Gold Particles Supported on Amino-Functionalized Silica Catalyze Transfer Hydrogenation of N-Heterocyclic Compounds

Article abstract of DOI:10.1002/adsc.201601147

In this work we demonstrate that exceptionally small gold particles (d=0.6±0.2 nm) supported on amino-functionalized mesoporous silicate SBA-15 are highly active in transfer hydrogenation of structurally diverse unsaturated N-heterocyclic compounds. The heterocyclic ring is reduced selectively. The gold particles aggregate to a diameter of 4–5 nm in the presence of formic acid/triethylamine (hydrogen donor) during the first catalytic run. In subsequent cycles the nanoparticles maintain their size, yielding a very stable catalytic system that was recycled more than five times. In contrast, analogous SBA catalysts featuring larger (～5–35 nm) gold particles are not active. Excess formic acid also leads to the formation of formamide derivatives of the products of hydrogenation, which can be deformylated quantitatively. Fifteen structurally different substrates, including the scaffolds of quinoline, isoquinoline, quinoxaline, acridine, phenanthroline, quinazoline, and phenanthridine are hydrogenated and deformylated to give the amine products in >90% overall yield. Deuterium labeling experiments indicate that 1,2-addition with subsequent disproportionation of the formed intermediate is the preferred reaction path over the 1,4-addition one, suggesting the participation of a gold hydride species. (Figure presented.).

Full text of DOI:10.1002/adsc.201601147

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DOI: 10.1002/adsc.201601147
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Gold Particles Supported on Amino-Functionalized Silica
Catalyze Transfer Hydrogenation of N-Heterocyclic Compounds
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a, b
a, c,
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Beata Vilhanova, Jeroen A. van Bokhoven, * and Marco Ranocchiari *
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Department of Chemistry and Applied Biosciences
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Institute for Chemical and Bioengineering, ETH Zurich, Vladimir-Prelog-Weg 1, CH-8093 Zurich, Switzerland
E-mail: jeroen.vanbokhoven@chem.ethz.ch
Department of Organic Technology
b
c
University of Chemistry and Technology Prague
Technickꢀ 5, CZ-166 28 Prague 6, Czech Republic
Laboratory for Catalysis and Sustainable Chemistry
Paul Scherrer Institute (PSI)
CH-5232 Villigen, Switzerland
E-mail: marco.ranocchiari@psi.ch
Received: October 17, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201601147
Introduction
Abstract: In this work we demonstrate that excep-
tionally small gold particles (d=0.6Æ0.2 nm) sup-
Saturated N-heterocyclic compounds are highly de-
ported on amino-functionalized mesoporous silicate
sired building blocks in the pharmaceutical industry as
SBA-15 are highly active in transfer hydrogenation
they often surpass their less soluble aromatic analogs
of structurally diverse unsaturated N-heterocyclic
in terms of key pharmacokinetic parameters such as
compounds. The heterocyclic ring is reduced selec-
bioavailability.[1] For instance, 1,2,3,4-tetrahydroquino-
tively. The gold particles aggregate to a diameter of
line (THQ) and 1,2,3,4-tetrahydroisoquinoline
4–5 nm in the presence of formic acid/triethylamine
(THIQ), well-known units present in many naturally-
(hydrogen donor) during the first catalytic run. In
occurring alkaloids (e.g. salsolinol, tubocurarine
subsequent cycles the nanoparticles maintain their
chloride, helquinoline), have been employed in the
size, yielding a very stable catalytic system that was
structures of active pharmaceutical ingredients (diclo-
recycled more than five times. In contrast, analo-
fensine, nomifensine, oxamniquine, etc.). Related com-
gous SBA catalysts featuring larger (~5–35 nm)
pounds such as derivatives of quinoxaline and phenan-
gold particles are not active. Excess formic acid
throline are known to have lipid-lowering[2] and anti-
also leads to the formation of formamide deriva-
tives of the products of hydrogenation, which can
HIV[3] effects, respectively (Figure 1).
be deformylated quantitatively. Fifteen structurally
different substrates, including the scaffolds of
quinoline, isoquinoline, quinoxaline, acridine, phe-
nanthroline, quinazoline, and phenanthridine are
hydrogenated and deformylated to give the amine
products in >90% overall yield. Deuterium label-
ing experiments indicate that 1,2-addition with
subsequent disproportionation of the formed inter-
mediate is the preferred reaction path over the 1,4-
Figure 1. Examples of biologically active compounds con-
addition one, suggesting the participation of a gold
taining the saturated N-heterocyclic building blocks derived
hydride species.
from quinoline, quinoxaline, and phenanthroline.
Keywords: Heterogeneous Catalysis; Gold; Silica;
Transfer Hydrogenation; Saturated N-Heterocycles
The compounds containing saturated N-heterocy-
clic motifs can be prepared by hydrogenation of the
corresponding unsaturated congeners, which is a
domain where homogeneous catalysts are very well
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established.[4] However, their excellent reactivity and (SBA-15 or 3-aminopropyl-functionalized SBA-15,
selectivity are accompanied by difficult or impossible further referred to as NH2-SBA-15) and pH adjust-
catalyst separation and recycling – issues typically ment during synthesis (Table S1).[32] Z-contrast scan-
resolved by heterogeneous catalysis.[5] The reported ning transmission electron microscopy (ZC-STEM)
heterogeneous catalytic systems include catalysts revealed the gold particles as white spots (Figures 2
based on Ru (supported on SiO2,[6,7] hectorite,[8] and S1). The smallest particles (0.6Æ0.2 nm, catalyst
glucose-derived carbon spheres,[9] poly(4-vinylpyri- A) were obtained with NH2-SBA-15 and a pH of 9.5
dine),[10] MgO,[11] and RuÀCu nanocages and nano- achieved by aqueous K2CO3. As evident from Fig-
crystals[12]), Rh (on Al2O3,[13] ionic liquid,[14] various ure 2, the particles were finely and homogeneously
10 metal oxides,[15] MgO,[16] and PEG[17]), Pd (on hydroxy- dispersed in the pores. Catalysts B–E featured sub-
11 apatite,[18] methacrylic polymer;[19] tannin-[20] and met- stantially larger gold particles (Table 1, Figure S1).
12 al-carbon stabilized[21]), Pt (unsupported,[22,23] on vari- The observations thus suggest that the NH2-SBA-15
13 ous
metal
oxides[15]),
Co
(on
nitrogen- support and pH control by K2CO3 contribute to the
14 dopedgraphene[24,25]), and Au (unsupported nanopo- successful synthesis of a catalyst with finely dispersed
15 rous,[26] on TiO2 support[27–29]). The reductions have sub-nanometer gold particles.
16 been performed with pressurized gaseous hydrogen in
17 most cases.[6–25,27] On the other hand, transfer hydro-
Table 1. Gold particle size and loading of catalysts A–E.
18 genation reactions[30] employing hydrogen donors such
19 as PhMe2SiH/H2O,[26] PhMe2SiH/EtOH,[29] and
20 HCOOH/triethylamine[28] are often preferred owing
21 to the use of simple reactors, without the need of
22 hazardous gaseous hydrogen. The scope of unsatu-
23 rated N-heterocycles that were reduced in the afore-
24 mentioned studies comprises for instance derivatives
25 of quinoline[6–29] isoquinoline,[7,9,16,23,25–28] quinoxa-
26 line,[7,9,19,25,29] acridine,[6,11,23–25,27] and phenanthroline.[23]
Catalyst Support
Size of Au particles Au loading
[nm][a]
[wt.%][b]
A
B
C
D
E
NH2-SBA-15 0.6Æ0.2
NH2-SBA-15 34Æ10
2.9
3.8
0.4
2.7
2.8
SBA-15
SBA-15
SBA-15
14Æ1
4.6Æ6.1
23Æ9
[a] Determined by analysis of the ZC-STEM images.
[b] Determined by AAS.
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Hydrogenation catalyzed by supported gold clus-
28 ters is still largely underdeveloped. The main advance-
29 ment occurred around 2000, when many reports on
30 the regioselective hydrogenation of alkenes, alkynes,
31 aldehydes and ketones emerged.[31] However, the area
32 of hydrogenation of N-heterocyclic compounds was
33 entered only recently by the groups of Jin (nano-
34 porous gold with the PhMe2SiH/H2O hydrogen do-
35 nor[26]), Stratakis (Au/TiO2 with PhMe2SiH/EtOH as
36 the hydrogen source[29]), and Cao (Au/TiO2 using
37 either H2,[27] or HCOOH/triethylamine hydrogen-
38 donor mixture[28]).
Figure 2. ZC-STEM images of catalyst
dispersion of sub-nanometer gold particles.
A showing the
39
Our group recently disclosed a material featuring
40 exceptionally small sub-nanometer gold particles
41 supported on 3-aminopropyl-functionalized silicate
42 SBA-15.[32] The material was highly active and selec-
Nitrogen adsorption-desorption isotherms (Fig-
43 tive in dehydrogenation of formic acid.[32] We envi- ure S2) of SBA-15, NH2-SBA-15 and A–E provided
44 sioned that the unusually small gold particles could the specific surface area and pore volume at various
45 have a larger potential for applications in catalysis and stages of catalyst synthesis (Table S2). Small-angle
46 compete with much more frequently used systems powder X-ray diffraction (PXRD) measurements
47 such as Au/TiO2. As a result, we report here the use of showed diffraction maxima typical of SBA-15 materi-
48 our material in transfer hydrogenation of various N- als (Figure S3). FT-IR spectrum (Figure S4) of SBA-15
49 heterocyclic compounds with a high selectivity and displayed a characteristic band around 3730 cmÀ1
50 activity, broad substrate scope, and facile catalyst corresponding to the stretching vibrations of isolated
51 recycling.
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silanols. The presence of the 3-aminopropyl groups in
NH2-SBA-15 was confirmed by CH2 stretching at 2866
and 2938 cmÀ1, NH2 stretching at 3314 and 3371 cmÀ1,
and NH2 bending at 1591 cmÀ1, while the spectrum of
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Results and Discussion
55 We first explored the conditions of catalyst synthesis, A was almost identical to that of NH2-SBA-15. Gold
56 which resulted in a series of five catalysts A–E loading was determined by atomic absorption spectro-
57 (Table 1) differing in the selection of the solid support scopy (AAS) and is listed in Table 1.
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The prepared catalysts were examined in the trans-
To explore the substrate scope, we tested quinoline
fer hydrogenation of N-heterocyclic compounds. Ini- (2) and 2-methylquinoline (quinaldine, 3). While 1
tially, we focused our attention on isoquinoline (1), (Table 3, entry 1) gave only amide 1b in full con-
using 1 mol% catalyst loading, HCOOH/triethylamine version, 2 (Table 3, entry 2) was almost completely
and DMF as the solvent.[21] With catalyst A, the converted to a mixture of amine 2a (79%) and amide
substrate was fully converted to the product in 2 h 2b (11%), and its methylated derivative 3 (Table 3,
(Table 2, entry 1). Importantly, the N-formylated entry 3) was hydrogenated with 82% conversion to 3a,
product 1b, further referred to as the “amide prod- while the amide was not detected.
uct”, was exclusively formed instead of the formyl-
We extended our study not only to other quino-
10 free amine product 1a. Bigger gold particles sup- lines (4 and 6–8) and isoquinolines (5, 9), but also
11 ported on NH2-SBA-15 (catalyst B, Table 2, entry 2) quinoxaline (10), quinazoline (11), acridine (12),
12 afforded only 10% conversion after 2 h and small and phenanthroline (13), phenanthridine (14), and ben-
13 big particles on SBA-15 (catalysts C–E, Table 2, zo[h]quinoline (15) (Table 3). The amount of formic
14 entries 3–5) were not reactive at all under identical acid was investigated with regard to the formation
15 conditions. Control experiments using the supports of the amine and amide products. For instance,
16 without gold clusters showed no reactivity (Table 2, quinoline 4 with 15 equiv. of formic acid exhibited a
17 entries 6 and 7). Therefore, the amino groups present conversion of 55% to amine 4a (Table 3, entry 4),
18 on the solid support together with the small gold 30 equiv. gave 84% of 4a (entry 5), and 50 equiv.
19 clusters of A are both crucial for the hydrogenation afforded an 83:16 mixture of amine 4a and amide 4b
20 reaction.
21
(entry 6). Similar observations were made with
quinolines 6 (entries 8–10) and 7 (entries 11–13) and
suggest that the hydrogenation proceeds first and
the formylation is a subsequent step. In some cases,
the formylation proceeded smoothly after hydro-
genation (5, 9–11, and 14), while in others it was not
observed at all (8, 12, 13, and 15). The reactivity of
individual substrates in hydrogenation and/or N-
formylation thus strongly depended on the substrate
structure.
Apart from 1–15, other substrates (16–23, Figure 3)
were also examined. With halogenated substrates 16–
18, the dechlorination and debromination occurred
prior to hydrogenation of the N-heterocyclic core. 8-
Nitroquinoline (19) underwent selective hydrogena-
tion of the nitro group to an amino group, similarly
like in the recent work of Cao and co-workers.[33]
Substrates 20–22, typical benchmark compounds for
asymmetric transfer hydrogenation,[34,35] were hydro-
genated and formylated in full conversion. The hydro-
genation of the C=C bond in iminostilbene (23) and
also derivatives of imidazole and indole did not
proceed.
22
Table 2. Screening of catalysts A–E in the transfer hydro-
genation of substrate 1[a]
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Entry
Catalyst
Support
Conversion [%][b]
1
2
3
4
5
6
7
A
B
C
D
E
–
NH2-SBA-15
NH2-SBA-15
SBA-15
SBA-15
SBA-15
>99
10
0
0
0
SBA-15
NH2-SBA-15
0
0
–
[a] Reaction conditions: isoquinoline (0.03 mmol), catalyst
(1 mol% Au vs. substrate), DMF (170 mL), formic acid
(0.45 mmol), triethylamine (0.16 mmol), 1308C, 2 h
[b] Determined by GC-MS.
Next, different reaction conditions were tested in
44 transfer hydrogenation of 1. After 2 h at 1308C in
45 reagent grade DMF, the conversion to 1b was 70%
46 (Table S4, entry 1), while in anhydrous DMF we
47 observed full conversion (Table S4, entry 2). Lower
48 temperatures afforded inferior conversions (Table S4,
49 entries 3 and 4). The reaction did not proceed in
50 toluene, acetonitrile, DMSO and THF (Table S4,
51 entries 5–9) and only 20% conversion was obtained in
52 1,4-dioxane (Table S4, entry 5). Omitting triethyl-
53 amine with anhydrous DMF resulted in 6% conver-
54 sion (Table S4, entry 10) – the fact that the reaction
55 proceeded to a small extent can be attributed to the
56 amino-functionalization of silica.
Figure 3. Structures of substrates 16–23 tested in transfer
hydrogenation catalyzed by A.
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Table 3. Screening of compounds 1–15 as substrates for transfer hydrogenation catalyzed by A[a]
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[a] Reaction conditions: substrate (0.03 mmol), catalyst A (1 mol% Au vs. substrate), anhydrous DMF (170 mL), formic acid
(mol. equiv. to substrate), triethylamine (0.16 mmol), 1308C, 2 h.
[b] The ratios were determined by GC-MS.
Consequently, substrates 1–15 – various scaffolds, to develop a universal synthetic protocol giving solely
54 some of them bearing sterically and electronically the isolated amine products of hydrogenation – after
55 diverse functional groups – were subjected to hydro- hydrogenation, which was performed for 3 h to ensure
56 genation on the preparative scale. The strikingly full conversion, the crude product was subjected to
57 different reactivity among them (Table 3) prompted us deformylation conditions. The amine products of
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Table 4. Isolated yields of products 1b–15b from transfer hydrogenation of substrates 1–15 catalyzed by A[a]
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2
3
4
5
6
7
8
9
10
11
12
13
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[a] Reaction conditions: Substrate (0.4 mmol), catalyst A (1 mol% Au vs. substrate), DMF (2.2 mL), formic acid (mol. equiv. to
substrate), triethylamine (2.1 mmol), 1308C, 3 h.
[b] The yields correspond to isolated products (5 mmol scale in parentheses).
51 transfer hydrogenation of substrates 1–15 (Table 4) aromatic rings remained intact (1–9, 13, and 15) –
52 were isolated in yields in excess of 90% – including notably, 13 was reduced only on one side of the
53 hydrogenation of isoquinoline 1 on a 5 mmol scale – molecule. Quinoxaline 10 and quinazoline 11 under-
54 and individually characterized.
went reduction of both C=N bonds. Interestingly, 12
55
Most products of hydrogenation were the 1,2,3,4- was selectively reduced at the nitrogen atom and the
56 tetrahydro analogues, i.e. the C=N bond and the bridging methine group, with the aromatic rings
57 neighboring C=C bond reacted, while the other preserved. The product was prone to rearomatization
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Scheme 1. Two plausible pathways in the hydrogenation of protonated quinoline 3.
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11
12
13 (back to 12), which is typical of such 1,4-dihydropyr- substrate, the sub-nanometer gold particles sinter to
14 idine Hantzch compounds.[4k,36] In the case of 14, the d= ~4.5 nm in the first run due to the presence of
15 dihydro-analogue was obtained due to the presence of formic acid, and the consecutive cycles are catalyzed
16 adjacent aromatic rings.
17
by stable clusters of a similar diameter (Table S5). The
A hot filtration[37] test was performed for catalyst size of gold nanoparticles in catalysis is a frequently
18 A in the hydrogenation of 1. After 5 min under discussed topic.[31,38] Below ~3 nm, the metallic charac-
19 standard reaction conditions, the catalyst was filtered ter of gold diminishes[39] and the catalytic activity often
20 off – the conversion observed was 59%. Analysis of (but not always[40,41]) decreases.[42,43] Our catalytic
21 the filtrate after 1 h revealed essentially the same system thus appears to operate with metallic gold
22 concentration of the substrate and product – as the nanoparticles, which are in situ formed from the sub-
23 conversion did not increase after the removal of A, nanometer clusters of A. After having stabilized in
24 the catalysis was of purely heterogeneous nature. size, they show fixed conversion.
25 Moreover, no leached gold was detected by ICP-OES
26 in the hydrogenation of 1 (Table 3, entry 1).
27
Many studies have already focused on the mecha-
nism of hydrogenation of quinolines with various
The possibility of recycling A was also investigated. catalysts.[4c,e,l,m,7,26,27,29] The substrate is essentially pro-
28 Isoquinoline 1 was hydrogenated for 20 min at 1308C tonated in the presence of formic acid. The iminium
29 (Figure S5). After each run, the catalyst was filtered species (3-H+) can then undergo addition of a hydride
30 off, washed with ethanol, and dried — this way, A was at positions 2 or 4 (Scheme 1).[4e,m] In the case of the
31 reused 7 times. The conversion was slightly decreasing 1,4-addition, an enamine intermediate (1,4-diH-3) is
32 in the first five runs, and was stabilized at 68% in the formed, which rearranges to its tautomer, a 3,4-
33 last two runs. ZC-STEM images (Figure S6) showed dihydroquinoline (3,4-diH-3). This imine is again
34 an average gold particle diameter of 4.3Æ1.1 nm after protonated and the final product (3a) is obtained by
35 the 1st run and 4.9Æ2.3 nm after the 7th run. An 1,2-addition of a hydride. On the other hand, when
36 additional catalyst (F) with intentionally low gold the 1,2-addition on 3-H+ takes place, a 1,2-dihydro-
37 loading (0.45%) was synthesized on the NH2-SBA-15 quinoline (1,2-diH-3) originates – such compounds are
38 support, featuring gold clusters with d=0.7Æ0.2 nm. known to disproportionate, giving 3 and 3a.[4e,m,44]
39 Recycling F in the transfer hydrogenation of 1 (Fig-
Deuterium labeling experiments were performed
40 ure S5) revealed a conversion of 60% after 2 h, which to understand the mechanism of the hydrogenation
41 dropped to 24% after the first run (d=4.4Æ1.7 nm reaction (Scheme 2). The reduction of 3 was carried
42 particles) and in the subsequent four runs remained out under standard reaction conditions (Table 3), at
43 constant, with d being 4.5Æ1.9 nm after the last cycle first using HCOOH, triethylamine and DMF-d7. The
44 (Figure S6).
isolated product did not contain any deuterium,
45
In all catalytic runs, an immediate color change indicating that the solvent did not participate in the
46 from pale yellow to pink was observed on addition of hydrogenation. Taking advantage of this behavior,
47 formic acid, which was attributed to the particle DMF-d7 was employed in further experiments, which
1
48 sintering. To probe when and to what extent this facilitated the elucidation by HNMR spectroscopy.
49 occurs, we suspended the catalyst in anhydrous DMF
50 and added triethylamine and formic acid. Already
51 after stirring the mixture for 5 min at rt, the particle
52 size increased considerably (d=2.8Æ0.8 nm, Fig-
53 ure S7). After 5 min at 1308C, the particles (d=4.1Æ
54 1.6 nm) resembled those observed after performing
Scheme 2. Deuteration
DCOOH and DCOOD in the hydrogenation of substrate 3
with catalyst A.
experiments
using
HCOOD,
55 the catalytic reaction (Figure S6).
All three experiments showed that, irrespective of
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Three different isotopologues of formic acid were substrate, product, the NH2-SBA-15 support) and the
tested: HCOOD, DCOOH, and DCOOD. resulting formate anion interacts with the gold
At low conversion (5–10%), the 3-position of the clusters.[45] It is expected that the gold particles
product was significantly deuterated with HCOOD, activate the formate, thus forming an AuÀH species
while DCOOH caused deuteration in position 2, and and liberating carbon dioxide. The AuÀH bond
DCOOD yielded the product markedly deuterated in formation has been shown by several authors through
both positions 2 and 3 (Figure S8). Notably, only slight spectroscopic studies with gaseous H2 and gold nano-
deuteration of position 4 was observed in all cases. particles supported on alumina[46,47] and ceria,[48,49] and
The methyl group was labeled with HCOOD and others assumed its existence in their mechanistic
10 DCOOD, but not with DCOOH. Similarly, recovered conceptions of heterogeneous Au-catalyzed hydro-
11 substrate underwent deuteration of the methyl group genations.[26,27,40]
12 with HCOOD and DCOOH. At a higher conversion
The substrate can possibly interact with the support
13 (40–50%), position 3 was deuterated to a considerable via hydrogen bonding between the heteroatoms.[7,26,27]
14 extent with both HCOOD and DCOOD, however, in Supposing that the gold hydride is formed, a hydride
15 this case DCOOH also caused mild deuteration. addition on the captured substrate can proceed in a
16 Moreover, the 2-position was labeled not only with metal-support cooperative mechanism.[7,47]
17 DCOOH and DCOOD, but also with HCOOD.
18 Position 4 again exhibited only slight deuteration. The
19 methyl groups of both substrate and product were
Conclusion
20 deuterated in all cases. A separate experiment (Fig- As an Update to the recent works focused mainly on
21 ure S9) showed the substrate’s methyl group was quinolines and isoquinolines,[26,28,29] this study shows
22 deuterated even in the absence of catalyst A, where that also silica-supported gold nanoclusters can utilize
23 HCOOD and DCOOD (“D+” acids) caused signifi- formic acid, a cheap and readily available hydrogen
24 cant deuteration, but DCOOH only minor labeling. donor, in highly efficient transfer hydrogenation of a
25 The isotope labeling experiments at low conversion wide range of N-heterocyclic compounds. Using this
26 show the clear preference of position 2 for hydride methodology on a preparative scale, a collection of
27 and 3 for proton incorporation. The labeling in fifteen saturated N-heterocycles was obtained in a
28 position 4 was very low and almost did not increase high yield and purity. After an initial deactivation,
29 towards higher conversion.
caused by particle sintering to about ~4.5 nm in the
30
The findings thus imply that the 1,2-addition path- presence of formic acid, stable conversion was reached
31 way is the main one (Scheme 3), while the 1,4- in five consecutive cycles. Selective isotope-labeling of
32 addition, principal in some homogeneous systems,[4- formic acid identified multiple reaction pathways in
33 c,e,l,m,36] proceeds to a minor extent. As the 1,2-addition the transfer hydrogenation of 2-methylquinoline,
34 path contains the disproportionation step, we hydro- where the 1,2-addition of hydride with consecutive
35 genated a 1:1 mixture of 3 and 1,2-diH-3 to verify it disproportionation of the resulting 1,2-dihydroquino-
36 (Scheme S1). Without the catalyst, 1,2-diH-3 was line dominates.
37 consumed by disproportionation, thus increasing the
On the whole, the fine-structured silica-based
38 amount of substrate 3, while with A the substrate catalyst, broad substrate scope, and detailed reaction
39 almost fully reacted.
mechanism study make this Update a timely contribu-
tion to the exciting and rapidly developing field of fine
chemical synthesis aided by heterogeneous gold
catalysis.
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Experimental Section
General
Reactions with air- or moisture and oxygen sensitive
materials were carried out under argon atmosphere using
standard Schlenk techniques. All solvents were dried on a
column of activated alumina, and stored in presence of
activated molecular sieves (4 ꢂ). NMR spectra of liquid
solutions were recorded on Bruker 500, 400, 300 and
200 MHz spectrometers at ambient temperature. 1HNMR
spectra were referenced to the residual solvent signals (dH
2.50 ppm for DMSO-d6, dH 7.26 ppm for CDCl3), 13C spectra
were referenced to the deuterated solvents (dC 39.5 ppm for
DMSO-d6, dC 77.0 ppm for CDCl3), and 19F spectra were
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Scheme 3. Schematic representation of the preferred path-
way of transfer hydrogenation of 3 catalyzed by A.
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Some parallels can be drawn based on similarity
56 with existing heterogeneous systems. Firstly, the
57 formic acid protonates the basic sites (triethylamine,
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referenced to internal or external CFCl3 (dF 0.0 ppm). High
resolution MS spectra (HRMS) were recorded on a Bruker
maXis using electrospray ionization (ESI). Z-contrast scan-
ning transmission electron microscopy (ZC-STEM) images
were acquired on an aberration-corrected Hitachi HD-
2700CS with cold field emission gun, HAADF detector, and
an acceleration voltage of 200 kV. The particle size analysis
was done using the ImageJ software (imagej.net). The gold
content was determined by atomic absorption spectroscopy
(AAS, Varian SprectrAA 220 FS) or inductively coupled
plasma optical emission spectroscopy (ICP-OES, Horiba
Ultima 2). PXRD analysis was measured at room temper-
ature on D8 Advance Bruker AXS diffractometer with Cu
Catalyst B: NH2-SBA-15 (300 mg) was suspended in water
(25 mL) [pH was 8.94]. Chloroauric acid (HAuCl4·3H2O)
(24.5 mg, 0.062 mmol) was added to the reaction mixture
[pH was 3.01]. The suspension was stirred for 60 min at RT
[after 1 h pH was 3.18]. Sodium citrate dihydrate (130.4 mg,
0.61 mmol) was added [pH was 3.75]. The suspension was
stirred at 808C for 30 minutes [pH was 3.72], the solid was
filtered, washed repeatedly with water, and dried under
vacuum at room temperature under exclusion of light,
affording a purple solid. Yield: 188 mg.
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Catalyst C: SBA-15 was activated overnight at 1008C under
vacuum. SBA-15 (600 mg) was suspended in water (40 mL)
[pH was 5.97]. The pH was elevated to 9.48 by adding
aqueous K2CO3. Chloroauric acid (HAuCl4·3H2O) (49 mg,
0.124 mmol) was added to the reaction mixture [pH was
5.49]. The pH was adjusted again to 9.47 and the suspension
was stirred for 60 min at RT [after 1 h pH was 8.97]. Sodium
citrate dihydrate (260.9 mg, 1.22 mmol) was added [pH was
5.52] and the pH was adjusted back to 9.42. The suspension
was stirred at 808C for 30 minutes [pH was 9.2], the solid
was filtered, washed repeatedly with water, and dried under
vacuum at room temperature under exclusion of light,
affording a slightly purple solid. Yield: 496 mg.
13 Ka radiation. IR spectra were recorded on a Nicolet iS50
FT-IR. BET and Langmuir surface areas were obtained using
a Micromeritics Tristar II 3020 equipped with a VacPrep 061
degassing station. GC-MS analyses were carried out on
Agilent 7693/7890 GC equipped with Agilent HP-5MS
column (30 m, 0.25 mm, 0.25 mm), Agilent 5975C Triple-Axis
MSD detector and helium as the carrier gas.
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Synthesis of materials
SBA-15: A 3 L Teflon autoclave was charged with Pluronicꢃ
P-123 (16 g), 2 M HCl (480 g) and water (120 g), and the
mixture was stirred at 358C for 3 h. Tetraethyl orthosilicate
(34 g, 36.4 mL) was added, and the mixture was stirred at
358C for 5 min. Then the stirring was stopped and the
reaction mixture was kept at 358C for 20 h and 808C for
24 h. After cooling down to RT, the white solid was filtered
off on sintered glass, washed with water (ca. 33 volume of
the autoclave until reaching neutral pH), dried at 808C for
8 h, and calcined in a muffle furnace at 5508C for 6 h with a
ramp of 18C/min. Rehydroxylation was done in boiling water
for 8 h under reflux. Drying at 1108C gave the parent SBA-
15 support. Yield: 9.9 g.
Catalyst D: SBA-15 was activated overnight at 1008C under
vacuum. SBA-15 (300 mg) was suspended in water (20 mL)
[pH was 5.17]. The pH was elevated to 10.8 by adding
solution of NH4OH. Chloroauric acid (HAuCl4·3H2O)
(24.5 mg, 0.062 mmol) was added to the reaction mixture
[pH was 10.46]. The pH was adjusted again to 10.9 and the
suspension was stirred for 60 min at RT [after 1 h pH was
10.63]. Sodium citrate dihydrate (130.4 mg, 0.61 mmol) was
added [pH was 10.45] and the pH was adjusted back to 10.87.
The suspension was stirred at 808C for 30 minutes, the solid
was filtered, washed repeatedly with water, and dried under
vacuum at room temperature under exclusion of light,
affording a slightly yellow solid. Yield: 215 mg.
NH2-SBA-15: SBA-15 was dried at 4008C in a muffle furnace
for 7 h, and at 2208C overnight under vacuum. Dried SBA-
15 (3.4 g) was mixed with (3-aminopropyl)triethoxysilane
(2.9 mL, 12.2 mmol) and anhydrous toluene (79 mL), and the
mixture was refluxed for 8 h. After cooling down to RT, the
mixture was stirred at RT overnight. Water (13 mL) was
added and the mixture was stirred for 4 h at RT. The material
was filtered on sintered glass and washed with toluene (33
35 mL) and water (500 mL). The white solid was dried at
2008C for 1 h at atmospheric pressure while stirring, under
vacuum at 2008C for 5 h, and under vacuum at RT overnight.
Yield: 3.9 g.
Catalyst E: SBA-15 was activated overnight at 1008C under
vacuum. SBA-15 (600 mg) was suspended in water (40 mL)
[pH was 5.23]. Chloroauric acid (HAuCl4·3H2O) (49 mg,
0.124 mmol) was added to the reaction mixture [pH was
2.75]. The suspension was stirred for 60 min at RT [after 1 h
pH was 2.53]. Sodium citrate dihydrate (260.9 mg,
1.22 mmol) was added [pH was 3.71]. The suspension was
stirred at 808C for 30 minutes [pH was 3.42], the solid was
filtered, washed repeatedly with water, and dried under
vacuum at room temperature under exclusion of light,
affording a dark red solid. Yield: 546 mg.
Catalyst F: NH2-SBA-15 (200 mg) was suspended in water
(20 mL) [pH was 9.02]. The pH was elevated to 9.5 by adding
aqueous K2CO3. Chloroauric acid (HAuCl4·3H2O) (2.4 mg,
0.006 mmol) was added to the reaction mixture [pH was
8.92]. The pH was adjusted again to 9.45 and the suspension
was stirred for 60 min at RT [after 1 h pH was 9.45]. Sodium
citrate dihydrate (13.0 mg, 0.0609 mmol) was added [pH was
7.47] and the pH was adjusted back to 9.55. The suspension
was stirred at 808C for 30 min [pH was 9.1], the solid was
filtered, washed repeatedly with water, and dried under
vacuum at room temperature under exclusion of light,
affording an off-white solid. Yield: 146 mg.
Catalyst A: NH2-SBA-15 (300 mg) was suspended in water
(20 mL) [pH was 9.22]. The pH was elevated to 9.5 by adding
aqueous K2CO3. Chloroauric acid (HAuCl4·3H2O) (24.5 mg,
0.062 mmol) was added to the reaction mixture [pH was
4.00]. The pH was adjusted again to 9.47 and the suspension
was stirred for 60 min at RT [after 1 h pH was 9.04]. Sodium
citrate dihydrate (130 mg, 0.61 mmol) was added [pH was
5.07] and the pH was adjusted back to 9.45. The suspension
was stirred at 808C for 30 min [pH was 8.94], the solid was
55 filtered, washed repeatedly with water, and dried under
vacuum at room temperature under exclusion of light,
affording a slightly yellow solid. Yield: 264 mg.
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[3] J. G. Catalano, K. S. Gudmundsson, A. Svolto, S. D.
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General Procedures: Hydrogenation and
Deformylation
Boggs, J. F. Miller, A. Spaltenstein, M. Thomson, P.
Wheelan, D. J. Minick, D. P. Phelps, S. Jenkinson,
Bioorg. Med. Chem. Lett. 2010, 20, 2186–2190.
Hydrogenation: Formic acid (relevant amount), triethyl-
amine (293 mL, 2.10 mmol), anhydrous dimethylformamide
(2.2 mL), catalyst A (27.2 mg, 0.004 mmol) and substrate
(0.4 mmol) were placed in a round-bottom flask. The
reaction mixture was stirred at 1308C for 3 h. After cooling
down to RT, the mixture was filtered and pH was adjusted to
13–14 by adding 20% aqueous NaOH. The mixture was
extracted with dichloromethane (53 15 mL), ethyl acetate
(23 5 mL), the combined organic layers were washed with
brine (53 20 mL), dried over NaSO4, filtered, and concen-
trated to dryness.
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Deformylation: 20% aqueous NaOH (5 mL) and ethanol
(8 mL) were added, and the mixture was stirred at 1008C for
16 1.5 h. After cooling down to RT, the mixture was extracted
to dichloromethane (53 15 mL), ethyl acetate (23 5 mL),
washed with brine (33 20 mL), dried over NaSO4, filtered,
and anchored on Celite. The amine product was isolated by
automated flash column chromatography.
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Hydrogenation and deformylation on a large scale:
The general procedures described above were scaled up as
follows: formic acid (5.7 mL, 0.15 mol), triethylamine
(3.7 mL, 26 mmol), anhydrous DMF (27 mL), catalyst A (291
mg, 0.05 mmol), and 1 (0.59 mL, 5.0 mmol).
Hydrogenation with deuterated formic acid: Formic acid
(85 mL, 2.25 mmol), triethylamine (110 mL, 0.79 mmol), anhy-
drous dimethylformamide-d7 (0.75 mL), catalyst A (14.8 mg,
0.0015 mmol) and quinaldine (20.3 mL, 0.15 mmol) were
placed in a round-bottom flask. The reaction mixture was
stirred at 1308C for 5 h. After cooling down to RT, the
mixture was filtered, extracted with dichloromethane (53
15 mL), ethyl acetate (23 5 mL), the combined organic layers
were washed with brine (53 20 mL), dried over NaSO4,
filtered, and anchored on Celite. The amine product was
isolated by automated flash column chromatography.
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Acknowledgements
The authors thank Dr. Frank Krumeich from the Electron
¨
Microscopy Center of ETH Zurich (EMEZ) for the trans-
mission microscopy imaging, and Dr. Vitaly Sushkevich for
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Silica Catalyze Transfer Hydrogenation of N-Heterocy-
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