Reliable and safe, gram-scale hydrogenation and hydrogenolysis of O-benzyl ether groups with in situ Pd0/C catalyst

Article abstract of DOI:10.1055/s-0030-1260167

Hydrogenation of alkenes, alkynes, and hydrogenolysis of O-benzyl ethers with Pd⁰/C catalyst generated in situ can be readily scaled up under safer conditions than with traditional procedures. The precise control of the palladium loading and the mild conditions developed allow the formation of a very active and reliable Pd⁰/C catalyst, leading to highly reproducible results. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260167

PRACTICAL SYNTHETIC PROCEDURES
2893
Reliable and Safe, Gram-Scale Hydrogenation and Hydrogenolysis of
O-Benzyl Ether Groups with In Situ Pd0/C Catalyst
H
ydrogenation
r
s
a
nd H
a
n
sis
w
ith
P
d
0/CçCatalyst ois-Xavier Felpin,*a,b,1 Eric Fouqueta
a
Université de Bordeaux, CNRS-UMR 5255, Institut des Sciences Moléculaires, 351 cours de la Libération, 33405 Talence, France
Université de Nantes, UFR Sciences et Techniques, UMR CNRS 6230, CEISAM,
2 rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3, France
b
Fax +33(5)40006286; E-mail: fx.felpin@univ-nantes.fr
Received 1 July 2011; revised 28 July 2011
PSP
No207
Abstract: Hydrogenation of alkenes, alkynes, and hydrogenolysis of O-benzyl ethers with Pd0/C catalyst generated in situ can be readily
scaled up under safer conditions than with traditional procedures. The precise control of the palladium loading and the mild conditions de-
veloped allow the formation of a very active and reliable Pd0/C catalyst, leading to highly reproducible results.
Key words: hydrogenation, hydrogenolysis, palladium, charcoal, gram-scale synthesis
procedure 1
Pd(OAc)2 (0.05 mol%)
H2, charcoal
i-PrOH, 25 °C, 20 h
1a
1b
2a, 17.9 g, 98% yield
procedure 2
Pd(OAc)2 (2 mol%)
H2, charcoal
i-PrOH–THF (1:1)
25 °C, 72 h
2b, 38.0 g, 98% yield
HO
H
HO
procedure 3
O
O
Pd(OAc)2 (0.1 mol%)
H2, charcoal
O
O
OH
Cbz
OH
NH2
i-PrOH–H2O (1:1)
25 °C, 24 h
O
HN
1c
O
2c, 9.35 g, 99% yield
Scheme 1 Typical procedures for hydrogenations and hydrogenolyses
Metal-mediated reductive processes, including hydroge- commercial Pd/C catalysts due to the unpredictable qual-
nation and hydrogenolysis, are indispensable methods in ity of batches. Moreover, the random distribution and size
the tool box of synthetic chemists.2 Among the different of palladium nanoparticles on the charcoal frequently led
metals that are active in reductive processes, palladium to discrepancies in the catalytic activity, forcing chemists
supported on activated carbon (Pd/C) catalysts have be- to frequently use high loadings of catalysts (~5 mol%).
come a standard in both industrial and academic laborato-
In order to address these issues, we devised a cost-effec-
ries.3 For instance, it is estimated that approximately 75%
tive and reliable procedure for hydrogenations and hydro-
of industrial hydrogenations involves the use of a Pd/C
genolyses by taking advantage of a Pd0/C catalyst
catalyst. The denomination ‘Pd/C’ is quite evasive and
generated in situ with perfectly controlled properties.5 The
confusing because Pd/C catalysts can have many different
Pd0/C catalyst was generated in situ by reduction of palla-
forms, according to the palladium loading, size distribu-
dium(II) acetate, one of the cheapest sources of palladium,
tion, dispersion, and degree of oxidation. The nature of the
followed by deposition of the palladium nanoparticles
charcoal (i.e., surface area, porosity, water content, etc.)
formed onto charcoal during the reaction. By using such
may also have a role in the catalytic efficiency.4 Unfortu-
an approach, we observed a high level of reproducibility
nately, these important properties are rarely available for
because the properties of Pd0/C are perfectly controlled.
Moreover, we also observed that the quality of palladi-
um(II) acetate is relatively consistent over time, regard-
less of the commercial source.
SYNTHESIS 2011, No. 18, pp 2893–2896
Advanced online publication: 10.08.2011
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x.
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2
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DOI: 10.1055/s-0030-1260167; Art ID: T66211SS
© Georg Thieme Verlag Stuttgart · New York

2894
F.-X. Felpin, E. Fouquet
PRACTICAL SYNTHETIC PROCEDURES
In this paper, we report our optimisation studies for gram- of the reducible substrate (Scheme 1).6 For compounds
scale (50–100 mmol) hydrogenations of alkenes and that are fairly soluble in isopropanol, procedure 1 was de-
alkynes as well as hydrogenolyses of O-benzyl ethers.
veloped. On the other hand, with substrates that are insol-
uble in isopropanol, we observed irreproducible results
with this procedure due to difficulties with stirring. After
extensive solvent screening it was found that, for highly
lipophilic compounds, tetrahydrofuran could be added as
co-solvent (procedure 2), whereas for hydrophilic com-
pounds, water should be preferred as co-solvent
(procedure 3). We opted for palladium(II) acetate as pal-
ladium source instead of palladium(II) chloride because it
is highly soluble in most organic solvents and does not
produce salts that would need to be be specifically treated
on industrial scales and that could react with sensitive
functional groups.
Under our original conditions on a laboratory scale (1–
5 mmol), we used methanol as the sole solvent. However,
although setting up and starting the reaction did not re-
quire special handling, because Pd/C was formed in situ
from palladium(II) acetate and charcoal, the filtration step
proved to be more risky. Indeed, Pd/C is highly pyro-
phoric and even spontaneously flammable in the presence
of oxygen and methanol vapours. To address this issue for
multigram-scale procedures, we selected isopropanol as
solvent instead of methanol. Moreover, we also observed
that, for substrates that are weakly soluble in alcoholic
solvents, the stirring process can be interrupted, particu-
larly in gram-scale syntheses. Based on these observa- With these three procedures in hand, we screened the re-
tions, we revisited our procedure and we are now able to duction of a representative variety of alkenes, alkynes,
propose three different procedures according to the nature and O-benzyl ethers on multigram scales (50–100 mmol;
Table 1 Reduction of Alkenes, Alkynes, and O-Benzyl Ethers
Entry Substrate
Product
Procedure Scale
Pd loading Time Yield
(mmol) (mol%)
(h)
(%)
1
2
3
1a
1b
1c
2a
1
2
3
100
100
50
0.05
20
98
2b
2
72
24
98
99
HO
HO
H
O
O
O
2c
O
0.05
OH
Cbz
OH
O
HN
O
NH2
CO2Me
CO2Me
4
5
1d
1e
2d
2e
1
1
100
100
0.1
0.1
48
15
98
92
OH
OH
6
7
1f
2f
1
1
100
100
0.05
0.1
22
14
97
99
O
O
1g
2g
OBn
OH
8
9
1h
1i
2h
2i
3
1
50
0.05
0.3
15
48
99
97
CO2H
CO2H
N
N
H
Cbz
CO2Bn
CO2H
100
Synthesis 2011, No. 18, 2893–2896 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Hydrogenations and Hydrogenolysis with Pd0/C Catalyst
2895
Table 1). The reduction of unhindered alkynes and alk- In summary, we have reported scalable procedures for the
enes using procedure 1 was carried out with very low hydrogenation of alkenes and alkynes, as well as hydro-
loading of palladium (0.05–0.1 mol%) at room tempera- genolysis of O-benzyl ethers. The main procedure in-
ture under one atmosphere of hydrogen (Table 1, entries 1 volves the formation of a highly active Pd0/C catalyst in
and 3–9). Similarly, O-benzyl ether cleavage proceeded situ from palladium(II) acetate and charcoal in isopro-
smoothly to give the corresponding alcohol (entry 5), acid panol. However, with weakly soluble substrates in isopro-
(entry 7), or amine (entries 3 and 8). With substrates hav- panol, we recommend the use of a co-solvent in order to
ing multiple reduction sites, such as benzyl cinnamate ensure good stirring and reproducible results. For lipo-
(1i), procedure 1 still proved to be very efficient. On the philic compounds, tetrahydrofuran has been found to be
other hand, hydrogenation of highly lipophilic cholesterol an excellent co-solvent, whereas with hydrophilic com-
1b into 5a-cholestan-3b-ol 2b required tetrahydrofuran as pounds, water should be preferred. These procedures al-
co-solvent for convenient stirring (procedure 2). With low the isolation of reduced compounds with high purity
such a challenging olefin, a higher loading (2 mol%) was that are free of palladium residues, and should find appli-
required, but, compared to literature precedents reported cations for biologically active compounds for which metal
on laboratory scales, this catalytic system is still very contamination is closely monitored.
competitive.7 With highly hydrophilic substrates, the ad-
dition of water as co-solvent did not hamper the catalytic
All reactions were carried out under a hydrogen atmosphere
activity and avoided the precipitation of the deprotected
amino acids 2c and 2h into the solvent. All compounds re-
ported in Table 1 were isolated in high purity (>98%; de-
(1 atm). All starting materials were commercially available and
used as received without further purification. The progress of the re-
actions were monitored by TLC analyses and by 1H NMR analysis
of the crude mixture. 1H and 13C NMR spectra were recorded with
a Bruker Avance 300 spectrometer; chemical shifts were referenced
using residual solvent peak. Yields refer to isolated compounds es-
timated to be >98% pure as determined by 1H NMR spectroscopic
1
termined by H NMR and HPLC analyses) after simple
filtration over a nylon membrane followed by evaporation
of volatiles.
We also analysed the content of palladium residues in the and HPLC analyses. HPLC analyses were performed with a Luna
5 mm C18–2 column (Phenomenex), 250 × 46 mm; flow rate: 1 mL/
isolated product by inductively coupled plasma mass
spectrometry (ICP-MS). To our great pleasure, the con-
centration of residual palladium species polluting the
products typically ranged from 0.4 to 16.8 ppb, indicating
that 99.9% of palladium initially introduced had been ad-
sorbed onto the charcoal (Table 2). The only exceptions
observed concerned amino acids 2c and 2h, for which we
found, respectively, 10.6 and 6.7 ppm metal residue. The
discrepancy could be explained by the amino acid func-
tion that could act as a pincer ligand for palladium. We ex-
plained the high activity and reproducibility of our
catalytic system by the excellent control in the dispersion,
size distribution, and spherical shape of the palladium
nanoparticles adsorbed on charcoal.5
min; UV detection (254 nm).
Dibenzyl (2a); Typical Procedure 1
To a stirred solution of stilbene (1a; 18 g, 100 mmol) in i-PrOH (120
mL) were added charcoal (100 mg, 90% wt/Pd) and Pd(OAc)2 (11.2
mg, 0.05 mol%) at 25 °C. The resulting mixture was stirred for 20 h
at 25 °C under H2 (1 atm) and then filtered. The catalyst was
washed with EtOAc (2 × 15 mL) and the clear solution was concen-
trated under reduced pressure to give dibenzyl (2a) with high purity
after filtration.
Yield: 17.9 g (98%); white solid; mp 52 °C (Lit.8 51 °C); HPLC
(MeCN–H2O, 80:20): tR = 9.33 min.
1H NMR (CDCl3, 300 MHz): d = 3.06 (s, 4 H), 7.30–7.44 (m,
10 H).5
5a-Cholestan-3b-ol (2b); Typical Procedure 2
To a stirred solution of cholesterol 1b (38.6 g, 100 mmol) in i-PrOH
(60 mL) and THF (60 mL) were added charcoal (4 g, 90% wt/Pd)
and Pd(OAc)2 (448 mg, 2 mol%) at 25 °C. The resulting mixture
was stirred for 72 h at 25 °C under H2 (1 atm) and then filtered. The
catalyst was washed with EtOAc (2 × 15 mL) and the clear solution
was concentrated under reduced pressure to give 5a-Cholestan-3b-
ol 2b with high purity after filtration.
Table 2 Palladium Content in the Isolated Product Measured by
ICP-MS
Entry
Product
Procedure
Pd loading ICP-MS
(mol%)
0.05
2
(ppb)
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
1
2
3
1
1
1
1
3
1
1.1
Yield: 38.0 g (98%); white solid; mp 141 °C (Lit.9 141 °C).
0.4
1H NMR (CDCl3, 300 MHz): d = 0.59–0.69 (m, 1 H), 0.66 (s, 3 H),
0.82 (s, 3 H), 0.88 (d, J = 6.6 Hz, 6 H), 0.91 (d, J = 6.6 Hz, 3 H),
0.79–1.82 (m, 30 H), 1.94–2.00 (m, 1 H), 3.55–3.64 (m, 1 H).5
0.1
10.6 ppm
4.4
0.1
4-tert-Butyl L-Aspartate (2c); Typical Procedure 3
0.1
10.8
To a stirred solution of Z-Asp(Ot-Bu)-OH 1c (16.17 g, 50 mmol) in
i-PrOH (30 mL) and H2O (30 mL) were added charcoal (100 mg,
90% wt/Pd) and Pd(OAc)2 (11.2 mg, 0.1 mol%) at 25 °C. The re-
sulting mixture was stirred for 24 h at 25 °C under H2 (1 atm) and
then filtered. The catalyst was washed with EtOAc (2 × 10 mL) and
the clear solution was concentrated under reduced pressure to give
4-tert-butyl L-aspartate (2c) with high purity after filtration.
0.05
0.1
2.1
2g
2h
2i
11.2
0.1
6.7 ppm
16.8
0.3
Yield: 9.35 g (99%); white solid; mp 190 °C (Lit.10 177–178 °C).
Synthesis 2011, No. 18, 2893–2896 © Thieme Stuttgart · New York

2896
F.-X. Felpin, E. Fouquet
PRACTICAL SYNTHETIC PROCEDURES
Dihydrocinnamic Acid (2i)
Following procedure 1, benzyl cinnamate (1i; 23.8 g, 100 mmol) in
i-PrOH (120 mL) was reduced under H2 (1 atm) with charcoal (600
mg, 90% wt/Pd) and Pd(OAc)2 (67.2 mg, 0.3 mol%) for 48 h, into
dihydrocinnamic acid (2i), which was isolated with high purity after
filtration.
1H NMR (D2O, 300 MHz): d = 1.44 (s, 9 H), 2.91 (d, J = 5.5 Hz,
2 H), 3.96 (t, J = 5.5 Hz, 1 H).5
Methyl 3-Phenylpropanoate (2d)
Following procedure 1, methyl cinnamate (1d; 16.2 g, 100 mmol)
in i-PrOH (120 mL) was reduced under H2 (1 atm) with charcoal
(100 mg, 90% wt/Pd) and Pd(OAc)2 (11.2 mg, 0.05 mol%) for 48 h,
into dihydrocinnamic acid 2d, which was isolated with high purity
after filtration.
Yield: 14.5 g (97%); white solid; mp 46 °C (Lit.13 46.4–46.8 °C);
HPLC (MeCN–H2O, 70:30): tR = 3.42 min.
1H NMR (CDCl3, 300 MHz): d = 2.72 (dd, J = 7.0, 8.1 Hz, 2 H),
Yield: 16.1 g (98%); colourless oil; HPLC (MeCN–H2O, 70:30):
tR = 5.72 min.
2.99 (t, J = 7.5 Hz, 2 H), 7.23–7.36 (m, 5 H), 11.0 (br s, 1 H).5
1H NMR (CDCl3, 300 MHz): d = 2.64 (t, J = 7.5 Hz, 2 H), 2.99 (t,
J = 7.5 Hz, 2 H), 3.68 (s, 3 H), 7.19–7.33 (m, 5 H).5
Acknowledgment
We gratefully acknowledge the ‘Univesité de Bordeaux’, the ‘Cen-
tre National de la Recherche’, and the ‘Agence Nationale de la Re-
cherche’ (ANR JCJC 7141) for financial support of this project. We
thank M. Olivier Bruguier (Université de Montpellier) for ICP-MS
analyses.
3-Phenylpropan-1-ol (2e)
Following procedure 1, cinnamyl alcohol (1e; 13.4 g, 100 mmol) in
i-PrOH (120 mL) was reduced under H2 (1 atm) with charcoal (200
mg, 90% wt/Pd) and Pd(OAc)2 (22.4 mg, 0.1 mol%) for 15 h, into
hydrocinnamyl alcohol 2d, which was isolated with high purity af-
ter filtration.
References
Yield: 12.5 g (92%); colourless oil; HPLC (MeCN–H2O, 50:50):
tR = 5.56 min.
1H NMR (CDCl3, 300 MHz): d = 1.64 (br s, 1 H), 1.86–1.95 (m,
2 H), 2.72 (t, J = 7.5 Hz, 2 H), 3.68 (t, J = 6.4 Hz, 2 H), 7.18–7.32
(m, 5 H).5
(1) Present address: Université de Nantes.
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Hydrogenation for Organic Synthesis; Wiley: New York,
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2nd ed.; American Chemical Society: Washington DC,
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Academic Press: New York, 1985.
(3) Rylander, P. N. Hydrogenation and Dehydrogenation, In
Ullmann’s Encyclopedia of Industrial Chemistry; Wiley-
VCH: Weinheim, 2005.
(4) Chaston, J. C.; Sercombe, E. J. Plat. Met. Rev. 1961, 5, 122.
(5) Felpin, F.-X.; Fouquet, E. Chem. Eur. J. 2010, 16, 12440.
(6) Activated Carbon, Darco® G-60, 100 mesh, was used in this
study. However, we did not observe dramatic differences
with other types of charcoal.
Benzoic Acid (2g)
Following procedure 1, benzyl benzoate (1g; 21.2 g, 100 mmol) in
i-PrOH (120 mL) was hydrogenolysed under H2 (1 atm) with char-
coal (200 mg, 90% wt/Pd) and Pd(OAc)2 (22.4 mg, 0.1 mol%) for
14 h, into benzoic acid (2g), which was isolated with high purity af-
ter filtration.
Yield: 12.1 g (99%); white solid; mp 122 °C (Lit.11 121.5 °C);
HPLC (MeCN–H2O, 5:95): tR = 20 min.
1H NMR (CDCl3, 300 MHz): d = 7.49 (t, J = 7.7 Hz, 2 H), 7.63 (t,
J = 7.4 Hz, 1 H), 8.13 (d, J = 8.5 Hz, 2 H), 9.75 (br s, 1 H).5
(7) (a) Dayal, B.; Ertel, N. H.; Rapole, K. R.; Asgaonkar, A.;
Salen, G. Steroids 1997, 62, 451. (b) Akiyama, R.;
Kobayashi, S. J. Am. Chem. Soc. 2003, 125, 3412.
(c) Okamoto, K.; Akiyama, R.; Kobayashi, S. J. Org. Chem.
2004, 69, 2871. (d) Kwon, M. S.; Kim, N.; Park, C. M.; Lee,
J. S.; Kang, K. Y.; Park, J. Org. Lett. 2005, 7, 1077.
(e) Park, C. M.; Kwon, M. S.; Park, J. Synthesis 2006, 3790.
(8) Serijan, K. T.; Wise, P. H. J. Am. Chem. Soc. 1951, 73, 4766.
(9) Richer, J.-C.; Eliel, E. J. Org. Chem. 1961, 26, 972.
(10) Stein, K. A.; Toogood, P. L. J. Org. Chem. 1995, 60, 8110.
(11) Kaeding, W. W. J. Org. Chem. 1964, 29, 2556.
(12) Thimann, K. V. Biochem. J. 1930, 24, 368.
(13) Maryott, A. A.; Hobbs, M. E.; Gross, P. M. J. Am. Chem.
Soc. 1949, 71, 1671.
L-Proline (2h)
Following procedure 3, Cbz-proline 1h (g, 50 mmol) in i-PrOH (30
mL) and H2O (30 mL) was reduced under H2 (1 atm) with charcoal
(100 mg, 90% wt/Pd) and Pd(OAc)2 (11.2 mg, 0.1 mol%) for 15 h,
into proline (2h), which was isolated with high purity after filtra-
tion.
Yield: 4.98 g (99%); white solid; mp 220 °C (Lit.12 220–222 °C).
1H NMR (CD3OD, 200 MHz): d = 1.87–2.37 (m, 4 H), 3.16–3.43
(m, 2 H), 3.97 (dd, J = 6.0, 8.4 Hz, 1 H).5
Synthesis 2011, No. 18, 2893–2896 © Thieme Stuttgart · New York