Hydrogenolysis of N-protected aminooxetanes over palladium: An efficient method for a one-step ring opening and debenzylation reaction

Article abstract of DOI:10.1016/j.molcata.2011.02.008

An efficient method for the palladium mediated hydrogenation of an optically active, N-protected aminooxetane derivative has been developed. Using appropriate solvents, in a one-step reaction, a chiral 1,4-aminoalcohol derivative [(2S,3R)-4-amino-3-benzoyloxy-2-benzylbutan-1-ol] was formed over a Pd/C catalyst, during hydrogenolytic ring opening and debenzylation reactions.

Full text of DOI:10.1016/j.molcata.2011.02.008

Journal of Molecular Catalysis A: Chemical 339 (2011) 32–36
Contents lists available at ScienceDirect
Journal of Molecular Catalysis A: Chemical
journal homepage: www.elsevier.com/locate/molcata
Hydrogenolysis of N-protected aminooxetanes over palladium: An efficient
method for a one-step ring opening and debenzylation reaction
Ervin Kovácsa, Angelika Thurnerb, Ferenc Farkasa,c, Ferenc Faigla,b, László Hegedu˝ sb,∗
a Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Budafoki út 8, H-1111 Budapest, Hungary
b Research Group for Organic Chemical Technology, Hungarian Academy of Sciences, Department of Organic Chemistry and Technology,
Budapest University of Technology and Economics, Budafoki út 8, H-1111 Budapest, Hungary
c Gedeon Richter Plc., Gyömro˝i út 19-21, H-1103 Budapest, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient method for the palladium mediated hydrogenation of an optically active, N-protected
aminooxetane derivative has been developed. Using appropriate solvents, in a one-step reaction, a chi-
ral 1,4-aminoalcohol derivative [(2S,3R)-4-amino-3-benzoyloxy-2-benzylbutan-1-ol] was formed over a
Pd/C catalyst, during hydrogenolytic ring opening and debenzylation reactions.
© 2011 Elsevier B.V. All rights reserved.
Received 23 November 2010
Accepted 16 February 2011
Available online 23 February 2011
Keywords:
Optically active oxetanes
Chiral 1,4-aminoalcohols
Hydrogenolysis
Catalytic hydrogenation
Palladium
Solvent effects
1. Introduction
In this work, adopting the aforementioned hydrogenation
method, the heterogeneous catalytic hydrogenolysis of (–)-(2S,3S,
Chiral 1,4-aminoalcohols can be useful intermediates for the
synthesis of biologically active N-heterocycles. Ring closuring reac-
tion between the amino and hydroxyl groups, under the Mitsunobu
protocol [1], is an alternative route to produce non-racemic pyrro-
lidines. There are several protein kinase C enzyme inhibitors among
the optically active, 3,4-disubstituted pyrrolidines used in the
treatment of certain cancer diseases [2]. Previously we reported
a method, in which aminooxetanes could stereoselectively be
obtained from chiral disubstituted oxiranes in the presence
of potassium tert-butoxide activated lithium diisopropylamide
(LiDA–KOR) [3]. Furthermore, pure enantiomers of 3-[1ꢀ-hydroxy-
2ꢀ-(dibenzylamino)ethyl]-2-phenyloxetane were synthesized from
cis-4-benzyloxy-2,3-epoxybutanol using enzymatic kinetic resolu-
tion followed by consecutive tosylation, dibenzylamination and
organometallic base promoted enantioselective rearrangement
reactions [4]. Recently we have developed an efficient, one-step
process for the palladium mediated hydrogenation of an optically
active, O-trityl hydroxyoxetane derivative, in which chiral 1,4-diol
was formed over a Pd/C catalyst, in a dichloromethane/methanol
solvent mixture (1:4), during hydrogenolytic ring opening and
detritylation reactions [5].
1ꢀS)-3-[1ꢀ-benzoyloxy-2ꢀ-(dibenzylamino)ethyl]-2-phenyloxetane
(1) to (2S,3R)-4-amino-3-benzoyloxy-2-benzylbutan-1-ol (2) was
investigated in detail (Scheme 1). Compound 2 is a potential start-
ing material for preparing optically active, practically important
pyrrolidine derivatives.
Since the hydrogenolysis of 1 has never been described in the
literature, the ring opening methods of oxetanes and the benzyl
group removing procedures, respectively, are shown through other
examples.
To open an oxetane ring the common methods are applying
acidic conditions, such as H2SO4 in methanol [6], CF3COOH in
dichloromethane [7], ethereal H2O2 in the presence of Yb(OTf)3
[8] or benzoyl chloride with SmI2 in tetrahydropyran [9]. Few
examples have been reported on the hydrogenolysis of oxetanes.
Thus, 1,2-diols were prepared via hydrogenolysis of 2-aryl-3-
(silyloxy)oxetanes over Pd(0) catalysts (e.g. Pd/C), but the acid
sensitive silyloxy group remained intact if Pd(OH)2 was applied
as a catalyst for the hydrogenolysis [10]. Oxetane ring containing
cycloadducts of 3,4-dihydro-2(1H)-pyridinone derivatives were
transformed into 2-arylmethyl-3-piperidinols by hydrogenoly-
sis of the oxetane ring, in methanol, over Pd(OH)2 [11]. Other
cyclic ethers, 2-phenyltetrahydropyran or phenyldioxane, were
hydrogenated to the corresponding alcohols with 72–75% yields,
∗
over
a 5% Pd/C catalyst, in acetic acid, in the presence of
Corresponding author. Tel.: +36 1 4631261; fax: +36 1 4631261.
E-mail address: lhegedus@mail.bme.hu (L. Hegedu˝ s).
HClO4 or H2SO4, at 3 bar and room temperature [12], i.e.
1381-1169/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.molcata.2011.02.008

E. Kovács et al. / Journal of Molecular Catalysis A: Chemical 339 (2011) 32–36
33
OH
O
1
2
1
H
1'
H
3
2
Ph
2'
3
4
Ph
N
Ph
H2N
H2 , Pd/C
solvent(s)
OH
O
4
O
+
Ph
3
Ph
2
1
O
O
N
O
H
OH
1
2
3
Scheme 1. Hydrogenolysis of (–)-(2S,3S,1ꢀS)-3-[1ꢀ-benzoyloxy-2ꢀ-(dibenzylamino)ethyl]-2-phenyloxetane (1).
these hydrogenolytic reactions took place under strong acidic
conditions.
was added to the mixture and it was stirred for 40 min. After
adding benzoyl chloride (0.93 mL, 8.03 mmol), the reaction mix-
ture was stirred for 40 min again, then it was warmed up to room
temperature and stirred overnight. Afterwards it was diluted
with diethyl ether (60 mL), distilled water (30 mL) and saturated
sodium hydrogen carbonate solution (30 mL) and the two phases
formed were separated. The aqueous phase was extracted with
diethyl ether (3 × 50 mL) and the combined ethereal extracts
were washed with saturated sodium hydrogen carbonate solution
(3 × 50 mL) and brine (2 × 50 mL), then dried over Na2SO4. After
evaporating the solvent, 3.52 g crude product was obtained. It was
purified by column chromatography on silica gel (n-hexane/ethyl
acetate = 4:1) to give 3.11 g yellowish oil of 1 (81%). 1H NMR (CDCl3,
500 MHz), ı ppm 2.44 (1H, dd, J = 4.5, 14.0 Hz, NCHaHb), 2.71 (1H,
dd, J = 7.5, 15.0 Hz, NCHaHb), 3.14 (1H, m, oxetane CH), 3.43 (2H,
d, J = 13.5 Hz, NCH2Ph), 3.73 (2H, d, J = 13.5 Hz, NCH2Ph), 4.49 (1H,
t, J = 6.5 Hz, oxetane CH2O), 4.55 (1H, t, J = 6.5 Hz, oxetane CH2O),
5.62 (1H, d, J = 6.5 Hz, oxetane CHPh), 5.81 (1H, m, CHOCOPh),
7.20–7.31 (17H, m, Ar–CH), 7.45 (2H, t, J = 8.0 Hz, benzoyl m-Ph),
7.57 (1H, t, J = 8.0 Hz, benzoyl p-Ph), 8.01 (2H, d, J = 8.0 Hz, benzoyl
o-Ph); 13C-NMR (CDCl3, 75 MHz), ı ppm 47.0, 55.5, 69.8, 72.5, 85.4,
As well known, debenzylation is a common method to obtain
the active forms of amines or alcohols from the corresponding N-
or O-protected derivatives [13,14]. Among the typical hydrogena-
tion catalysts, such as platinum metals, nickel or copper chromite,
palladium is by far the most favoured one due to its high activ-
ity and selectivity [15]. Removing the benzyl group attached to
nitrogen, however, does not readily take place as its cleavage from
oxygen does [16,17]. The ease of N-debenzylation is influenced by
substitution on the nitrogen atom [18], namely the quaternary and
tertiary amines can easily be debenzylated already at atmospheric
pressure and room temperature, while that of the secondary or
primary ones require higher pressure (>4 bar) and temperature
(>40 ◦C). Moreover, the products of hydrogenolysis are strongly
basic amines which can deactivate the supported precious metal
catalysts due to their poisoning effects [19–21], therefore a higher
amount of catalyst or adding acids are necessary to complete the
reaction.
In this paper the effects of solvents and catalyst/substrate ratio
on the hydrogenation of 1 and the selectivity to 2 are discussed.
96.4, 125.6, 127.3, 128.1, 128.6, 128.7, 129.2, 130.1, 130.2, 130.8,
20
133.4, 139.0, 142.5, 166.4. ˛
= −7.2, (c 1.65, CHCl3), ee 93%.
[ ]D
2. Experimental
2.1. Materials
2.2. Hydrogenations
The 10% Pd/C (Selcat Q) catalyst was manufactured in accor-
dance with the patent [22], in the Szilor Fine Chemicals (Budapest,
Hungary). The dispersion of the catalyst, determined by H2−, O2−
and CO-chemisorption measurements, is D = 0.50 [23].
Methanol (p.a.) and tetrahydrofuran (p.a.) were sup-
plied by Merck-Schuchardt (Hohenbrunn, Germany), while
dichloromethane (p.a.) were purchased from Reanal Fine Chemicals
(Budapest, Hungary).
Synthesis of compound 1 (Scheme 2): a solution of (–)-(2S,
3S,1ꢀS)-3-[1ꢀ-hydroxy-2ꢀ-(dibenzylamino)ethyl]-2-phenyloxetane,
prepared according to our procedure described in [4], (3.0 g,
8.03 mmol) in THF (40 mL) was cooled to −75 ◦C under nitrogen
atmosphere, then buthyllithium in hexane (5.1 mL, 8.03 mmol)
The hydrogenation reactions were carried out either in a
conventional atmospheric pressure apparatus with a magnetic
stirrer (stirring speed: 1100 rpm) or in a 250 cm3 stainless steel
autoclave (Technoclave, Budapest, Hungary) equipped with a
magnetic stirrer (stirring speed: 1100 rpm), at 10 bar hydrogen
pressure and room temperature. The reactor containing the start-
ing material, catalyst and solvent was flushed with nitrogen and
hydrogen, then charged with hydrogen to the specified pressure.
The reaction was followed by TLC (n-hexane/ethyl acetate = 4:1;
Rf (1) = 0.50, and dichloromethane/methanol = 5:1; Rf (2) = 0.46,
Rf (3) = 0.91). After the hydrogenation was completed, the cata-
lyst was filtered off and the solvent was removed in vacuum.
The residue was purified by column chromatography on sil-
O
1
H
H
3
2
1'
2'
Ph
N
Ph
O
1
1. BuLi, THF
O
H
H
3
2
O
1'
2'
Ph
Ph
N
Ph
Cl
O
OH
2.
Ph
1
Scheme 2. Synthesis of (–)-(2S,3S,1ꢀS)-3-[1ꢀ-benzoyloxy-2ꢀ-(dibenzylamino)ethyl]-2-phenyloxetane (1).

34
E. Kovács et al. / Journal of Molecular Catalysis A: Chemical 339 (2011) 32–36
Table 1
Hydrogenolysis of 1 in different solvents.a
No.
Solvents
Pressure (bar)
1
Reaction time (h)
Conversion of 1 (%)
Isolated yield (%)
Compound 2
Compound 3
1
Methanol
4.0
72.0
5.0
24.0
5.0
12.0
12.0
24.0
100
100
0
0
0
0
100
100
0
0
–
–
–
20
52
–
–
–
2
Tetrahydrofuran
Dichloromethane
Dichloromethane
1
10
1
10
10
3
–
–
4b
57c
70c
0d
0d
a
Conditions: 0.3 g (0.63 mmol) substrate, 0.15 g 10% Pd/C catalyst (Selcat Q), 30 mL solvent, 30 ◦C.
b
c
45 ◦C.
Prepared in a form of 2.HCl salt.
No formation of compound 3 was observed.
d
ica gel (dichloromethane/methanol = 5:1). Representative physical
and spectroscopic data of the products are the following:
matic polarimeter. TLC was carried out on Kieselgel 60 F254 (Merck)
sheets.
(2S,3R)-4-Amino-2-benzyl-3-benzoyloxybutan-1-ol (2), oil, 1H
NMR (CDCl3, 500 MHz) ı ppm 2.39–2.54 (2H, m, CHaHbPh and
CHCH2OH), 2.78 (1H, dd, J = 4.2, 13.5 Hz, CHaHbPh), 3.30 (1H,
m, CH2NH2), 3.37 (1H, dd, J = 4.5, 14.4 Hz, CH2NH2), 3.47 (1H,
m, CHaHb–OH), 3.62 (1H, dd, J = 2.4, 11.7 Hz, CHaHb–OH), 5.51
(1H, m, CHOCOPh), 7.12–7.34, (7H, m, Ar–CH), 7.47 (1H, t,
J = 7.5 Hz benzoyl p-Ph), 8.01 (2H, d, J = 7.5 Hz, benzoyl o-Ph); 13C
NMR (CDCl3, 125 MHz) ı ppm 33.5, 42.0, 44.5, 60.1, 72.4, 126.6,
3. Result and discussion
3.1. Effect of solvents
As known [24], in the catalytic hydrogenations both the selec-
tivity of a reaction and the activity of a catalyst can be influenced
by using appropriate solvents.
The results of the hydrogenolysis of 1 in different organic
solvents, over 10% Pd/C (Selcat Q) catalyst are summarized in
Table 1.
128.6, 128.7, 129.3, 129.4, 133.6, 139.0, 166.8; ꢀmax (film, cm−1
)
20
3301, 2936, 1633, 1536, 1038, 695.
ee 93%.
˛
= 0 (c 1.55, CHCl3),
[ ]D
(2R,3S)-N-(3-Benzyl-2,4-dihydroxybutyl)benzamide (3), white
crystal, m.p. 153 ◦C; 1H NMR (CDCl3, 500 MHz) ı ppm 1.92 (1H, m,
CHCH2Ph), 2.58 (1H, m, CHaHbPh), 2.92 (1H, m, CHaHbPh), 3.55 (2H,
m, CH2OH), 3.74 (1H, m, CHaHbNH), 3.90 (1H, m, CHaHbNH), 4.00
(1H, m, CHOH), 7.10–8.20 (10H, m, Ar–CH).
In methanol, the conversion of compound 1 was complete
at atmospheric pressure and 30 ◦C after 4 h reaction time, but
the wanted compound 2 was not formed. Surprisingly a side-
product, (2R,3S)-N-(3-benzyl-2,4-dihydroxybutyl)benzamide (3),
was isolated from the reaction mixture with 20% yield. Further
hydrogenation of 1, after 72 h, also provided compound 3 with
higher isolated yield (52%). It means that after opening the oxetane
ring, the two benzyl groups were removed already at atmospheric
pressure and room temperature, but hydrogenolysis of secondary
amines, in general, requires higher pressure (>4 bar) and tempera-
ture (>40 ◦C) [18]. This unexpected result will be discussed later.
Using tetrahydrofuran or dichloromethane no conversion of 1
was observed even after 12–24 h reaction time and at 10 bar and
30 ◦C. In dichloromethane, however, compound 2 was obtained
with 57% yield, when the temperature was raised to 45 ◦C, but it was
isolated in a form of hydrogen chloride salt (2.HCl). Further hydro-
genation of 1 at 10 bar and 45 ◦C, after 24 h, provided compound
2.HCl with 70% yield, moreover no compound 3 was detected.
This was due to the hydrodehalogenating ability of palladium
[25], i.e. under such conditions palladium is able to hydrogenol-
yse dichloromethane, and the hydrogen chloride formed gives a
salt with compound 2.
2.3. Synthesis of (–)-(3R,4S)-3-benzoyloxy-
4-benzylpyrrolidine (5)
(2S,3R)-4-Amino-3-benzoyloxy-2-benzylbutan-1-ol
(2,
2.6 mmol, 0.8 g) was dissolved in tetrahydrofuran (25 mL) and
the solution was cooled down to 0 ◦C. Triphenylphosphine
(2.6 mmol, 0.68 g) and diethyl azodicarboxylate (2.6 mmol, 1.13 g)
was added, then the mixture was stirred for an hour at 0 ◦C and
48 h at 25 ◦C. The solvent was evaporated in vacuum and the
crude product (2.2 g) was purified by column chromatography
(eluent: dichloromethane/metanol = 10:1) to give (–)-(3R,4S)-3-
benzoyloxy-4-benzylpyrrolidine (5) as an oil (0.56 g, 75%). 1H NMR
(CDCl3, 500 MHz) ı ppm 2.86 (1H, dd, J = 4.8, 12.3 Hz, PhCHaHb),
3.04 (1H, dd, J = 4.8, 12.3 Hz, PhCHaHb), 3.17 (2H, m, BnCHCH2),
3.54 (2H, m, OCHCH2), 3.76 (1H, m, BnCH), 5.32 (1H, m, CHOCOPh),
7.23–7.37 (5H, m, Ar–CH), 7.49 (2H, t, J = 7.8 Hz benzoyl m-Ph),
7.60 (1H, t, J = 7.8 Hz, benzoyl p-Ph), 8.07 (2H, d, J = 7.8 Hz, benzoyl
o-Ph); 13C NMR (DMSO-d6, 75 MHz) ı ppm 35.5, 44.9, 47.6, 48.8,
126.4, 128.5, 128.6, 128.8, 129.1, 129.4, 133.6, 138.7, 165.0; ꢀmax
To avoid the unwanted side-reactions,
a
mixture of
dichloromethane and methanol was applied in the hydro-
genation of 1, similarly to our previous results concerning the
hydrogenolysis of O-protected hydroxyoxetanes [5]. The effect of
solvent mixtures with different composition on the conversion of
1 and the isolated yield of 2 is given in Table 2.
(KBr, as oxalate salt, cm−1) 3434, 2925, 1720, 1632, 1277, 720.
20
˛
= −26.9 (c 2.05, CHCl3), ee 93%.
[ ]D
2.4. Analysis
As seen, in the 50:50 (v/v%) dichloromethane/methanol mixture
compound 2 was isolated with 50% yield (by complete conversion
of 1), over palladium on carbon, at 10 bar and 30 ◦C, after 4 h reac-
tion time. Similarly to dichloromethane used by itself, no formation
of compound 3 was observed, but compound 2 was in a form of
free base. Using a 80:20 (v/v%) mixture the complete conversion
of 1 required longer reaction time (20 h), moreover the isolated
yield of 2 became slightly better (50 → 54%). Whereas, increasing
The 1H and 13C NMR spectra were recorded on a Bruker DRX-
500 or DRX-300 spectrometers operating at 500 or 300 and 125
or 75 MHz, respectively, in chloroform-D1 (CDCl3) or in dimethyl
sulfoxide (DMSO-d6). Chemical shifts are given relative to ıTMS
IR spectra were taken on a Perkin-Elmer 1600 FT spectrometer.
Optical rotations were measured with a Perkin-Elmer 241 auto-
.

E. Kovács et al. / Journal of Molecular Catalysis A: Chemical 339 (2011) 32–36
35
Table 2
Hydrogenolysis of 1 in the mixture of dichloromethane (CH2Cl2) and methanol (MeOH).a
No.
CH2Cl2/MeOH (v/v %)
Reaction time for complete conversion of 1 (h)
Isolated yield of compound 2b (%)
1
2
50:50
80:20
70:30
70:30
4.0
20.0
16.0
16.0
50
54
79
87
3
4c
a
Conditions: 0.3 g (0.63 mmol) substrate, 0.15 g 10% Pd/C catalyst (Selcat Q), 30 mL solvent, 30 ◦C, 10 bar.
No formation of compound 3 was observed.
2.85 g (5.98 mmol) substrate, 1.42 g 10% Pd/C catalyst (Selcat Q), 50 mL solvent.
b
c
Table 3
Influence of amount of catalyst (Pd/C) in the hydrogenolysis of 1.a
No.
Catalyst/substrate ratio (g g−1
)
Reaction time (h)
Conversion (%)
Isolated yield of compound 2b (%)
1
2
3
0.5
0.3
0.1
16.0
24.0
24.0
100
32
1
79
25
–
a
Conditions: 0.3 g (0.63 mmol) substrate, 10% Pd/C catalyst (Selcat Q), 21 mL dichloromethane and 9 mL methanol (70:30 v/v %), 30 ◦C, 10 bar.
No formation of compound 3 was observed.
b
the amount of methanol to 30 (v/v%) the rate of hydrogenolysis
also increased, namely 16 h reaction time was sufficient to com-
plete the hydrogenation of 1, as well as compound 2 was achieved
with 79% isolated yield. Further increase in isolated yield of 2 was
obtained (87%), when this reaction was repeated using about ten
times higher amount of starting material (0.3 → 2.85 g), presum-
ably due to the smaller loss of 2 suffered during the working-up
procedure.
OH
Ph
OH
Ph
O
H
O
H
Ph
N
Ph
Ph
N
HN
H2
H2
O
O
Ph
Ph
- PhCH3
Ph
O
O
'fast'
'fast'
O
1
4
'slow'
CH3OH
OH
Ph
O
OH
Ph
CH3
O
+
HN
- CH3OH
N
O
OH
Ph
OH
'fast'
methyl benzoate
Ph
H2 - PhCH3
'fast'
OH
Ph
N
O
H
OH
3
Scheme 3. Proposed mechanism of the formation of compound 3.

36
E. Kovács et al. / Journal of Molecular Catalysis A: Chemical 339 (2011) 32–36
therefore, starting from optically active 1, the products (2 and 5)
were obtained with the same ee.
OH
1
2
Ph
3
4
Ph3P, DEAD
THF
H2N
4. Conclusions
Ph
O
O
O
Efficient, selective methods for the palladium mediated
hydrogenation of an optically active, N-protected aminooxetane
derivative (1) have been developed. In a one-step reaction chiral
1,4-aminoalcohol (2) was formed over a Pd/C catalyst, during a
hydrogenolytic ring opening reaction followed by debenzylation.
The selectivity and the yield of compound 2 were improved by
appropriate solvents. In a dichloromethane/methanol solvent mix-
ture (7:3) the isolated yield of 2 increased to 87%. These results gave
further evidences that selectivity, yield and rate of the catalytic
hydrogenation reactions can be influenced by changing solvents or
solvent mixtures.
In methanol, due to the transesterification of O-benzoyl group,
a benzamide type by-product (3) was formed already at atmo-
spheric pressure and room temperature, because N-acetylation
made easier the N-debenzylation in consequence of a tertiary
amine derivative formed.
O
N
H
2
5
Scheme 4. Synthesis of (–)-(3R,4S)-3-benzoyloxy-4-benzylpyrrolidine (5).
According to our results, it can be stated that methanol, sim-
ilarly to other protic and polar solvents, is very efficient in
the hydrogenolysis of oxetane ring and the removal of benzyl
protecting group, as well as provides high reaction rate, while
dichloromethane prevents the possibility of side-reactions (e.g.
hydrolysis of the ester bond).
3.2. Influence of amount of catalyst
The results of hydrogenolysis of
amount of 10% Pd/C (Selcat Q) catalyst, in
dichloromethane/methanol solvent mixture are summarized
in Table 3.
1
over different
70:30 (v/v%)
The synthesized chiral 1,4-aminoalcohol (2) can be a promis-
ing starting material for synthesis of optically active, valuable and
important pyrrolidine derivatives, like compound 5.
a
As seen, the hydrogenation of 1, at 0.5 catalyst/substrate ratio,
was complete after 16.0 h reaction time and compound 2 was
obtained with 79% isolated yield. At lower catalyst/substrate ratio
(0.3) the conversion of 1 was only 32% after 24 h, but the isolated
yield of 2 (25%) was proportional with that of the previous experi-
ment. Further decreasing the catalyst/substrate ratio to 0.1 resulted
in practically no conversion of 1 even after 24 h, presumably, due
to complete poisoning of the palladium catalyst used.
These results indicate that the hydrogenolysis of 1 requires a rel-
atively high catalyst/substrate ratio (0.5) to complete the reaction,
probably, due to poisoning effect of the strongly basic nitrogen of
these amino compounds.
Acknowledgements
This work is connected to the scientific program of the “Devel-
opment of quality-oriented and harmonized R + D + I strategy and
functional model at BME” project and to the bilateral scientific
cooperation between CNR (Firenze) and the Hungarian Academy
of Sciences. The project is supported by the New Hungary Develop-
ment Plan (Project ID: TÁMOP-4.2.1/B-09/1/KMR-2010-0002). The
authors thank Dr. László Vida for GC–MS measurements.
References
3.3. Possible reaction mechanism for the formation of
[1] O. Mitsunobu, Synthesis (1981) 1.
side-product 3
[2] V. Pande, M.J. Ramos, F. Gago, Anti-Cancer Agents Med. Chem. 8 (2008) 638.
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To explain the formation of side-product benzamide derivative
(3) we suggested the following mechanism shown in Scheme 3.
First, the oxetane ring was opened and a benzyl group was
removed by the cleavage of carbon–nitrogen bond in a fast
reaction step. Then methanol, which was present as a solvent
in large excess, could initiate transesterification of the benzoyl
ester moiety of 4 in a slow reaction to form methyl benzoate,
which could acylate fast the secondary N-monobenzyl aminodiol
derivative. Since this N-benzoyl-N-benzyl aminodiol became a
tertiary amine again, the hydrogenolysis of benzyl group could
take place already at atmospheric pressure and room tem-
perature, over palladium. The appearance of methyl benzoate
(Mrel = 136.15 g mol−1) was proved by GC–MS measurements. The
MS data are the following: m/z (rel%) 136 (39), 105 (100), 77 (63),
51 (26), which are in agreement with the literary data [26]. This
analytical result gives an indirect evidence of the proposed mech-
anism.
[4] F. Faigl, A. Thurner, M. Battancs, F. Farkas, L. Poppe, V. Bódai, I. Kmecz, B. Simándi,
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3.4. Practical importance of product 2
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In order to demonstrate the practical usefulness of the prepared
1,4-aminoalcohol derivative 2, a ring closure reaction was carried
out using the Mitsunobu conditions. Product 5 was isolated in pure
form (Scheme 4) which can be used as a key intermediate in the
synthesis of Balanol analogues [27].
It has to be emphasized, these chemical transformations have no
influence on the configurations of the stereogenic carbon atoms,