Palladium-catalyzed direct α-arylation of benzyl thioethers with aryl bromides

Article abstract of DOI:10.1002/adsc.201400679

The arylation of sp³-hybridized C-H bonds is a powerful strategy to build molecular complexity and diversity. A novel and efficient palladium-catalyzed direct sp³ C-H arylation of aryl and alkyl benzyl thioether derivatives with aryl bromides is reported. The reaction involves reversible deprotonation of the benzylic C-H bond of the thioether with either lithium or sodium bis(trimethylsilyl)amide [LiN(SiMe₃)₂ or NaN(SiMe₃)₂] and subsequent cross-coupling to provide the functionalized products in up to 97% yield. A screen of 24 of the most successful ligands in cross-coupling chemistry led to the identification of NiXantPhos as the only viable ligand for this challenging coupling.

Full text of DOI:10.1002/adsc.201400679

FULL PAPERS
DOI: 10.1002/adsc.201400679
Palladium-Catalyzed Direct a-Arylation of Benzyl Thioethers
with Aryl Bromides
Gustavo Frensch,a,b Nusrah Hussain,a Francisco A. Marques,b
and Patrick J. Walsha,*
a
P. Roy and Diana T. Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104,
USA
E-mail: pwalsh@sas.upenn.edu
Departamento de Quꢀmica, Universidade Federal do Paranꢁ, CP 19081, 81531-990, Curitiba – PR, Brazil
b
Received: July 13, 2014; Published online: July 30, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400679.
3
À
Abstract: The arylation of sp -hybridized C H bonds coupling to provide the functionalized products in up
is a powerful strategy to build molecular complexity to 97% yield. A screen of 24 of the most successful
and diversity. A novel and efficient palladium-cata- ligands in cross-coupling chemistry led to the iden-
lyzed direct sp3 C H arylation of aryl and alkyl tification of NiXantPhos as the only viable ligand for
À
benzyl thioether derivatives with aryl bromides is re- this challenging coupling.
ported. The reaction involves reversible deprotona-
tion of the benzylic C H bond of the thioether with
À
À
either lithium or sodium bis(trimethylsilyl)amide Keywords: arylation; C H functionalization; cross-
[LiN
(SiMe3)2 or NaN
(SiMe3)2] and subsequent cross- coupling; palladium; sulfides
Introduction
their higher pKa values.[11] Although thioethers can be
deprotonated with organolithiums[12] and then
[1]
À
The direct arylation of C H bonds is an appealing quenched with a variety of electrophiles, the in situ
alternative to classic coupling of prefunctionalized metallation/arylation of thioethers has never been
partners, because it circumvents the use of preformed achieved. Given the importance of organosulfur small
organometallic reagents. In the context of a broader molecule libraries, we set out to develop conditions
program to functionalize weakly acidic sp3-hybridized for the tandem reversible metallation of thioethers
[2–4]
À
C H bonds,
we became interested in the arylation with subsequent arylation.
To accomplish this objective, two hurdles would
À
of C H bonds situated alpha to sulfur atoms, since
sulfur-based compounds are commonplace in the need to be surmounted. First, bases must be identified
chemistry of life and in medicinal chemistry.[5] Our in- that are sufficiently strong to deprotonate thioethers,
À
itial efforts focused on the direct a-arylation of C H yet are compatible with transition metal arylation cat-
bonds adjacent to sulfur(II), such as found in sulfox- alysts. Second, a catalyst would need to be found that
ides, including the parent DMSO (Scheme 1, A).[6] could withstand reactive organolithium,[13] -sodium, or
À
Based on these results, we then examined a-C H ary- -potassium intermediates. Furthermore, given the
lations of sulfur(IV) of methyl and benzyl sulfones.[7] known propensity of palladium catalysts to cleave C
À
In both cases, the reactions were promoted by a palla- S bonds[14] the catalyst must also exhibit a high degree
dium catalyst employing Kwongꢂs indole-based phos- of chemoselectivity.
phine[8,9] in the presence of LiO-t-Bu at 1108C
Herein we report the first examples of C H aryla-
tion alpha to sulfur in thioethers (Scheme 2). Given
À
(Scheme 1, B).
Our development of a successful reaction system the distinct chemistry of thioethers relative to sul-
for the arylation of sulfoxides and sulfones inspired us fones and sulfoxides, and the increased reactivity of
to conjecture about the possibility of a-arylation of metallated sulfides compared to their sulfoxide and
less oxidized sulfur compounds such as thioethers.[10] sulfone counterparts, it is not surprising that different
À
The a-C H bonds of thioethers are more difficult to bases, conditions, palladium precursor and ligand
metallate than either sulfoxides or sulfones due of were required for the a-arylation of thioethers.
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Gustavo Frensch et al.
Table 1. Benzylation of benzyl phenyl sulfide with benzyl
chloride.
Entry
Base
1H NMR assay yield [%]
1
2
3
4
5
6
LiO-t-Bu
NaO-t-Bu
KO-t-Bu
0
0
0
53
60
74
LiN
NaN
KN(SiMe3)2
G
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
arylation of thioethers. Interestingly, these results are
in contrast to the arylation of aryl methyl sulfoxides[6]
and sulfones,[7] where LiO-t-Bu was the optimal base
(Scheme 1). On the other hand, benzylation products
were observed in increasing conversions, with
Scheme 1. Direct a-arylation of sulfoxides (A) and sulfones
(B) promoted by a palladium catalyst based on Kwongꢂs
indole-based phosphine.
LiN
6).
ACTHUGNNERT(NUNG SiMe3)2 <NaNACHNUTRTEGNGN(UN SiMe3)2 <KNACHTNUGTERN(NUGN SiMe3)2 (entries 4–
Having identified three potential bases for the cata-
lytic arylation of thioethers, we next turned our atten-
tion to the hunt for a catalyst. Based on our experi-
ence with deprotonative cross-coupling processes of
weakly acidic substrates,[3,4] we chose to use van Leeu-
wenꢂs NiXantPhos ligand as
(Figure 1).[16,17] Eight different palladium sources
{Pd(OAc)2, [PdCl(allyl)]2, Pd(dba)2, Pd(PPh3)4, PdCl2
(cod), Pd(acac)2, Pd(tfa)2 and PdCl2}, the three bases
identified in the benzylation screen in Table 1
[LiN(SiMe3)2, NaN(SiMe3)2 and KN(SiMe3)2] and 4
a
starting point
Scheme 2. Direct a-arylation of sulfides outlined herein.
G
E
E
ACHTUNGTRENNUNG
G
E
ACHTUNGTRENNUNG
Results and Discussion
E
E
G
ACHTUNGTRENNUNG
solvents [CPME, THF, DME (dimethoxyethane) and
À À
Given the high pKa values of thioethers, it seemed toluene] were examined in the coupling of Ph S
wise to initiate research in this area with a class of CH2Ph (1a) with bromobenzene (2a). Screens were
thioACHTUNGTRENNUNGethers wherein the a-lithiated substrates had been conducted at 508C using microscale high-throughput
generated and studied. Benzyl phenyl sulfide satisfied experimentation (HTE) techniques (see the Support-
our criteria: it can be deprotonated by n-BuLi and it ing Information for details and complete results). The
is monomeric in solution and the solid state.[15]
7 leading hits in the HTE screen were performed on
Our first step toward development of the arylation laboratory scales and the assay yields of 4a are listed
of sulfides is to identify base and solvent combina- in Table 2. The combination of [PdCl(allyl)]2 and
tions for the reversible deprotonation of the benzylic LiN(SiMe3)2 in THF was the top contender and was
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
À
À
C H bonds of ArS CH2Ar’ under conditions amena- employed in a broader screen of ligands, as outlined
ble to catalysis. To this end, we employ base and below. Interestingly, in contrast to the benzylation in
benzyl chloride to trap any metallated sulfide. By Table 1, the results of the catalyst screening (Table 2)
measuring the yield of the benzylation product, we
can determine which bases deprotonate the benzylic
À
C H bonds of the substrate over the course of the re-
action (Table 1).[3] Thus, we screened 6 bases [LiO-t-
Bu, NaO-t-Bu, KO-t-Bu, LiN
ACHTUTGNERN(NGU SiMe3)2, NaNACHTUGNTERN(NUGN SiMe3)2,
KN(SiMe3)2] at room temperature in CPME (cyclo-
ACHTUNGTRENNUNG
pentyl methyl ether). As outlined in Table 1, en-
tries 1–3, alkoxide bases MO-t-Bu (M=Li, Na, K) did
not generate detectable amounts of benzylation prod-
Figure 1. Structures of van Leeuwenꢂs NiXantPhos and
ucts, suggesting they would not be applicable in the XantPhos ligands.
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Palladium-Catalyzed Direct a-Arylation of Benzyl Thioethers with Aryl Bromides
Table 2. Laboratory-scale reactions using the top HTE con-
ditions.
ingly, of the 24 ligands examined, only NiXantPhos
generated the coupling product in meaningful
amounts. Structurally similar XantPhos[18] (Figure 1)
generated only a trace of product. Well known dppf
derivatives and bulky monodentate phosphines (mem-
bers of the Buchwald family,[19] Kwongꢂs indole-based
phosphine,[8] Q-Phos,[20] etc.) failed to generate any
product under these conditions, attesting to the chal-
lenging nature of this cross-coupling reaction. These
Entry Base
Pd source
Solvent Assay yield
[%][a]
À
results further indicate that NiXantPhos, with an N
H that can be deprotonated under the basic reaction
conditions, is a uniquely effective ligand.[17]
1
2
3
4
5
6
7
LiN
LiN
LiN
LiN
NaN
NaN
NaN
N
G
(allyl)]2 THF
61
DME 57
toluene 35
toluene 0
CPME 56
CPME 58
CHTUNGTRENNUNG
CHTUNGTRENNUNG
In order to optimize the reaction conditions with
the NiXantPhos/
ferent ratios of thioether (1a), bromobenzene (2a),
LiN(SiMe3)2 (3a) and various reaction times
ACHUTNGTRNENUG[PdClCAHTUNTGERN(NUGN allyl)]2 system, we tested dif-
G
R
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
CHTUNGTRENNUNG
(Table 3). At this point, we did not yet understand the
sensitivity of the yield to reaction time (due to prod-
uct decomposition). The yield of the reaction was
[a]
1
Yields determined by H NMR analysis of crude mixture
with CH2Br2 as internal standard.
higher when 2 equiv. each of LiNACTHNUTRGEN(UNG SiMe3)2 and bromo-
benzene were used (entries 1–3, up to 52% yield).
To minimize by-product formation, we reduced the
indicate the opposite efficacy ordering of the bases in reaction temperature from 808C to 508C and to room
the
arylation
[LiN
(SiMe3)2 ~NaN
ACHTUNGTRENNUNG
KNACHTUNGTRENNUNG(SiMe3)2].
Based on the results in Table 2, we subsequently ex- The effect of the reaction time was next evaluated.
amined 24 sterically and electronically diverse ligands The yield of 4a in entries 6–9 reached a maximum
in the arylation of PhSCH2Ph with bromobenzene when the reaction was quenched after 30 min
using HTE techniques with [PdCl
ACHTUNGTRNE(NUGN allyl)]2 and (entry 8, 86% yield). We next decreased the palladi-
LiN(SiMe3)2 in THF (see the Supporting Information um and ligand loading from 10 mol% Pd to 5 mol%.
ACHTUNGTRENNUNG
for details and a full list of ligands tested). Interest- Unfortunately, the yield decreased from 86 to 67%
Table 3. Optimization of palladium-catalyzed DCCP of benzyl phenyl sulfide.
Entry
1a:2a:3a
Solvent
Temp. [oC]
Time [h]
Pd:NiXantPhos (mol%)
4a[a] [%]
1
2
3
4
5
6
7
8
2:1:2
2:1:3
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
CPME
DME
dioxane
hexanes
toluene
80
80
80
50
12
12
12
12
12
6
1
0.5
0.25
0.5
0.5
0.5
0.5
0.5
0.5
0.5
10:20
10:20
10:20
10:20
10:20
10:20
10:20
10:20
10:20
5:10
45
0
52
53
60
67
80
86
76
67
64[b]
0
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
9
10
11
12
13
14
15
16
5:10
10:20
10:20
10:20
10:20
10:20
58
0
0
0
[a]
1
Yields determined by H NMR analysis of crude mixture with CH2Br2 as internal standard.
Concentration is 0.2M.
[b]
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Gustavo Frensch et al.
Table 4. Substrate scope of aryl bromides in the a-arylation
of benzyl phenyl sulfide.
entries 7 and 8). Both 1- and 2-bromonaphthalene
were good substrates, forming product in 70 and 72%
yield (4i and 4j, entries 9 and 10, respectively). Nitro-
gen-protected 5-bromoindole 2k was also a good cou-
pling partner, producing the heterocyclic product 4k
in 68% yield (entry 11). Reactions with heteroaryl
bromides bearing 2- or 3-pyridyl, 2- or 3-furyl, or 2-
or 3-thiophenyl did not yield coupling products. This
is not totally unexpected given the sensitivity of these
heterocycles and the strongly basic conditions in these
coupling reactions.
À
Br Ar
Entry
Product
Isolated Yield [%]
1
2
3
4a
4b
4c
86
84[a]
82[a]
We next turned our attention to the scope of sulfide
substrates (Table 5). Sulfides with electron-donating
À
substituents in the S Ar group resulted in good to ex-
cellent yields (4l–n, 80–97%, entries 1–3) while one
with a para-CF3 group gave lower yield (4o, 60%,
entry 4).
4
5
6
4d
4e
4f
83
Variation of the benzylic group was also examined.
73[b]
93
Substitution of 1-naphthyl for phenyl (Ar2) and cou-
À
À
À
pling with Ph Br, 3-MeOC6H4 Br, 4-t-BuC6H4 Br re-
sulted in formation of 4i, 4p, and 4q in 77, 70, and
65% yields, respectively (entries 5–7). An electron-do-
nating 4-MeOC6H4CH2 group is expected to decrease
the acidity of the benzylic hydrogens. Nonetheless,
7
8
4g
4h
50
63
À
À
coupling with Ph Br or 3-MeOC6H4 Br resulted in
formation of 4e and 4r in 60 and 74%, respectively
(entries 8 and 9). Electron poor 4-ClC6H4 CH2SPh
coupled with 3-MeOC6H4 Br to furnish product 4s in
74% yield (entry 10), illustrating the chemoselectivity
of the catalyst for the C Br bond over the C Cl
bond.
À
À
9
4i
4j
72[a]
70[a]
À
À
10
Heterocycle-containing compounds are important
in medicinal chemistry.[21] We, therefore, examined
heterocycles in the benzylic position of the thioether.
Initially, coupling reactions with bromobenzene and
Ph S CH2(3-pyridyl) failed due to decomposition of
the pyridyl-containing substrate in the presence of
11
4k
68[c]
À À
[a]
Slow addition of base for 40 min follows by an additional
30 min reaction time.
Slow addition of base for 40 min at 108C followed by an
additional 15 min reaction time.
LiNACTHNURTGNE(NUG SiMe3)2. We, therefore, screened alkoxide bases
[b]
[c]
LiO-t-Bu, NaO-t-Bu and KO-t-Bu at room tempera-
ture, which led to traces of products with NaO-t-Bu
and KO-t-Bu. Heating reaction mixtures with these
bases to 508C resulted in generation of the coupling
4 h reaction time.
(entries 8 vs. 10). Furthermore, increasing the reaction product 4t in 56% yield with KO-t-Bu (entry 11).
À À
À
concentration at the lower catalyst loading did not im- Coupling of Ph S CH2(3-pyridyl) with 3-MeOC6H4
À
À
prove the yield of 4a (entry 11). Substituting other Br, 4-t-BuC6H4 Br, and 4-FC6H4 Br resulted in mod-
solvents for THF did not lead to the desired product, erate to good yields of the coupled products 4u–4x
except in the case of DME where the yield was not (57–71%, entries 12–14).
improved (entries 12–16).
To examine the scalability of the reaction, we pre-
With our optimized conditions (entry 8, Table 3), formed the arylation of benzyl phenyl sulfide (1a)
we examined the substrate scope of the arylation of with bromobenzene (2a) on a 5 mmol (1.00 g) scale
benzyl phenyl sulfide (4a) with aryl bromides (2a–k, (Scheme 3). The desired product 4a was afforded in
Table 4). The DCCP showed good to excellent yields 78% isolated yield (1.076 g).
for alkyl-substituted aryl bromides (82–84%, 4b–d,
entries 2–4) and those with methoxy substituents in ylation of alkyl benzyl sulfides, R S CH2Ar. Under
the para or meta positions (73–93%, 4e and 4f, en- our standard conditions with LiN
tries 5 and 6). Electron-withdrawing groups in the S CH2Ph the reaction failed and we observed only re-
Finally, we wanted to expand our method to the ar-
À À
À
(SiMe3)2 and c-Hex
À
para position led to lower yields (50–63%, 4g and 4h, covered starting materials. We hypothesized that this
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Palladium-Catalyzed Direct a-Arylation of Benzyl Thioethers with Aryl Bromides
Table 5. Substrate scope of aryl bromides in the a-arylation of aryl benzyl thioethers.
[a]
1 h.
[b]
Slow addition of base for 40 min followed by an addition 15 min reaction time.
KO-t-Bu as base, 508C for 30 min reaction time.
[c]
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Gustavo Frensch et al.
Scheme 3. Arylation of benzyl phenyl sulfide with bromobenzene on a 5 mmol scale.
À
À
À
was due to the decreased acidity of the alkyl thioether DCCP with Ph Br, 4-MeOC6H4 Br, 3-MeOC6H4 Br
À
substrate. Based on the difference between estimated and 4-FC6H4 Br to provide 6e–h in 75–87% yields
pKa values of dimethyl sulfide (pKa ~45)[22] and Me
(entries 5–8).
À
[11]
À
À À
S Ph (pKa ~42), it is likely that c-Hex S CH2Ph is
These results suggest that a variety of alkyl benzyl
À À
about 3 pKa units less acidic than Ph S CH2Ph (pKa thioethers can be selectively coupled with aryl bro-
30.8 in DMSO).[11] Following this line of reasoning, mides at the benzylic position.
we tested the more reactive bases NaN
KN
(SiMe3)2.[4] At room temperature in THF, we ob-
served trace formation of products after 0.5 h with Conclusions
both NaN(SiMe3)2 and KN(SiMe3)2. Heating reaction
mixtures with NaN(SiMe3)2 or KN(SiMe3)2 to 508C Direct and selective functionalization of C H bonds
for 1 h resulted in coupled product 6a in 84% yield by transition metal catalysts is a powerful method to
ACHTUNGTERN(NUNG SiMe3)2 and
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
À
N
ACHTUNGTRENNUNG
for the benzyl cyclohexyl sulfide with NaNACTHUNRGTNEUNG(SiMe3)2 facilitate the synthesis of diverse products from
À À
(entry 1, Table 6). Coupling of c-Hex S CH2Ph with simple and readily available precursors. An expanding
À
À
À
4-MeOC6H4 Br, 3-MeOC6H4 Br and 4-FC6H4 Br re- repertoire of substrates bearing various functional
sulted in generation 6b–d in 60–95% yields of the groups is now amenable to such reactions. Herein we
coupled products (entries 2–4). These conditions also have advanced the first method for the arylation adja-
À À
worked well with t-Bu S CH2Ph, which underwent cent to sulfur of thioethers. This method enables the
synthesis of various aryl and alkyl (diarylmethyl) sul-
fides, which have demonstrated bioactivity.[23]
Table 6. Substrate scope of aryl bromides in the a-arylation
Our approach involves deprotonative cross-cou-
pling of aryl benzyl sulfides, wherein the weakly
of alkyl phenyl sulfides.
acidic sulfide is reversibly metallated by LiN
ACHTUNGTRNE(NUNG SiMe3)2
or NaN(SiMe3)2 in the presence of a palladium-
AHCTUNGTRENNUNG
NiXantPhos-based catalyst. The reaction proved chal-
lenging due to the difficult deprotonation of the
weakly acidic benzyl thioether. Nonetheless, moder-
ate to excellent yields were obtained (50–97%). This
study highlights the compatibility of the NiXantPhos-
based palladium catalyst to highly reactive organo-
lithium, -sodium, and -potassium intermediates that
are structurally quite different than those employed
previously as coupling partners.[3,18]
Experimental Section
General Procedures for a-Arylation of Thioethers
General Procedure A: An oven-dried 10-mL reaction vial
equipped with a stir bar was charged with LiNACHTUNGTRENNUNG(SiMe3)2
(2 equiv.) and the benzyl thioether (1 equiv.) under a nitro-
gen atmosphere. A 1 mL solution (from a stock solution) of
[PdClACTHUNTRGNE(UNG allyl)]2 (5 mol%) and NiXantPhos (20 mol%) in dry
THF was added to the vial via a syringe. After stirring for
5 min at 248C, aryl bromide (2 equiv.) was added to the re-
action mixture. The reaction mixture was stirred for 30 min
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Palladium-Catalyzed Direct a-Arylation of Benzyl Thioethers with Aryl Bromides
at 248C, quenched with three drops of H2O, diluted with References
1 mL of dichloromethane, and filtered over a pad of silica.
The pad was rinsed with additional dichloromethane, and
the solution was concentrated under reduced pressure. The
crude material was loaded onto a silica gel column and puri-
fied by flash chromatography.
General Procedure B: An oven-dried 10-mL reaction vial
equipped with a stir bar was charged with the benzyl thio-
ether (1 equiv.) under a nitrogen atmosphere. A 1 mL solu-
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tion (from a stock solution) of [PdClACTHNUTRGNEN(UG allyl)]2 (5 mol%) and
NiXantPhos (20 mol%) in dry THF was added to the vial
via a syringe. After stirring for 5 min at 248C, aryl bromide
(2 equiv.) was added to the reaction mixture followed by
slow addition of a solution of LiNACTHNUTRGEN(UNG SiMe3)2 (2 equiv.) in
0.5 mL of THF for 40 min. The reaction mixture was stirred
for 15 min at 248C, quenched with three drops of H2O, dilut-
ed with 1 mL of dichloromethane, and filtered over a pad of
silica. The pad was rinsed with additional dichloromethane,
and the solution was concentrated under reduced pressure.
The crude material was loaded onto a silica gel column and
purified by flash chromatography.
General Procedure C: An oven-dried 10-mL reaction vial
equipped with
a stir bar was charged with KO-t-Bu
(2 equiv.) and the benzyl thioether (1 equiv.) under a nitro-
gen atmosphere. A 1 mL solution (from a stock solution) of
[PdClACHTUNGTRENNUNG(allyl)]2 (5 mol%) and NiXantPhos (20 mol%) in dry
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THF was added to the vial via a syringe. After stirring for
5 min at 248C, aryl bromide (2 equiv.) was added to the re-
action mixture. The reaction mixture was stirred for 30 min
at 508C, cooled to room temperature, quenched with three
drops of H2O, diluted with 1 mL of dichloromethane, and
filtered over a pad of silica. The pad was rinsed with addi-
tional dichloromethane and the solution was concentrated
under reduced pressure. The crude material was loaded
onto a silica gel column and purified by flash chromatogra-
phy.
General Procedure D: An oven-dried 10-mL reaction vial
equipped with a stir bar was charged with NaNACTHNUGTRNEUNG(SiMe3)2
(2 equiv.) and the benzyl thioether (1 equiv.) under a nitro-
gen atmosphere. A 1 mL solution (from a stock solution) of
[PdClACHTUNGTRENNUNG(allyl)]2 (5 mol%) and NiXantPhos (20 mol%) in dry
THF was added to the vial via a syringe. After stirring for
5 min at 248C, aryl bromide (2 equiv.) was added to the re-
action mixture. The reaction mixture was stirred for 1 hour
at 508C, cooled to rt, quenched with three drops of H2O, di-
luted with 1 mL of dichloromethane, and filtered over a pad
of silica. The pad was rinsed with additional dichlorome-
thane, and the solution was concentrated under reduced
pressure. The crude material was loaded onto a silica gel
column and purified by flash chromatography.
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Acknowledgements
We thank the NSF (CHE-1152488) and NIH (NIGMS
104349) for partial support of this work. G. F. thanks the
Brazilian Science Without Borders program (237849/2012-7)
for financial support.
Adv. Synth. Catal. 2014, 356, 2517 – 2524
ꢃ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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