylamine (4.18 mL, 30.0 mmol,
À1
washed with water (500 mL), 50% H O:MeOH (500 mL),
3 equiv.; FW: 101.19 gmol ), and a Teflon-coated stir bar.
2
5
0% THF:MeOH (500 mL), THF (500 mL), and CH Cl
Di-tert-butyl dicarbonate (2.18 g, 10.0 mmol, 1 equiv.; FW:
2
2
À1
(
500 mL). The light-yellow resin 3c was dried under reduced
218.25 gmol ) was added and the solution was stirred for
pressure at 408C for 24 h, then weighing 1.92 g. The resin
3 h. The reaction mixture was poured into aqueous HCl
(1N, 30 mL) and extracted with ethyl acetate (3ꢆ100 mL).
The organic layer was washed with water (1ꢆ100 mL) and
was carried forward assuming a functionalization equal to
À1
fmax =0.407 mmolg , and used without further characteriza-
tion.
brine (2ꢆ50 mL), dried with MgSO , filtered, and concen-
4
trated under reduced pressure to obtain 5a as white solid;
À1
yield: 1.72 g (9.09 mmol, 91%; FW: 189.21 gmol ). The
Synthesis of MR-3b
product was obtained as a 1:0.95 mixture of rotamers based
1
A 50-mL round-bottom flask was charged with resin 3c
on H NMR integration and matched the previously report-
À1
[18]
(
2.52 g, 1.03 mmol, fmax =0.407 mmolg ), CH Cl (25 mL),
ed spectra.
2
2
trifluoroacetic acid (TFA, 3 mL, 39.2 mmol, 38.2 equiv.; FW:
À1
1
14.02 gmol ), and a Teflon-coated stir bar. The reaction
Synthesis of 5b
mixture was stirred for ~18 h at room temperature. After
the disappearance of the characteristic peak for the carbonyl
A 500-mL round-bottom flask was charged with 1-ethyl-3-
À1
group had been observed by IR (1736 cm ) the solid was
(3-dimethylaminopropyl)carbodiimide
(EDC·HCl, 8.11 g, 42.3 mmol, 1 equiv.; FW: 191.70 gmol ),
hydrochloride
À1
filtered and washed with water (200 mL), MeOH (500 mL),
a solution of NEt3 in THF (2% v/v, 500 mL), and THF
hydroxybenzotriazole monohydrate (HOBT·H O, 7.12 g,
2
À1
(
300 mL).The light yellow resin MR- 3b was dried at 408C
46.5 mmol, 1.1 equiv.; FW: 153.14 gmol ), CH Cl2
2
for 48 h, then weighing 2.31 g. The functionalization was an-
(400 mL), and a Teflon-coated stir bar. The solution was
8
asc.wiley-vch.de
ꢄ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

FULL PAPERS
Non-Covalent Immobilization of Rare Earth Heterobimetallic Frameworks
À1
cooled to 08C, and DIPEA (14.77 mL, 85 mmol, 2 equiv.;
FW: 129.24 gmol ) was added to the stirring solution fol-
by IR (1390 and 1366 cm ) the solid was filtered and
washed with water (500 mL), MeOH (500 mL), a solution of
À1
lowed by prop-2-ynylamine (2.71 mL, 4 2.3 mmol, 1 equiv.;
FW: 55.08 gmol ). The reaction mixture was allowed to
NEt in THF (2% v/v, 500 mL), and THF (300 mL). The
light yellow resin 5d was dried at 408C for 12 h, then weigh-
3
À1
warm to room temperature and stirred for ~12 h until com-
plete as judged by TLC. The reaction mixture was washed
ing 4.06 g. The resin was carried forward assuming a func-
tionalization equal to fmax =0.479 mmolg , and used without
À1
with NaHCO (1ꢆ200 mL), followed by brine (1ꢆ200 mL).
further characterization.
3
The aqueous layer was extracted with CH Cl (2ꢆ50 mL)
2
2
and the combined organic layers were dried with MgSO , fil-
4
Synthesis of MR-5b
tered, and concentrated under reduced pressure. The residue
was purified by column chromatography (SiO , CH Cl ) to
Four 30-mL glass vials were charged with 5d (2.90 g,
2
2
2
À1
obtain 5b as a white solid; yield: 8.99 g (39.8 mmol, 94%;
1.39 mmol;
f
max =0.479 mmolg ), boric acid (0.970 g,
À1
1
À1
FW: 226.28 gmol ). H NMR (500 MHz, CDCl , 298 K): d=
15.7 mmol, 11.3 equiv.; FW: 61.36 gmol ), and a Teflon-
coated stir bar. Under an N
3
6
.44–6.12 (m, 1H, CONH), 4.09–4.08 (m, 2H, CHCCH ),
2
flow trimethyl borate (1.75 mL,
2
À1
3
.88 (s, 2H, NHCH ), 2.96 (s, NCH ), 2.25–2.24 (m, 1H,
15.7 mmol, 11.3 equiv.; FW: 103.91 gmol ) and borane
(1.0M solution in THF, 57.6 mL, 57.6 mmol, 41.5 equiv.;
2
3
1
3
1
CHCCH ), 1.49 [s, 9H, C ACHTUNGNRTEUNG( CH ) ]; C{ H} NMR (126 MHz,
2
3 3
À1
CDCl , 298 K): d=169.16 (NHCO), 156.30 (NCH CO),
FW: 13.83 gmol ) were added. After the evolution of hy-
3
3
1
55.43 (NCH CO), 80.54 [C
A
H
U
G
R
N
N
(CH ) ], 79.46 (CHCCH ), 71.47
drogen gas was complete, the reaction mixture was stirred at
3
3
3
2
(
(
(
(
(
(
CHCCH ), 52.83 (COCH N), 52.49 (COCH N), 35.80
658C under N
2
for ~60 h. After disappearance of the car-
2
2
2
1
3
1
À1
NCH ), 28.86 (CHCCH ), 28.23 [C
A
H
U
G
R
N
N
(CH ) ]; C{ H} NMR
bonyl band was observed by IR (1673 cm ) the batches
were filtered together and washed with THF (1ꢆ200 mL).
The resin was then treated with piperidine (30.0 mL) and
gently stirred for 20 h. The resin was then filtered and
3
2
3 3
126 MHz, CDCl3, 328 K): d=169.10 (NHCO), 155.93
NCH CO), 80.56 [C(CH ) ], 79.57 (CHCCH ), 71.45
AHCTUNGTRENNUNG
3
3
3
2
CHCCH ), 52.87 (COCH N), 35.77 (NCH ), 28.91
2
2
3
.
+
CHCCH ), 28.29 [C
A
H
U
G
R
N
U
G
washed with MeOH (500 mL), THF (500 mL), and CH Cl
(500 mL). The off-white resin MR- 5b was dried at 408C for
48 h, then weighing 2.00 g. The functionalization was ana-
2 2
2
3 3
2
49.1210, calculated for C H N NaO : 249.1220; IR
1
1
18
2
3
(
ATR): n=3295, 3231, 2977, 2931, 1661, 1552, 1451, 1390,
À1
1
5
361, 1311, 1231, 1148, 1080, 1015, 962, 908, 884, 772, 692,
83, 556 cm ; mp 90.7–92.58C.
lyzed by element analysis based on N: fmax =0.482 mmolg ,
À1
À1
f=0.471 mmolg , 98% yield, 81% overall yield (starting
from MR); 85.26% C, 7.65% H, 3.30% N).
Synthesis of 5c
Synthesis of MR-6a
A 100-mL Schlenk tube was charged with MR-N (4.00 g,
3
À1
À1
À1
2
0
1
.04 mmol; f=0.510 mmolg ), CuI (80.0 mg, 0.420 mmol,
.21 equiv.; FW: 190.45 gmol ), and 5b (0.57 g, 2.52 mmol,
.2 equiv.; FW: 226.28 gmol ), and a Teflon-coated stir bar
A 50-mL round-bottom flask was charged with Merrifield
resin (3.77 g, 2 mmol, f=0.530 mmolg ), anhydrous K
À1
CO
2
3
À1
(1.66 g, 12 mmol, 6 equiv.; FW: 138.21 gmol ), toluene
(24 mL), ethylenediamine (1.2 g, 20 mmol, 10 equiv.; FW:
under an N flow. DIPEA (4.76 mL, 27.3 mmol, 13.4 equiv.;
2
À1
À1
FW: 129.24 gmol ), DMF (30 mL) and THF (30 mL) were
60.10 gmol ), and a Teflon-coated stir bar. The mixture was
added to the reaction mixture, gently stirred, and heated at
heated to reflux and gently stirred. After disappearance of
the C
was filtered and the solid phase was washed with water (2ꢆ
À1
ÀCl band (679 cm , ~24 h) was observed, the mixture
4
08C for 12 h. After disappearance of the characteristic
À1
azide peak (2100 cm ) the resultant mixture was cooled to
room temperature, filtered, and the solid was washed with
water (500 mL) and MeOH (500 mL). The following steps
were performed three times: 1) a 100-mL round-bottom
flask was charged with the resin, THF (50 mL), and ethyle-
nediamine (1 mL) were added, 2) shaken (orbital shaker) at
room temperature for 20 min, 3) filtered, and 4) washed
with THF (50 mL) and MeOH (50 mL). Finally the solid
30 mL), MeOH (2ꢆ20 mL), THF (2ꢆ20 mL) and CH Cl
2 2
(2ꢆ20 mL). The white resin MR-6a was dried under
vacuum at 408C for 24 h, then weighing 3.78 g. The func-
tionalization was determined by elemental analysis based on
À1
À1
% N: fmax =0.523 mmolg ; f=0.493 mmolg , 94% yield;
89.00% C, 7.79% H, 1.38% N).
was washed with water (500 mL), 50% H O:MeOH
2
General Procedure A
(
500 mL), 50% THF:MeOH (500 mL), THF (500 mL), and
Synthesis of MR-X AHCUTNGRENNUG( REMB) [MR-1a ACTHUNGTRNENUNG( RENaB)]: A 20-mL
scintillation vial was charged with MR-1a (247.5 mg,
CH Cl (500 mL). The off-white resin 5c was dried under re-
2
2
duced pressure at 408C for 24 h, then weighing 3.82 g. The
À1
1
.00 mmol; f=0.404 mmolg ), CH Cl
(10 mL), and
resin was carried forward assuming a functionalization equal
2
2
À1
a Teflon-covered stir bar. The resin immediately was swol-
to fmax =0.457 mmolg , and used without further characteri-
len.
A
clear colorless solution of LaNaB (164.2 mg,
zation.
À1
0
.110 mmol, 1.1 equiv.; FW: 1493.50 gmol ) in CH Cl
2
2
(
2 mL) was added to the gently stirring colorless slurry.
Synthesis of 5d
After 24–48 h the reaction mixture was filtered over
a coarse porosity frit and washed with CH Cl (3ꢆ10 mL).
A 100-mL round-bottom flask was charged with resin 5c
2
2
À1
(
4.20 g, 1.92 mmol; fmax =0.457 mmolg ), CH Cl (50 mL),
The resin was transferred while swollen and slightly wet to
a pre-weighed 20-mL scintillation vial and dried under re-
duced pressure for 3 h; yield: 362.5 mg, 105% yield based
on functionalization, which was calculated on the basis of ni-
trogen elemental analysis (Supporting Information, Eqs. S1–
2
2
À1
TFA (5.0 mL, 65.3 mmol, 34 equiv.; FW: 114.02 gmol ), and
a Teflon-coated stir bar. The reaction mixture was gently
stirred for ~18 h at room temperature. After the disappear-
ance of characteristic peaks for the Boc group was observed
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢄ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
9
ÞÞ
These are not the final page numbers!

Jerome R. Robinson et al.
FULL PAPERS
À1
À1
À1
S3): fmax =0.283 mmolg (% N=1.19), f=0.300 mmolg
(168.0 mg, 0.110 mmol, 1.1 equiv.; FW: 1527.63 gmol );
(
(
% N=1.19); % CHN found: C 81.96, H 6.12. N 1.26; % La
ICP-AES) calculated: 3.9%; found: 3.8%.
yield: 0.237 mg, 88% yield based on functionalization: f
=
max
À1
À1
0.320 mmolg
(% N=0.90), f=0.350 mmolg
(% N=
MR-2a
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(LaNaB): The title compound MR-2a
A
H
U
G
R
N
U
G
0.98); % CHN found: C 83.64, H 6.68, N 0.98; % Yb (ICP-
AES) calculated: 5.50%; found: 3.16%.
MR-7a AHCUTNGTRENNUNG( LaNaB): The title compound MR-7a ACHTUGNTRENNU(GN LaNaB) was
prepared by General Procedure A using MR-2a (500 mg,
.271 mmol; f=0.542 mmolg ) and LaNaB (445.2 mg,
.298 mmol, 1.1 equiv.; FW: 1493.50 gmol ); yield:
.711 mg, 79% based on functionalization. fmax
À1
0
0
0
0
0
prepared by General Procedure A using MR-7a (450 mg,
À1
0.450 mmol; f=1.00 mmolg ) and LaNaB (739.3 mg,
À1
À1
.344 mmolg
(% N=0.48), f=0.271 mmolg
0.495 mmol, 1.1 equiv.; FW: 1493.50 gmol ); yield:
.38); % CHN found: C 80.70, H 6.41, N 0.38; % La (ICP-
AES) calculated: 3.54%; found: 3.91%.
MR-2b(LaNaB): The title compound MR-2b
prepared by General Procedure A using MR-2b (266 mg,
.0998 mmol; f=0.375 mmolg ) and LaNaB (164.0 mg,
0.713 mg, 106% yield based on functionalization: fmax
=
À1
À1
0.485 mmolg
(% N=0.68)
f=0.514 mmolg
(% N=
,
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
1.53); % CHN found: C 79.48, H 5.69, N 0.72; % La (ICP-
AES) calculated: 6.70%; found: 4.46%.
À1
0
0
0
0
1
.110 mmol, 1.1 equiv.; FW: 1493.50 gmol ); yield: General Procedure B: Reversible Binding of MR-
.373 mg, 95% yield based on functionalization. f
.268 mmolg
.43); % CHN found: C 81.15, H 6.27, N 1.43; % La (ICP-
AES) calculated: 3.30%; found: 3.64%.
MR-3b(LaNaB): The title compound MR-3b AHCTUNGTERNNUN(G LaNaB) was
prepared by General Procedure A using MR-3b (300 mg,
.0702 mmol; f=0.234 mmolg ) and LaNaB (115.3 mg,
.0772 mmol, 1.1 equiv.; FW: 1493.50 gmol ); yield:
.389 mg, 105% yield based on functionalization. f
X AHCTUNGTERNNUN(G LaNaB)
À1
(% N=1.50), f=0.255 mmolg
Between 60–100 mg of MR-X ACHUTNRGNENUG( LaNaB) were washed with
THF (2ꢆ10 mL) over a coarse porosity frit. The resin was
transferred while swollen and slightly wet to a pre-weighed
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
2
0-mL scintillation vial and dried under reduced pressure at
À1
808C. The filtrate was evaporated under reduced pressure
0
0
0
0
2
and weighed. Quantitation of LaNaB released into the fil-
1
trate as observed by H NMR with use of an internal stan-
À1
dard (mesitylene, Figure S8 and Table S3, Supporting Infor-
.221 mmolg
(% N=2.16), f=0.234 mmolg
mation).
.29); % CHN found: C 79.66, H 6.27, N 2.29; % La (ICP-
AES) calculated: 3.10%; found: 3.26%.
MR-4a(LaNaB): The title compound MR-4a AHCTUNGTERNNUN(G LaNaB) was
prepared by General Procedure A using MR-4a (290 mg,
.100 mmol; f=0.345 mmolg ) and LaNaB (164.3 mg,
.110 mmol, 1.1 equiv.; FW: 1493.50 gmol ); yield:
.396 mg, 88% yield based on functionalization. f
.253 mmolg
.93); % CHN found: C 83.69, H 6.39, N 0.93; % La (ICP-
AES) calculated: 2.90%; found: 3.25%.
MR-5b(LaNaB): The title compound MR-5b AHCTUNGTERNNUN(G LaNaB) was
prepared by General Procedure A using MR-5b (250 mg,
.118 mmol; f=0.471 mmolg ) and LaNaB (193.9 mg,
.130 mmol, 1.1 equiv.; FW: 1493.50 gmol ); yield:
.386 mg, 95% yield based on functionalization: f
.314 mmolg
.10); % CHN found: C 77.96, H 6.05, N 2.10; % La (ICP-
AES) calculated: 3.90%; found: 3.89%.
MR-6a(LaNaB): The title compound MR-6a AHCTUNGTERNNUN(G LaNaB) was
prepared by General Procedure A using MR-6a (250 mg,
.247 mmol; f=0.493 mmolg ) and LaNaB (405.8 mg,
.272 mmol, 1.1 equiv.; FW: 1493.50 gmol ); yield:
.366 mg, 88% yield based on functionalization: f
.324 mmolg
.80); % CHN found: C 77.96, H 6.05, N 2.10; % La (ICP-
AES) calculated: 3.70%; found: 3.42%.
MR-6a(EuNaB): The title compound MR-6a
was prepared by General Procedure A using MR-6a
203 mg, 0.100 mmol; f=0.493 mmolg ) and EuNaB
165.7 mg, 0.110 mmol, 1.1 equiv.; FW: 1506.55 gmol );
yield: 0.307 mg, 96% yield based on functionalization: f
.322 mmolg
1
A[ Na
H
U
G
R
N
U
A
T
N
T
N
U
G
A
H
U
G
R
N
U
G
3
6
3
dine-d ): d=7.75 (d, J=7.8 Hz, 2H), 7.70 (d, J=8.9 Hz,
5
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
2
H), 7.22 (m, 4H), 6.98 (t, J=7.3 Hz, 2H), 6.85 (t, J=
À1
7.6 Hz, 2H). Lanthanum content was obtained from ICP-
AES measurements of the dried resin and is listed in the
0
0
0
0
0
Supporting Information, Table S2 [%La
ACHTUNGTNRENUNG( obs)].
wash
À1
(% N=1.06), f=0.221 mmolg
General Procedure C: Asymmetric Michael Addition
Catalyzed by MR-X(LaNaB) (MR-6a(LaNaB)
A
H
U
G
R
N
U
G
ACHTUNGTRENNUNG
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
In an N atmosphere glovebox, a 2-mL snap-cap vial was
2
charged with MR-6a
A
H
U
G
R
N
U
G
À1
0
0
0
0
2
À1
0
.286 mmolg ), CH Cl (200 mL), and a Teflon-coated stir
2
bar.
Cyclohexenone
(9.70 mL,
0.100 mmol;
FW=
À1
9
6.13 gmol ) was added to the swollen resin, resulting in
À1
(% N=2.20), f=0.300 mmolg
a color change of the resin from off-white to yellow. Diben-
À1
zyl malonate (24.9 mL, 0.100 mmol; FW=284.31 gmol )
was added and the reaction was gently stirred. After 12 h,
the reaction was diluted with CH Cl (2–4 mL) and filtered
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
2
2
over celite. The filtrate was removed from the glovebox and
solvent was removed under reduced pressure. The resulting
À1
0
0
0
0
0
residue was purified by column chromatography (SiO , 25%
2
acetone:hexanes), and enantioselectivities were then deter-
À1
(% N=0.91), f=0.286 mmolg
mined by HPLC (Chiralcel AS-H, 10% i-PrOH:hexanes,
À1
1
1
.0 mLmin , l =210 nm, t =29.6, 25.6 min). The H and
obs R
1
13
C{ H} NMR spectra match the previously reported spec-
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
[9b]
tra.
À1
(
(
Recycling Studies of MR-6a ACHNTUGRNENUG( LaNaB) as a Catalyst in
the Asymmetric Michael Addition
À1
0
(% N=0.90), f=0.311 mmolg
In an N atmosphere glovebox, a 4-mL vial was charged
2
0
.87); % CHN found: C 82.89, H 6.46, N 0.87; % Eu (ICP-
with
MR-6a
A
H
U
G
R
N
U
(LaNaB)
(175 mg,
0.05 mmol;
f=
À1
AES) calculated: 4.40%; found: 4.05%.
MR-6a(YbNaB): The title compound MR-6a
was prepared by General Procedure A using MR-6a
0.286 mmolg ), CH Cl (1.00 mL), and a Teflon-coated stir-
2
2
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
A
T
N
T
E
N
N
(YbNaB)
bar. The vial was cooled to À358C (freezer) and cyclohexe-
À1
none (48.4 mL, 0.500 mmol; FW=96.13 gmol ) was added
À1
(
203 mg, 0.100 mmol; f=0.493 mmolg ) and YbNaB
to the swollen resin, resulting in a color change of the resin
10
asc.wiley-vch.de
ꢄ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

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0
.500 mmol; FW=284.31 gmol ) was added at À358C and
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2
2
nted. The resin was washed with additional CH Cl (2ꢆ
2
2
4
mL) and the combined organic layers were brought out-
side of the glovebox and worked up in an analogous manner
to General Procedure C. The resin was recharged with
CH Cl and reactants at À358C and stirred for another 12 h.
2
2
Supporting Information
[
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Acknowledgements
JY thanks MINECO (Spain) for a post-doctoral contract.
GRS and JRR thank University of Pennsylvania for graduate
scholarships. XF thanks CSC (Chinese scholarship commit-
tee) and ICIQ Foundation for a fellowship. This work was
supported by the NSF (NSF-ICC:CHE-1026553) to PJW and
EJS, the University of Pennsylvania and by MINECO
(
Grants PIB2010US-00616 and CTQ2012-38594-C02-01),
AGAUR (Grant 2009SGR623) and ICIQ Foundation to
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[
24] We have found that the addition of 30 mol% water was
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