Transfer hydrogenations of alkenes with formate on Pd/C: Synthesis of dihydrocinchona alkaloids

Article abstract of DOI:10.1055/s-0032-1318156

Protocols for preparative (1-80 gram scale) transfer hydrogenations of alkenes over a palladium on carbon catalyst using formic acid/ammonium formate as hydrogen donor are presented. Cinchona alkaloids have been converted to their dihydro derivatives in >94% yield. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0032-1318156

888▌
PRACTICAL SYNTHETIC PROCEDURES
pTrarctaicanl ssyfnethreticHpryocdedruroesgenations of Alkenes with Formate on Pd/C: Synthesis of
Dihydrocinchona Alkaloids
Transfer Hydrogenations with Formate
Haotian Wu, Lukas Hintermann*
Department Chemie, Technische Universität München, Lichtenbergstrasse 4, 85748 Garching bei München,
Germany
Fax +49(89)28913669; E-mail: lukas.hintermann@tum.de
PSP
Received: 08.01.2013; Accepted after revision: 14.01.2013
No246
Abstract: Protocols for preparative (1–80 gram scale) transfer hydrogenations of alkenes over a palladium on carbon catalyst using formic
acid/ammonium formate as hydrogen donor are presented. Cinchona alkaloids have been converted to their dihydro derivatives in >94%
yield.
Key words: alkaloids, alkenes, catalysis, hydrogen transfer, hydrogenation, palladium
HCO2H (3 equiv)
NH4·HCO2 (4 equiv)
OH
Pd/C (cat.)
OH
N
MeOH
50 °C, 23 h
N
N
H
94%
N
H
1–20 g scale
cinchonine (1)
dihydrocinchonine (5)
Scheme 1
The catalytic hydrogenation of alkenes over heteroge- scales and with up to 0.25 mol of the starting material.
neous metal catalysts is an important transformation in or- Specifically, in our work with cinchona alkaloids as chiral
ganic chemistry.1,2 Among the most common protocols1,2 organocatalysts,9,10 we found it desirable to convert the
is the direct reaction with hydrogen gas over a palladium characteristic alkaloid vinyl to an ethyl group11 as a simple
on carbon3 catalyst, often at elevated pressure. Pressur- means of catalyst structure variation.12 For the basic alka-
ized reactions require specialized equipment; in addition, loids, the use of formic acid alone or with added ammoni-
installation of hydrogen cylinders and work with this po- um formate recommended itself for catalytic transfer
tentially explosive gas may be subject to necessary, if la- hydrogenation (Scheme 1). Reactions in aqueous acid
borious, safety measures as defined by house rules and were tested, but this led to precipitation of the alkaloids
local legislation. To reduce the risk of fire or explosion, and incomplete reactions. Methanol was a suitable solvent
reactant solutions should be degassed prior to the addition to dissolve the alkaloids directly (quinine, quinidine) or
of catalyst and hydrogen.1 Most of those specific require- after addition of formic acid (cinchonine, cinchonidine).
ments are absent when alkene hydrogenations are per- Transfer hydrogenations over palladium on carbon pro-
formed as transfer hydrogenations,4 of which those using ceed at room temperature, but are faster when heated. For
formic acid5 or ammonium formate6 as hydrogen donors safety reasons, reactions were always started at ambient
are particularly simple and economic. A review on trans- temperature; namely, the addition of the catalyst to the
fer hydrogenations with ammonium formate did not yet concentrated formate solution induced evolution of gas,
mention examples of simple alkenes as substrates.6 In the even in the absence of substrate (presumably according to
meantime, such a procedure has been reported,7 but was HCO2H = H2 + CO2). This reaction became quite vigor-
optimized only to the 1 mmol scale.8 Over the past few ous at large scales and high concentrations of starting ma-
years, we have occasionally hydrogenated alkenes on pre- terials. A sufficiently large reaction vessel must be used to
parative scale and have unequivocally found that transfer allow for some foaming of the reaction mixture at this
hydrogenations with formate offer an operationally sim- stage.
ple work-around to direct hydrogenations in pressure
equipment. Reactions were performed on multi-gram
ammonium formate, the catalyst quantity, and the reaction
Reaction parameters such as the excess of formic acid and
temperature were optimized in a series of reactions of in-
creasing scale (100 mg, 500 mg, 1 g, 5 g alkaloid). Isola-
tion of the dihydroalkaloid products from the filtered
reaction mixtures by precipitation with aqueous ammonia
SYNTHESIS 2013, 45, 0888–0892
Advanced online publication: 14.02.2013
DOI: 10.1055/s-0032-1318156; Art ID: SS-2013-Z0022-PSP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

PRACTICAL SYNTHETIC PROCEDURES
Transfer Hydrogenations with Formate
889
was also optimized, such that products of satisfactory pu- newly ordered commercial catalysts and gave equally
rity were obtained after washing the solids with water or good results, often in shorter reaction times.13
aqueous methanol, with no need for chromatographic pu-
The examples shown in Table 1 have been optimized to
rification. The use of 3–6 equivalents each of formic acid
minimize use of catalyst, reagents, and solvent, at the cost
and ammonium formate gave good results. The excess of
of prolonged reaction times. Faster reactions can be
reagents was lowered for larger-scale reactions. Occa-
achieved by use of higher catalyst loading and excess for-
sionally, formic acid was combined with triethylamine
mate. The reaction temperature is well below the boiling
rather than ammonium formate.5 The catalyst quantity is
point of the solvent, thus simple air- rather than water-
an important parameter: a weight ratio of 1:10 (cata-
cooling of the reflux condenser is sufficient. All cinchona
alkaloids 1–4 were hydrogenated satisfactorily at 5 or 10
gram scales (Table 1, entries 1–4), or in one case also at
lyst/substrate) was sufficient in most cases, whereas a
ratio of 1:20 often was not. In case of incomplete conver-
sion, the addition of more formate or the use of prolonged
the 20 gram scale (cinchonine; not shown). The hydroge-
reaction times was not overly helpful, but the addition of
nation of cinchonidine was successfully repeated by un-
additional catalyst (and formate) would usually solve the
dergraduate students in a synthetic laboratory course.14
problem. Typically, a catalyst/substrate ratio of 1:15
For quinine (entry 3), the reaction mixture was diluted
(w/w) was chosen, or of 1:10 in nonoptimized cases with
with water, because the alkaloid/formic acid solution in
new substrates. All catalysts were commercial palladium
methanol started to crystallize after addition of ammoni-
on carbon products with 5–10% of Pd content,13 some of
um formate.
considerable age. A few experiments were repeated with
Table 1 Preparative-Scale Transfer Hydrogenations of Various Alkenes over Palladium on Carbon Catalysta
Entry
Substrate
Scale
(g)
MeOH
(mL)
Cat.b
(w/w)
AF + FAc Temp
Time
(h)
Product
Yield
(%)d
(equiv)
(°C)
OH
OH
N
N
1
10
10
50
50
1/15
1/15
4 + 3
50
23
26
94
96
N
H
N
H
5
cinchonine (1)
N
N
2
4 + 3
50
OH
OH
N
N
cinchonidine (2)
6
OMe
OMe
N
OH
N
20 + 10
(H2O)e
3
5
1/15
4 + 5
55
26
98
OH
N
N
quinine (3)
7
OMe
OMe
OH
OH
4
5
5
50
1/15
1/16
4 + 3
50
23
95
96
N
N
N
H
N
H
quinidine (4)
8
Ph
Ph
Ph
P
Ph
P
81.3
150
3.8 + 3.2 45
4
O
O
Et2N
Et2N
9
10
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 888–892

890
H. Wu, L. Hintermann
PRACTICAL SYNTHETIC PROCEDURES
Table 1 Preparative-Scale Transfer Hydrogenations of Various Alkenes over Palladium on Carbon Catalysta (continued)
Entry
Substrate
Scale
(g)
MeOH
(mL)
Cat.b
(w/w)
AF + FAc Temp
Time
(h)
Product
Yield
(%)d
(equiv)
(°C)
MeO
MeO
6
7
5
5
50
50
1/10
1/10
5 + 3
60
36
5
85
90
11
12
CO2Me
NHAc
CO2Me
NHAc
Ph
Ph
6 + 3
6 + 3
50
50
13
14
O
O
8
5
50
1/10
16
(48)f
HO
HO
16
15
a Reactions were performed according to the general procedure with given amounts of reagents and solvents; see experimental part.
b Weight ratio of 10% Pd on carbon catalyst relative to starting material is given.
c AF = ammonium formate, FA = formic acid.
d Yield of materials directly crystallized or extracted from the reaction mixture with satisfactory purity, as documented by 1H NMR spectra (see
the Supporting Information).
e Addition of H2O for complete solubilization of starting materials.
f Yield after TEMPO-oxidation of the crude product; see text.
The meso-2,5-dihydro-1H-phosphole-1-oxide (9) (entry the desired raspberry ketone 16, albeit in unsatisfactory
5), readily prepared by McCormack cycloaddition from yield (entry 8). This was somewhat disappointing, since
Et2NPCl2, AlCl3 and (E,E)-1,4-diphenylbuta-1,3- successful (transfer) hydrogenations of 15 over palladium
diene10,15 is a useful starting material in the synthesis of have been reported.17
phospholane ligands.15 Hydrogenation over Pd/C to phos-
In conclusion, transfer hydrogenations of alkenes with
formic acid/ammonium formate over a heterogeneous
palladium on carbon catalyst are operationally simple
pholane 10 at a pressure of 50 bar has been reported,15 but
we wished to develop a transfer hydrogenation instead. In
view of the sensitivity of 9 to bases, which induce isomer-
when compared to hydrogenations with H2 (g). They can
ization to conjugated 2-phospholenes, the presence of ex-
be performed on preparative scales in simple glassware, at
cess formic acid is advantageous to buffer the reaction
ambient pressure in air. Compared to homogeneous pro-
medium. When ammonium formate is the exclusive hy-
cedures,8 both the reaction setup and the purification of
drogen donor, it decomposes to CO2 (g) and dissolved
products are very simple, while the catalyst loading with
respect to palladium is similar (1–2 mol%). The dihydro-
NH3, generating a basic reaction medium. Ammonium
carbonate is occasionally observed in such reactions since
cinchona alkaloids can be synthesized in a simple manner
it crystallizes in the reflux condenser. In the presence of
without the need for pressure equipment, and the method
should have wider applicability. For new substrates, start-
ing with a catalyst/substrate ratio of 1:10 (w/w), and use
formic acid, 9 was successfully hydrogenated to 10, ini-
tially at the 1 gram, then the 5 gram, and eventually at 80
gram scale (entry 5) without isomerization. The high con-
of 3–5 equivalents each of formic acid and ammonium
centration of starting material ensured a short reaction
formate is recommended.
time.
Other compounds of interest were submitted to the trans-
All reactions were performed in round-bottom glass flasks with a
fer hydrogenation conditions, including anethole (11) (en-
try 6) and methyl α-acetamidocinnamate (13) (entry 7). A
catalyst to substrate ratio of 1:10 was chosen with no fur-
ther reaction optimization to give very satisfactory yields
of 12 or 14, respectively, with no need for chromatogra-
phy. A limitation of the method became apparent in the
hydrogenation of unsaturated ketone 15 to raspberry ke-
tone 16; the latter has recently been obtained by an elegant
organocatalytic transfer hydrogenation.16 Transfer hydro-
genation of 15 with formate over palladium gave a mix-
ture of product and over-reduced 4-arylbutan-2-ol;
oxidation of the crude mixture with NaOCl/TEMPO gave
mounted air-cooled reflux condenser open to air. Solvents were of
technical quality and were distilled before use. Starting materials,
reagents, and catalysts were commercial products unless otherwise
mentioned. Technical quality formic acid (98%) and ammonium
formate were used as received.
Caution! Dry, active Pd/C catalyst can produce sparks with solvent
vapors. Use of wetted catalyst is recommended. The addition of the
catalyst to the reaction mixture induces decomposition of formate,
which can produce considerable foaming at large scales. Catalyst
addition should always take place at r.t., and a reaction vessel with
sufficient empty volume above the reaction mixture must be used.
New reactions should be scaled up stepwise. Reaction vessels must
not be closed tightly to prevent the building of overpressure.
Synthesis 2013, 45, 888–892
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Transfer Hydrogenations with Formate
891
Transfer Hydrogenation of Cinchona Alkaloids; General Pro-
cedure
H2O (10 mL) was added to the suspension to give a homogeneous
solution. The mixture was cooled to r.t., and 10% Pd/C catalyst (333
mg) was added. After stirring for 1 h at r.t., the mixture was gradu-
ally heated to 50 °C and stirred for 26 h at that temperature. Reac-
tion progress was followed by TLC (EtOAc–MeOH–Et3N, 25:1:1).
After cooling to r.t., formic acid (0.74 g, 16 mmol) was added drop-
wise to the mixture with vigorous stirring. The reaction mixture was
filtered through a 1.5 cm layer of Celite in a 125 mL glass filter fun-
nel and the filter was washed with MeOH (20 mL). The filtrate was
evaporated (rotary evaporator) to leave a viscous liquid. To this was
slowly added concd (28–30%) aq ammonia (30 mL) with stirring,
and CH2Cl2 (50 mL) was added to the suspension after cooling to
r.t. (note). The organic phase was collected and the aqueous phase
was extracted with CH2Cl2 (2 × 30 mL). The combined organic
phases were washed with concd aq ammonia (30 mL) and H2O
(2 × 30 mL), dried (Na2SO4), filtered, and the filtrate concentrated
to give a slightly yellow solid (4.90 g, 98%); mp 171.0–171.5 °C.
To a stirred solution of the alkaloid (10.00 g, 34.0 mmol for cincho-
nine or cinchonidine; 30.8 mmol for quinine or quinidine) in MeOH
(50 mL) was added formic acid (4.70 g, 102 mmol, 3 equiv) drop-
wise with vigorous stirring at r.t. Ammonium formate (8.60 g, 136
mmol, 4 equiv) and 10% Pd/C (667 mg) were then added consecu-
tively. After 1 h, the reaction mixture was slowly heated to 50 °C
and stirred at that temperature for 23–26 h. Reaction progress was
followed by TLC (EtOAc–MeOH–Et3N, 20:1:1–30:1:1). After
cooling, formic acid (1.60 g, 34 mmol) was added dropwise to the
mixture with vigorous stirring to dissolve the precipitated product.
The mixture was filtered through a 1.5 cm layer of Celite in a 125
mL glass filter funnel and the filter was washed with MeOH (30
mL). The filtrate was evaporated to dryness (rotary evaporator) and
H2O (10 mL) was added to the residue. Concd (28–30%) aq ammo-
nia (50 mL) was slowly dropped into the vigorously stirred suspen-
sion to complete precipitation of the product (warming). The
mixture was stirred for 15 min with cooling to attain r.t. Filtration
and washing of the solid with H2O (50 mL; note a) gave a white
powder, which was collected and dried to constant weight in a ven-
tilated oven at 45 °C (note b).
Note: Isolation of dihydroquinine by filtration was not viable, since
the product did not form a nicely crystalline precipitate. In such
cases, isolation by extraction is generally recommended.
1H NMR (250 MHz, CDCl3): δ = 0.80 (t, J = 7.3 Hz, 3 H), 1.16–
1.32 (m, 2 H), 1.33–1.45 (m, 2 H), 1.46–1.56 (m, 1 H), 1.61–1.82
(m, 3 H), 2.32–2.40 (m, 1 H), 2.49–2.75 (m, 1 H), 2.91–3.18 (m, 2
H), 3.26–3.53 (m, 1 H), 3.76 (s, 1 H), 3.90 (s, 3 H), 5.49 (d, J = 4.3
Hz, 1 H), 7.25 (d, J = 2.7 Hz, 1 H), 7.31 (dd, J = 9.2, 2.7 Hz, 1 H),
7.48 (d, J = 4.5 Hz, 1 H), 7.96 (d, J = 9.2 Hz, 1 H), 8.62 (d, J = 4.5
Hz, 1 H).
Notes: a) The washing with H2O was continued until the product
represents a homogeneous fine powder. The washing removes for-
mate salt and formamide impurities. b) Constant weight was at-
tained after drying overnight.
Dihydrocinchonine (5)
Yield: 9.38 g (94%); white powder; mp 270.1–270.6 °C.
13C NMR (91 MHz, CDCl3): δ = 12.1, 21.4, 25.5, 27.7, 28.3, 37.5,
43.3, 55.7, 58.6, 59.7, 72.0, 101.4, 118.4, 121.4, 126.6, 131.4,
144.1, 147.5, 148.0, 157.7.
1H NMR (250 MHz, CDCl3): δ = 0.87 (t, J = 7.1 Hz, 3 H), 1.19–
1.33 (m, 1 H), 1.35–1.42 (m, 2 H), 1.43–1.62 (m, 2 H), 1.70 (s, 1 H),
1.75–2.01 (m, 2 H), 2.68–2.80 (m, 1 H), 2.88–2.91 (m, 2 H), 3.12
(td, J = 9.2, 5.0 Hz, 2 H), 5.66 (d, J = 5.0 Hz, 1 H), 7.47–7.57 (m, 1
H), 7.60 (d, J = 4.5 Hz, 1 H), 7.65–7.76 (m, 1 H), 8.03 (d, J = 8.1
Hz, 1 H), 8.13 (d, J = 8.1 Hz, 1 H), 8.90 (d, J = 4.5 Hz, 1 H).
(1s,2R,5S)-1-(Diethylamino)-2,5-diphenylphospholane 1-Oxide
(10)
In a 1 L round-bottom flask, ammonium formate (60.0 g, 0.95 mol)
and formic acid (90%; 41.6 g, 0.80 mol) were added to MeOH (150
mL) with stirring. The 10% Pd/C catalyst (5.10 g) was added, which
led to an immediate somewhat vigorous gas evolution. (1s,2R,5S)-
The low solubility of 5 in CDCl3 prevented from obtaining a 13C
NMR spectrum.
1-(Diethylamino)-2,5-diphenyl-2,5-dihydro-1H-phosphole
1-
oxide10 (9; 81.345 g, 0.250 mol) was added and the reaction mixture
slowly warmed to 30–35 °C over 1 h, such that gas evolution did not
become overly vigorous. The temperature was further increased to
45 °C over 1 h and held at that temperature for 3 h, when the sub-
strate had been fully consumed according to TLC (EtOAc). The re-
action mixture was filtered over Celite and the filter washed with
several portions of EtOH, H2O, EtOAc, and again EtOH. The com-
bined filtrates were evaporated in vacuum to remove organic sol-
vents, and the product was extracted from the aqueous slurry with
EtOAc (300 mL). The organic phase was collected and the aqueous
phase extracted with EtOAc (2 × 100 mL). The combined organic
phases were washed with dil. aq NH3 until the aqueous phase re-
mained basic (i.e., the smell of NH3 persists; use of pH indicator pa-
per is recommended). The organic phase was washed with H2O
(3 × 100 mL) and evaporated to a small volume. The residual oil
was diluted with a small volume of t-BuOMe (50 mL), overlayered
with hexanes (200 mL), and set aside for crystallization at 4 °C. Fil-
tration and washing gave 10 (74.79 g, 91%) as colorless needles.
The mother liquor was evaporated and recrystallized from t-
BuOMe–hexanes to give another 3.6 g of 10; total yield: 78.4 g
(96%); mp 109.5–110.0 °C.
Dihydrocinchonidine (6)
Yield: 9.63 g (96%); white powder; mp 232.0–232.5 °C.
1H NMR (250 MHz, CDCl3): δ = 0.81 (t, J = 7.2 Hz, 3 H), 1.14–
1.33 (m, 2 H), 1.34–1.47 (m, 2 H), 1.47–1.59 (m, 1 H), 1.62–1.86
(m, 2 H), 2.35–2.41 (m, 1 H), 2.56–2.66 (m, 1 H), 2.95–3.21 (m, 2
H), 3.46 (m, 2 H), 5.64 (d, J = 4.1 Hz, 1 H), 7.44–7.50 (m, 1 H), 7.58
(d, J = 4.5 Hz, 1 H), 7.65–7.71 (m, 1 H), 8.02 (d, J = 8.5 Hz, 1 H),
8.12 (d, J = 8.5 Hz, 1 H), 8.87 (d, J = 4.5 Hz, 1 H).
13C NMR (63 MHz, CDCl3): δ = 12.1, 21.6, 25.6, 27.6, 28.4, 37.6,
43.3, 58.7, 60.2, 72.3, 118.2, 123.1, 125.8, 126.6, 129.0, 130.4,
148.3, 149.2, 150.2.
Dihydroquinidine (8)
Yield: 4.73 g (95%); white powder; mp 169.5–170.0 °C.
1H NMR (360 MHz, CDCl3): δ = 0.88 (t, J = 7.1 Hz, 3 H), 1.07–
1.25 (m, 1 H), 1.41–1.45 (m, 2 H), 1.46–1.56 (m, 2 H), 1.70 (s, 1 H),
1.87–2.03 (m, 1 H), 2.17 (s, 2 H), 2.71–2.79 (m, 1 H), 2.82–2.96 (m,
2 H), 3.00–3.09 (m, 2 H), 3.87 (s, 3 H), 5.59 (d, J = 4.3 Hz, 1 H),
7.20 (d, J = 2.7 Hz, 1 H), 7.33 (dd, J = 9.2, 2.7 Hz, 1 H), 7.54 (d,
J = 4.5 Hz, 1 H), 7.99 (d, J = 9.2 Hz, 1 H), 8.68 (d, J = 4.5 Hz, 1 H).
13C NMR (91 MHz, CDCl3): δ = 12.0, 20.9, 25.1, 26.3, 27.1, 37.4,
50.2, 51.2, 55.5, 59.8, 71.9, 101.2, 118.4, 121.4, 126.6, 131.5,
133.4, 144.1, 147.5, 157.6.
1H NMR (400 MHz, CDCl3): δ = 0.25 (t, J = 7.1 Hz, 6 H), 2.34 (ψ-
dq, J = 9.0, 7.1 Hz, 4 H), 2.46–2.62 (m, 4 H), 3.68 (dt, J = 22.6, 8.2
Hz, 2 H), 7.15–7.22 (m, 2 HAr), 7.27–7.36 (m, 8 HAr).
13C NMR (75.4 Hz, CDCl3): δ = 13.4 (d, JP,C = 2.4 Hz), 27.0 (d,
Dihydroquinine (7)
Because of solubility reasons, the general reaction conditions were
slightly varied: Formic acid (2.15 g, 48 mmol, 3 equiv) was added
dropwise with stirring to a mixture of quinine (5.00 g, 15.4 mmol)
and ammonium formate (3.90 g, 64 mmol, 4 equiv) in MeOH (20
mL). The resulting suspension was heated to 55 °C, then sufficient
J
P,C = 13.1 Hz), 38.3 (d, JP,C = 2.7 Hz), 46.3 (d, JP,C = 71.5 Hz),
126.3 (d, JP,C = 2.7 Hz), 127.2 (d, JP,C = 4.8 Hz), 128.4 (d, JP,C = 2.3
Hz), 137.1 (d, JP,C = 5.6 Hz).
31P NMR (162 MHz, CDCl3): δ = 67.7 (s).
Synthesis 2013, 45, 888–892
© Georg Thieme Verlag Stuttgart · New York

892
H. Wu, L. Hintermann
PRACTICAL SYNTHETIC PROCEDURES
MS (EI+): m/z = 328 (21, [M + H]+), 328 (55, [M]+), 312 (44), 206
(20), 104 (100), 72 (80).
and the filtrate evaporated to dryness to give a slightly yellow solid
(2.40 g, 48%); mp 80.5–81.0 °C.
Anal. Calcd for C20H26NOP: C, 73.37; H, 8.00; N, 4.28. Found: C,
73.87; H, 7.86; N, 4.21.
1H NMR (250 MHz, CDCl3): δ = 2.14 (s, 3 H), 2.55–2.98 (m, 4 H),
5.73 (s, 1 H), 6.62–6.91 (m, 2 H), 6.91–7.16 (m, 2 H).
13C NMR (91 MHz, CDCl3): δ = 28.9, 30.2, 45.5, 115.4, 129.4,
132.6, 154.2, 209.7.
1-Methoxy-4-propylbenzene (12)
To a solution of anethole (11; 5.00 g, 33.7 mmol) in MeOH (50 mL)
was added formic acid (4.70 g, 102 mmol) with stirring. After addi-
tion of ammonium formate (10.60 g, 168 mmol) and 10% Pd/C (500
mg), the reaction mixture was stirred for 1 h at r.t., then slowly heat-
ed to 60 °C, and stirred at that temperature for 36 h. Reaction prog-
ress was monitored by TLC (Et2O–pentane 1:4). After cooling to
r.t., the mixture was filtered through Celite (1.5 cm layer in a 125
mL glass filter) and the filter washed was with MeOH (30 mL). The
filtrate was evaporated to dryness. The residue was dissolved in
CH2Cl2 (50 mL), washed with H2O (3 × 20 mL), dried (MgSO4),
and filtered. Evaporation in vacuum gave a faint yellow oil (4.23 g,
85%).
Acknowledgment
H.W. thanks the DAAD for a research stipend.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
References
1H NMR (250 MHz, CDCl3): δ = 0.93 (t, J = 7.3 Hz, 3 H), 1.61 (dq,
J = 14.7, 7.3 Hz, 2 H), 2.41–2.68 (m, 2 H), 3.79 (s, 3 H), 6.68–6.95
(m, 2 H), 6.99–7.20 (m, 2 H).
13C NMR (91 MHz, CDCl3): δ = 13.8, 24.8, 37.2, 55.2, 113.6,
129.3, 134.8, 157.6.
(1) Nylander, P. N. Hydrogenation Methods; Academic Press:
Orlando, 1985.
(2) Smith, M. B.; March, J. March’s Advanced Organic
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Methyl 2-Acetamido-3-phenylpropanoate (14)
Methyl (Z)-2-acetamido-3-phenylacrylate (13; 5.00 g, 22.8 mmol)
was dissolved in MeOH (50 mL). To the mixture was added formic
acid (3.20 g, 69 mmol, 3 equiv) dropwise with vigorous stirring.
Ammonium formate (8.60 g, 137 mmol, 6 equiv) and 10% Pd/C
(500 mg) were added consecutively. The reaction mixture was
stirred at r.t. for 1 h and then slowly heated to 50 °C, and stirred for
5 h at that temperature. Reaction progress was monitored by TLC
(EtOAc–hexane, 1:2). After cooling, the mixture was filtered
through a 1.5 cm layer of Celite in a 125 mL glass filter funnel and
the filter was washed with EtOAc (100 mL). The filtrate was evap-
orated to dryness, the residue taken up in EtOAc (150 mL) and
washed with aq 1 M HCl (15 mL). The organic phase was dried
(MgSO4), filtered, and the filtrate evaporated to dryness to give faint
yellow crystals (4.50 g, 90%); mp 88.5–89.0 °C.
(5) Cortese, N. A.; Heck, R. F. J. Org. Chem. 1978, 43, 3985.
(6) Ram, S.; Ehrenkaufer, R. E. Synthesis 1988, 91.
(7) Paryzek, Z.; Koenig, H.; Tabaczka, B. Synthesis 2003, 2023.
(8) For a versatile homogeneous transfer hydrogenation using
Pd(OAc)2/Pt-Bu3 as catalyst at the 1 mmol scale, see:
Brunel, J. M. Synlett 2007, 330.
(9) (a) Hintermann, L.; Schmitz, M.; Englert, U. Angew. Chem.
Int. Ed. 2007, 46, 5164; Angew. Chem. 2007, 119, 5256 .
(b) Hintermann, L.; Dittmer, C. Eur. J. Org. Chem. 2012,
5573. (c) Hintermann, L.; Ackerstaff, J.; Boeck, F. Chem.
Eur. J. 2013, 19, 2311.
(10) (a) Hintermann, L.; Schmitz, M. Adv. Synth. Catal. 2008,
350, 1469. (b) Hintermann, L.; Schmitz, M.; Maltsev, O. V.;
Naumov, P. Synthesis 2013, 45, 308.
(11) Hydrogenation of the alkaloids in dilute H2SO4 with PdCl2
and H2 close to regular pressure has been described:
(a) Heidelberger, M.; Jacobs, W. A. J. Am. Chem. Soc. 1919,
41, 817. (b) Vereinigte Chininfabriken Zimmer & Co.,
German Patent DE 252136, 1912; Chem. Abstr. 1913, 7,
2678.
1H NMR (250 MHz, CDCl3): δ = 1.96 (s, 3 H), 2.95–3.23 (m, 2 H),
3.70 (s, 3 H), 4.86 (dt, J = 7.7, 5.9 Hz, 1 H), 6.14 (d, J = 6.7 Hz, 1
H), 6.98–7.18 (m, 2 H), 7.19–7.40 (m, 3 H).
13C NMR (91 MHz, CDCl3): δ = 23.1, 37.8, 52.3, 53.1, 127.1,
128.6, 129.2, 135.8, 169.7, 172.1.
4-(4-Hydroxyphenyl)butan-2-one (16)
(12) Exner, C.; Pfaltz, A.; Studer, M.; Blaser, H.-U. Adv. Synth.
Catal. 2003, 345, 1253.
To a solution of (E)-4-(4-hydroxyphenyl)but-3-en-2-one (15; 5.00
g, 31 mmol) in MeOH (50 mL) was added formic acid (4.30 g, 93
mmol, 3 equiv) dropwise with stirring, followed by the addition of
ammonium formate (11.70 g, 186 mmol, 6 equiv) and 10% Pd/C
(500 mg). The reaction mixture was stirred for 1 h at r.t., then heated
to 50 °C, and stirred at that temperature for 15 h. Reaction progress
was monitored by TLC (EtOAc–hexane, 1:2). After cooling to r.t.,
the mixture was filtered through Celite, the filter was washed with
EtOAc (100 mL), and the filtrate evaporated to dryness. The inter-
mediate alcohol was then oxidized with TEMPO.18 The residue was
taken up in CH2Cl2 (50 mL). After addition of KBr (360 mg, 3
mmol; 10 mol%) and 4-NHAc-TEMPO (64 mg, 0.3 mmol; 1
mol%), the mixture was cooled to 0 °C in an ice bath with stirring.
A aq solution of NaOCl (27 mL, 1.42 M) containing NaHCO3 (1.1
g) as buffer was added dropwise to the vigorously stirred reaction
mixture at 0 °C. After completion of the addition, the reaction mix-
ture was stirred for 3 h at r.t. and monitored by TLC (EtOAc–hex-
ane, 1:2). The organic layer was separated, washed with aq 1 M HCl
(80 mL; containing 35.5 mg of KI), 10% aq Na2S2O3 (30 mL), and
brine (30 mL). After drying (MgSO4), the organic layer was filtered
(13) Transfer hydrogenation of cinchonine (1 g scale) with a
freshly ordered 10% Pd/C catalyst (67 mg, 1:15 ratio; Alfa
Aesar) gave a 87% yield within 36 h; with freshly ordered
5% Pd/C catalyst (67 mg, 1:15 ratio; Alfa Aesar), a 94%
yield was obtained within 22 h. Thus, the higher metal
content did not translate to higher catalytic activity.
(14) Individual student results for dihydrocinchonidine: scale and
yield: 4.0 g (98%), 5.0 g (93%), 10.0 g (88%).
(15) Guillen, F.; Rivard, M.; Toffano, M.; Legros, J.-Y.; Daran,
J.-C.; Fiaud, J.-C. Tetrahedron 2002, 58, 5895.
(16) Zumbansen, K.; Döhring, A.; List, B. Adv. Synth. Catal.
2010, 352, 1135.
(17) (a) Sharma, A.; Kumar, V.; Sinha, A. K. Adv. Synth. Catal.
2006, 348, 354. (b) Viviano, M.; Glasnov, T. N.; Reichart,
B.; Tekautz, G.; Kappe, C. O. Org. Process Res. Dev. 2011,
15, 858.
(18) Straub, T. S. J. Chem. Educ. 1991, 68, 1048.
Synthesis 2013, 45, 888–892
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