Oxa-Michael Addition to α,β-Unsaturated Nitriles: An Expedient Route to γ-Amino Alcohols and Derivatives

Article abstract of DOI:10.1002/cctc.201800509

Water addition to α,β-unsaturated nitriles would give facile access to the β-hydroxy-nitriles, which in turn can be hydrogenated to the γ-amino alcohols. We have previously shown that alcohols readily add in 1,4-fashion to these substrates using Milstein's Ru(PNN) pincer complex as catalyst. However, attempted water addition to α,β-unsaturated nitriles gave the 3-hydroxynitriles in mediocre yields. On the other hand, addition of benzyl alcohol proceeded in excellent yields for a variety of β-substituted unsaturated nitriles. Subsequent treatment of the benzyl alcohol addition products with TMSCl/FeCl₃ resulted in the formation of 3-hydroxy-alkylnitriles. The 3-benzyloxy-alkylnitriles obtained from oxa-Michael addition also could be hydrogenated directly in the presence of acid to give the amino alcohols as their HCl salts in excellent yields. Hydrogenation under neutral conditions gave a mixture of the secondary and tertiary amines. Hydrogenation in the presence of base and Boc-anhydride gave the orthogonally bis-protected amino alcohols, in which the benzyl ether can subsequently be cleaved to yield Boc-protected amino alcohols. Thus, a variety of molecular scaffolds with a 1,3-relationship between O- and N-functional group is accessible starting from oxa-Michael addition of benzyl alcohol to α,β-unsaturated nitriles.

Full text of DOI:10.1002/cctc.201800509

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Title: Oxa-Michael Addition to ￿ ꢀ￿ -ꢁnUatꢂꢃated NitꢃileU: an Expedient
Roꢂte to ￿ -Aꢄino AlcoholU and DeꢃivativeU
Authors: Beibei Gꢂoꢀ Doꢂwe Sjiꢃk ZijlUtꢃaꢀ HanU De VꢃieUꢀ and Edwin
Otten
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ChemCatChem
10.1002/cctc.201800509
FULL PAPER
Oxa-Michael Addition to ,-Unsaturated Nitriles: an Expedient
Route to -Amino Alcohols and Derivatives
Beibei Guo, Douwe S. Zijlstra, Johannes G. de Vries,*[a] [b] and Edwin Otten*[a]
[
a]
[a]
Abstract: Water addition to -unsaturated nitriles would give facile
access to the -hydroxy-nitriles which in turn can be hydrogenated to
H
N
S
O
F
the -amino alcohols. We have previously shown that alcohols
readily add in 1,4-fashion to these substrates using Milstein’s
Ru(PNN) pincer complex as catalyst. However, attempted water
addition to -unsaturated nitriles gave the 3-hydroxynitriles in
mediocre yields. On the other hand, addition of benzyl alcohol
O
N
H
F
F
Duloxetine
HO
Fluoxetine
2
H N
HO
N
H
proceeded in excellent yields for
unsaturated nitriles. Subsequent treatment of the benzyl alcohol
addition products with TMSCl/FeCl resulted in formation of 3-
a variety of β-substituted
(+)-8-Ethylnorlobelol
Chiral ligand
3
hydroxy-alkylnitriles. The 3-benzyloxy-alkylnitriles obtained from oxa-
Michael addition also could be hydrogenated directly in the presence
of acid to give the amino alcohols as their HCl salts in excellent
yields. Hydrogenation under neutral conditions gave a mixture of the
secondary and tertiary amines. Hydrogenation in the presence of
base and Boc-anhydride gave the orthogonally bis-protected
aminoalcohols, in which the benzyl ether can subsequently be
cleaved to yield Boc-protected amino alcohols. Thus, a variety of
molecular scaffolds with a 1,3-relationship between O- and N-
functional group is accessible starting from oxa-Michael addition of
benzyl alcohol to -unsaturated nitriles.
Scheme 1. Examples of applications of γ-amino alcohols
of -amino alcohol-containing compounds are shown in Scheme
1. Several elegant methods for the synthesis of (stereodefined)
-amino alcohols have been reported; recent examples include
aldol reactions of benzylic nitriles,[ reduction of β-hydroxy
3]
sulfinylimines,[4] nitrene insertion into C-H bonds, reductive
[5]
6]
hydration
hydrogenation.
of
propargylic
amines,[
and
asymmetric
[
7]
An alternative, atom-economical approach
would be via oxa-Michael addition of water to unsaturated
nitriles, followed by hydrogenation. However, only the
unsubstituted parent compound, acrylonitrile, has been shown to
undergo oxa-Michael addition (‘cyanoethylation’)[8] in a facile
manner; the decreased reactivity of -substituted derivatives
poses significant problems in this regard.[
Introduction
9]
Amino alcohols are an important class of organic molecules with
diverse applications, ranging from bulk chemicals to
pharmaceuticals. Most commonly, these compounds present a
We recently reported the use of Milstein’s Ru(PNN)-pincer
as catalyst for the oxa-Michael addition to ,-unsaturated
nitriles.[ This reaction operates via an unusual metal-ligand
cooperative activation[11] of the nitrile that involves (reversible)
C(ligand)-C(nitrile) bond formation (Scheme 2). With a new
catalytic method available, we became interested in expanding
this chemistry to access -amino alcohol derivatives via this
10]
2
-hydroxy-amine motif (with a C spacer between the O- and N-
moieties), and several synthesis routes to 1,2-amino alcohol
building blocks are known.[ This structural motif is present in a
variety of biologically active compounds such as β-blockers
1]
(propranolol and derivatives), hormones (norepinephrine) and
methodology.
antihistamines (carbinoxamine). The related -amino alcohols
are also present in pharmaceuticals, for example in the
antidepressant Fluoxetine (Prozac). In addition, both - and -
amino alcohols have been used extensively in synthetic
R
1
R OH
R
C
P
N
CN
N
R
N
R1
[2]
O
H
chemistry as ligands in (asymmetric) organic synthesis. Some
examples
N
Ru CO
H
N
C
P
N
Ru CO
H
N
N
P
N
Ru CO
H
1
N
Ru CO
H
P
t
P = P Bu
N = NEt
2
[
[
a]
b]
B. Guo, D. S. Zijlstra, Prof. Dr. J. G. de Vries, Prof. Dr. E. Otten
Stratingh Institute for Chemistry, University of Groningen
Nijenborgh 4, 9747AG Groningen
E-mail: j.g.de.vries@rug.nl; edwin.otten@rug.nl
Prof. Dr. J. G. de Vries
R
N
R
O
1
R
N
R
1
2
1-taut
O
H
C
P
C
P
N
N
N
N
R
1
Leibniz Institute für Katalyse e. V. an der Universität Rostock
Albert-Einstein-Strasse 29a, 18059 Rostock, Germany
johannes.devries@catalysis.de
O
Ru CO
H
Ru CO
H
CN
R
Supporting information for this article is given via a link at the end of
the document.
Scheme 2 Mechanism of oxa-Michael addition to -unsaturated nitriles
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ChemCatChem
10.1002/cctc.201800509
FULL PAPER
Catalyst 1
2
While it is found that direct conjugate addition of H O to
unsaturated nitriles with this catalyst system proceeds with
relatively poor yields, the addition of benzyl alcohol followed by
R
H
2
O
R
R
CN
CN
CN
solvent
+
OH
R
2
3
CN
4
2
Pd(OH) /C-catalyzed hydrogenation leads to the formation of the
R = Et (a); Me (b)
desired -amino alcohols in a synthetically useful manner.
Scheme 3. Direct addition of H
Et) catalyzed by 1.
2
O to crotonitrile (R = Me) and pentenenitrile (R
=
Results and Discussion
Oxa-Michael addition of benzyl alcohol. We next turned our
attention to benzyl alcohol addition followed by reductive
cleavage of the benzyl group as a method to obtain formal water
addition products. A series of unsaturated nitriles with different
steric and electronic properties was selected to examine the
scope of benzyl alcohol addition catalysed by 1. The substrates
examined were commercially available, or, in the case of 2d,
easily synthesized by olefin metathesis between acrylonitrile and
Oxa-Michael addition using water as nucleophile. Direct
conjugate addition of water to ,-unsaturated acceptors is
challenging due to the poor nucleophilicity of water and the
reversibility of the addition reaction.[ Although enzymes are
capable of performing hydration of (activated) olefins with
exquisite control and artificial metalloenzymes have been
12]
[13]
reported for this reaction, general synthetic methodologies are
lacking. Detours using water surrogates (e.g., oximes or boronic
acids) have been used, as well as (asymmetric) conjugate
addition of silyl and boryl nucleophiles.[ Conjugate additions to
methyl oleate using
a second generation Hoveyda-Grubbs
catalyst. The conditions we previously reported for oxa-Michael
14]
addition to unsaturated nitriles by 1 were employed (0.5 mol%
,-unsaturated substrates with a nitrile as electron-withdrawing
[18]
1
,
at room temperature in THF), and reaction progress was
group have been studied comparatively little due to their low
reactivity as Michael acceptors,[9] but Kobayashi and co-workers
recently reported Cu(II)-catalyzed borylation of these
monitored by TLC (Scheme 4). Upon completion, the catalyst
was quenched by opening the flask to air, and the crude mixture
was purified by column chromatography (Table 1). Using this
procedure, benzyl alcohol addition to crotonitrile afforded the
product 5b as colourless oil in 71% isolated yield. Similarly,
substrate 2c, containing a linear fatty ester-derived tail, allowed
full conversion and isolation of the benzyl ether 5c in 30% yield.
Branching in the -substituent is tolerated by the catalyst as
demonstrated by the formation of the 3-cyclopentylpropanenitrile
derivative 5d, although the conversion at room temperature was
found to be even lower. Given that oxa-Michael addition
reactions in general are not very much favoured
thermodynamically, we reasoned that the reaction might stall at
an equilibrium mixture of starting materials and product.
Conducting the reaction at lower temperature (-30 °C) indeed
gave higher conversion (70%) and allowed isolation of the
products 5c and 5d in moderate yields (63% and 40%,
respectively). As reported previously, oxa-Michael addition to
cinnamonitrile was unsuccessful,[16] but testing the reactivity of
substrates.[ We decided to test our ‘metal-ligand cooperative’
15]
nitrile activation strategy[
10, 16]
in the direct conjugate addition of
water to unsaturated nitriles. Thus, 2-pentenenitrile (2a) was
reacted with water (20 equiv) in tert-amyl alcohol (TAA, an
alcohol that itself is unreactive under these conditions) in the
presence of 0.5 mol% of 1 (Scheme 3). After stirring overnight
the reaction mixture was analyzed by GC/MS which showed
1
4
9% conversion of the pentenenitrile starting material, of which
7% is the H O addition product 3a (the remainder is the
2
pentene nitrile dimerization product 4a). Increasing the
temperature to 70 °C resulted in 53% conversion (of which 56%
is 3a). Subsequent column chromatography allowed isolation of
a fraction that was shown to contain 3a as the main component
based on NMR and GC/MS data, albeit in poor yield (13%) and
with impurities still present. The increased reactivity of 1 at 70 °C
is likely due to the reversibility of the reaction between H
1
2
O and
, resulting in a higher concentration of ‘free’ 1.[17] We attribute
3
the more activated p-CF substituted cinnamonitrile derivative 2e
the formation of relatively large amounts of dimer 4a to the
biphasic nature of these reactions, with only a limited amount of
water present in the organic phase. To minimize formation of
dimers 4, we switched to crotonitrile (2b) which is less prone to
isomerization, and carried out the catalysis in homogeneous
did form the oxa-Michael addition product 5e at -30 °C in 63%
yield. Similarly, 4,4,4-trifluorobutenenitrile 2f gave poor
conversion at room temperature, but decreasing the temperature
of the reaction to -30 °C allowed isolation of the benzyl alcohol
addition product 5f in 40% yield.
With compounds 5 in hand, we proceeded with attempts to
cleave the benzyl ether to form the corresponding 3-
hydroxynitriles 3. Treatment of 5b with a stoichiometric amount
2 2
mixtures of organic solvent/water (THF/H O,
O and tBuOH/H
both in 3/1 ratio; and t-amyl alcohol/H
2
O in a 30/1 ratio). At
t
ambient temperature, the protic solvents BuOH and TAA
afforded the oxa-Michael addition product according to GC/MS
analysis as minor product (up to 54% of the converted starting
material), while in THF only the dimer 4b was observed. At
3
of FeCl and TMSCl in DCM afforded 3-hydroxybutanenitrile 3b
in 45% isolated yield after column chromatography. The other
corresponding -hydroxy-nitriles (formal water addition products)
7
0 °C, the selectivity to the desired product 3b was increased
3c-f was obtained from moderate to excellent yields (Table 1)
t
(up to 84% in BuOH/H
2
O) but conversions remained low, which
thermodynamic equilibrium being
using the same method.
could be related to
reached.[
a
12]
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ChemCatChem
10.1002/cctc.201800509
FULL PAPER
although their chemical shifts are close, the 13C NMR spectra
clearly show 3 distinct resonances for the RRR, RSS and RSR
diastereomers (and their respective antipodes). The related
cat 1
R
R
CN
CN
5a R = Et
5b R = Me
BnOH
OBn
2
5
5
c R = (CH ) COOMe
2 7
tris(2-hydroxylalkyl)amines derived from ethylene and propylene
FeCl
3
DCM
R
5d R = c-Pent
[1a]
oxide,
have found extensive use (for example: main group
TMSCl
5
5
e R = p-CF C H
f R = CF3
3 6 4
[21]
tripodal ligands in coordination chemistry[22] and
atranes,
catalysis,[
23]
cosmetics additives[24]). On the other hand, the
CN
corresponding 3-hydroxyalkyl amines have not been extensively
OH
3
investigated.[ Testing the hydrogenation of compounds 5c and
25]
5
d under identical conditions also allowed isolation of the
Scheme 4. Synthesis of -hydroxy-nitriles via oxa-Michael addition of benzyl
alcohol to -unsaturated nitriles, followed by benzyl ether cleavage
corresponding substituted tris(3-hydroxyalkyl)amines 6c and 6d
in reasonable yields (Table 1). Thus, this oxa-Michael addition /
hydrogenation sequence provides
a
convenient entry to
trialcoholamines with C
functional groups.
3
linker in between the amine and alcohol
Table 1. Yields of oxa-Michael addition reactions to give compounds 5, and
subsequent benzyl ether cleavage to the -hydroxy-nitriles 3
yield (conversion) %[a]
H
Substrates
R
N
R
R =
5
3
Pd(OH) /C
2
OH
6'
OH
1
2
3
4
5
Me (b)
71(100)
63(100)
40(70)
62(68)
40(66)
45
77
85
94
63
H (5 bar)
R
2
+
CN
MeOH
2
(CH )
7
COOMe (c)
Cyp (d)
p-CF
CF
OBn
HO
R
5
5
5
5
5
b R = Me
c R = (CH ) COOMe
d R = c-Pent
e R = p-CF
f R = CF3
2
7
3
C
6
H
4
(e)
R
N
OH
C H
3 6 4
3
(f)
OH
6
R
[
a] Reaction conditions:ⅰ) oxa-Michael additions: nitrile (5 mmol), BnOH (7.5
Scheme 5. Hydrogenation of 3-benzyloxy-alkylnitriles to
secondary and tertiary amines
a mixture of
mmol), Milstein catalyst (0.5 mol%) in THF (10ml) at RT overnight (5b) or at -
o
3
(
0
C for 2 days (5c-f); ⅱ) Cleavage of benzyl ether: 5 (0.4 mmol), TMSCl
(0.44 mmol) in DCM (2 ml) at RT for 3h; isolated yields are
given; conversions determined by GC-MS analysis using n-pentadecane as
0.44 mmol), FeCl
3
19
internal standard or using F NMR spectroscopy (for e and f).
Carrying out the Pd(OH)
under basic conditions (MeOH with 6 equiv of NEt
presence of Boc O allowed isolation of the corresponding Boc-
2
/C-catalyzed hydrogenation of 5b
3
) in the
Hydrogenation of -benzyloxy-nitriles. The oxa-Michael
2
protected primary amine 7b in 78% yield (Scheme 6, Table 1).
Under these conditions, only the nitrile is hydrogenated; the
benzyl ether remains intact. Subsequent hydrogenation of 7b
under neutral conditions afforded the Boc-protected -amino
alcohol 8b in 91% isolated yield.
addition products
5
were subsequently submitted to
hydrogenation conditions. It proved possible to hydrogenate
compounds 5 to a mixture of secondary (6’) and tertiary (6)
amino alcohols in which both the benzyl group was removed and
also the nitrile was hydrogenated (Scheme 5). Specifically,
stirring a methanol solution of 5b under 5 bar of H
2
in the
presence of 10 wt% Pd(OH) /C allowed isolation of tris(3-
2
Pd(OH)
2
/C, H
2
R
R
NHBoc
H
2
R
NHBoc
hydroxybutyl)amine 6b in 65% yield as a colourless oil after
column chromatography. Moreover, the corresponding bis(3-
hydroxybutyl)amine 6a’ was also obtained from this mixture in
CN
(
Boc)
2
O, Et
3
N
2
Pd(OH) /C
OBn
OBn
OH
MeOH
5
7
8
2
3% yield. Thus, it appears that under these conditions, the
b R = Me
c R = (CH ) COOMe
d R = c-Pent
e R = p-CF C H
Pd(OH)
2
/C, H
2
imine that is initially formed by nitrile hydrogenation is
intercepted by the primary amine to yield the secondary product
2 7
HCl, MeOH
3
6 4
R
NHBoc
0e
R
NH Cl
3
6b’, which subsequently is transformed to the tertiary product 6b.
f R = CF
3
1
The lack of selectivity for the primary amine in these
OH
[19]
hydrogenation reactions is well-known, and product mixtures
are often obtained. Related to our observation of a reasonable
degree of selectivity to the tertiary product, Monguchi, Sajiki and
co-workers reported very recently that mild Pd/C-catalyzed
hydrogenation of aliphatic nitriles leads to tertiary amines as the
major product.[ Compound 6b is obtained as a mixture of
diastereoisomers, as can be seen from the NMR spectra:
9
R
NH
3
Cl
11e
Scheme 6. Hydrogenation of 3-benzyloxy-alkylnitriles
20]
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ChemCatChem
10.1002/cctc.201800509
FULL PAPER
Finally under acidic conditions (1.25 M HCl in MeOH) using
Pd(OH) /C as the catalyst, the unprotected -amino alcohol 9b
was obtained directly in good yield (88% as its HCl salt, 9b∙HCl).
The other 3-benzyloxy-nitriles (5) reacted similarly to give the -
amino alcohol derivatives 7-9 in synthetically useful yields (Table
of the secondary and tertiary amino alcohols 6’/6, which could
be separated by column chromatography. Reduction under
acidic conditions gave the HCl salts of the primary amino
alcohols 9 in very good yields. Reduction under basic conditions
in the presence of Boc anhydride gave the Boc-protected 3-
benzyloxyalkylamines 7, which could be hydrogenated further to
give the Boc-protected -amino alcohols 8. These products may
2
2).
ꢀ
ꢀ ꢀ ꢀ ꢀ use as building blocks for pharmaceuticals or for ligands.
Table 2. Yields of hydrogenation products
yield%
8[c]
substrates
Experimental Section
6
/6’[a]
7[b]
78
95
68
90
9[d]
88
93
General
considerations:
[2-(Di-tert-butylphosphinomethyl)-6-
chlorocarbonyl hydride,
/C, HCl in MeOH (~1.25M), di-tert-butyl-dicarbonate, TMSCl,
1
2
3
4
Me (b)
COOMe (c)
Cyp (d)
p-CF
65/23
53/nd
36/nd
-
91
83
97
(diethylaminomethyl)pyridine]ruthenium(II)
2
(CH )
7
Pd(OH)
2
FeCl
without further purification. THF (Aldrich, anhydrous, 99.8%) was dried by
percolation over columns of Al (Fluka). The compounds 2-
3
, triethylamine and methanol are commercially available and used
99
89[e]
2 3
O
3
C
6
H
4
(e)
-
86][
f]
[87]
[g]
[
pentenenitrile (Sigma-Aldrich, 98%), crotonitrile (TCI, 98%), 3-
cyclopentylpropenenitrile (Spirochem AG, 95%) and p-trifluoromethyl
cinnamonitrile (Enamine Ltd) were obtained commercially, degassed and
5
CF
3
(f)
-[h]
-[i]
89
95
2 3
passed over columns of Al O prior to use. Methyl 10-cyano-dec-9-
[
a]
°
[b]
5
+ Pd catalyst (10 wt%) in MeOH, 5 bar H
2
, 50 C for 3d. 5, Et
3
N (6 eq),
[c]
enoate (2c) was prepared according to a literature procedure.[26] NMR
spectra were recorded on Varian 400, Agilent 400 or Varian Inova 500
spectrometers and referenced using the residual solvent resonance. Gas
chromatography measurements were performed on HP6890 series
equipped with a Rxi-5Sil column for GC/MS and HP5890 series II
equipped with Rtx-1701 column for GC-MS/FID. Elemental analysis and
high resolution mass spectra (HRMS) were performed at the
Microanalytical Department of the University of Groningen.
(
+
(
Boc)
2
O (3 eq) + Pd catalyst (50 wt%) in MeOH, 1 bar H
2
at RT overnight.
d]
7
Pd catalyst (10 wt%) in MeOH, 1 bar H
2
at RT overnight. [ 5 + Pd catalyst
10 wt%) in MeOH/HCl, 5 bar H
2
at RT overnight. [e] as [d], but reactions
[f]
[g]
stopped after 3h. Yield of 10e, obtained using the conditions under [c].
[
h]
Yield of 11e. Products decompose during alumina column chromatography.
[i]
Hydrogenation using conditions under [b] gave 8f directly.
However,
trifluoromethylcinnamonitrile-derived compound 5e in the
presence of triethylamine/Boc led to 7e in good yield,
attempts to cleave the benzyl ether in this product by
subsequent Pd(OH) /C catalysed hydrogenation under neutral
conditions did not form the desired product 8e. Instead, we were
able to cleanly isolate compound 10e, in which the oxygen
functionality is lost. Similarly, hydrogenolysis conditions
although
hydrogenation
of
the
2
O
Typical procedure for oxa-Michael addition: A Schlenk flask was
loaded with THF (10 mL), Benzyl alcohol (7.5 mmol,1.5 eq., 0.78 mL)
and crotonitrile (5 mmol) in the glovebox. Then freshly prepared Milstein
catalyst in THF (0.5 ml), made by reacting the precursor ([2-(di-tert-
butylphosphinomethyl)-6-(diethylaminomethyl)pyridine]ruthenium(II)
chlorocarbonyl hydride) (0.025 mmol, 12.2 mg, 0.5 mol%) with t-BuOK
2
(
2 2
Pd(OH) /C, 5 bar H , in MeOH/HCl overnight) that for the other
(0.025 mmol, 2.8 mg, 0.5 mol%) was added in a glovebox into the
substrates allowed isolation of the amino alcohols (9∙HCl), led to
loss of the OH moiety and formation of 11e. It is likely that 9e is
an intermediate in the formation of 11e, as venting the reaction
mixture after 3 hours instead of overnight followed by workup did
give compound 9e in 89% isolated yield. These findings suggest
that cleavage of the unsubstituted benzyl ether bond is favoured,
but the remaining (substituted) benzylic C-OH moiety is also
susceptible to hydrogenolysis.
Schlenk flask dropwise via a syringe and the reaction was stirred under
nitrogen at ambient temperature (or -30˚C for 2d) overnight. After full
conversion of the substrate as observed by GC, the reaction was
quenched by exposure to air. Then removal of solvent under vacuum
gave
chromatography with
AcOEt/Hexane=1/9. Product 5b was obtained as colorless liquid (Yield:
1%, 0.62 g).
a
dark brown residue which was purified by column
a
gradient elution from hexane to
7
Typical procedure for the synthesis of compound 3: A Schlenk flask
was loaded with 3-benzyloxybutanenitrile (0.4 mmol, 70 mg), DCM (2 ml)
and TMSCl (0.44 mmol, 1.1 eq., 23.7 mg). To the solution was added
Conclusions
Attempted direct addition of water to -unsaturated nitriles
catalyzed by Milstein’s Ruthenium PNN pincer complex gave the
3
FeCl (0.44 mmol, 1.1 eq., 35.6 mg). The reaction was stirred under
nitrogen at ambient temperature for 3h. After full conversion of the
substrate was observed by TLC, the reaction mixture was quenched with
water and extracted with ether. The combined organic layers were dried
3-hydroxy-alkylnitriles 3 in mediocre yields. On the other hand,
the addition of benzyl alcohol catalyzed by the same catalyst
proceeded in excellent yields. The products (5) were reduced to
the -amino alcoholsin a number of different ways. Pd(OH)
catalyzed hydrogenation under neutral conditions gave a mixture
over Na
2
SO
4
, and concentrated under vacuum. The residue was purified
2
/C
by column
chromatography with gradient elution from
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ChemCatChem
10.1002/cctc.201800509
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AcOEt/Hexane=1/10 to AcOEt/Hexane=1/2 to give the alcohol 3b (Yield:
5%, 15 mg).
Financial support from the China Scholarship Council (CSC
fellowship to B.G.) and the Netherlands Organisation for
Scientific Research (NWO VIDI grant to E.O.) is gratefully
acknowledged.
4
Typical procedure for the synthesis of compounds 6 and 6’: A
solution of 3-benzyloxybutanenitrile (70 mg, 0.4 mmol) in methanol (2
2
mL) was treated with 20% Pd(OH) /C (10 wt% w.r.t. substrate, 7 mg).
°
The mixture was stirred under hydrogen (5 bar) at 50 C for 3d. After full
conversion of the substrate was observed by TLC, the reaction mixture
was filtered. Removal of the solvent under vacuum and purification of the
residue by column chromatography with gradient elution from DCM to
DCM/MeOH/Ammonia=9/9/1. The secondary and tertiary amine were
isolated as pure compounds using this chromatographic separation
procedure. Both are a colorless oit, and obtained as a mixture of
diastereoisomers: 6b (yield: 65%, 21 mg) and 6b’ (yield: 23%, 7.4 mg).
Typical procedure for the synthesis of compound 7: A Schlenk flask
was loaded with 3-benzyloxybutanenitrile (0.4 mmol, 70 mg),
trimethylamine (2.4 mmol, 6 eq., 242 mg), di-tert-butyl-dicarbonate (1.2
Conflict of Interest
The authors declare no conflict of interest.
Keywords: nitriles • amino alcohols • ruthenium • pincer ligand •
hydrogenation
[
1]
a) M. Frauenkron, J.-P. Melder, G. Ruider, R. Rossbacher, H. Höke in
Ethanolamines and Propanolamines, Wiley-VCH Verlag GmbH & Co.
KGaA, 2000; b) S. C. Bergmeier Tetrahedron 2000, 56, 2561-2576.
a) D. J. Ager, I. Prakash, D. R. Schaad Chem. Rev. 1996, 96, 835-876;
b) S. M. Lait, D. A. Rankic, B. A. Keay Chem. Rev. 2007, 107, 767-796.
P. R. Carlier, K. M. Lo, M. M. C. Lo, I. D. Williams J. Org. Chem. 1995,
[2]
2
mmol, 3.0 eq., 261 mg), 20% Pd(OH) /C (50 wt% w.r.t. substrate, 35 mg)
[
[
3]
4]
and MeOH (2 ml). The reaction was stirred under hydrogen (~1 bar) at
ambient temperature overnight. After full conversion of the substrate was
observed by GC, the reaction mixture was filtered and the solvent was
evaporated under vacuum. Purification by flash column chromatography
gave product 7b as colorless liquid (Yield: 78%, 85mg).
6
0, 7511-7517.
M. T. Robak, M. A. Herbage, J. A. Ellman Chem. Rev. 2010, 110, 3600-
740.
3
[5]
[6]
G. T. Rice, M. C. White J. Am. Chem. Soc. 2009, 131, 11707-11711.
M. Zeng, S. B. Herzon J. Org. Chem. 2015, 80, 8604-8618.
[
7]
J. M. M. Verkade, P. J. L. M. Quaedflieg, G. K. M. Verzijl, L. Lefort, F. L.
van Delft, J. G. de Vries, F. P. J. T. Rutjes Chem. Commun. 2015, 51,
Typical procedure for the synthesis of compound 8: A Schlenk flask
was loaded with tert-butyl 3-benzyloxy-butylcarbamate (0.2 mmol, 56 mg),
1
4462-14464.
a) H. A. Bruson Org. React. 1949; b) P. F. Butskus Russ. Chem. Rev.
961, 30, 583.
F. F. Fleming, Q. Wang Chem. Rev. 2003, 103, 2035-2078.
2
20% Pd(OH) /C (10 wt% w.r.t. substrate, 5.6 mg) and MeOH (1 ml). The
[
[
8]
9]
flask was connected with a hydrogen balloon (~1 bar) and the reaction
was stirred at ambient temperature overnight. After full conversion of the
substrate was observed by TLC, the reaction mixture was filtered and the
solvent was evaporated under vacuum. Purification by flash column
chromatography gave product 8b as colorless liquid (Yield: 91%, 34 mg).
Synthesis of compound 10e: A Schlenk flask was loaded 7e (0.17
1
[10] S. Perdriau, D. S. Zijlstra, H. J. Heeres, J. G. de Vries, E. Otten Angew.
Chem. Int. Ed. 2015, 54, 4236-4240.
[
11] J. R. Khusnutdinova, D. Milstein Angew. Chem. Int. Ed. 2015, 54,
2236-12273.
1
[
[
12] V. Resch, U. Hanefeld Catal. Sci.Techn. 2015, 5, 1385-1399.
13] a) A. J. Boersma, D. Coquière, D. Geerdink, F. Rosati, B. L. Feringa, G.
Roelfes Nat. Chem. 2010, 2, 991-995; b) J. Bos, A. Garcia-Herraiz, G.
Roelfes Chem. Sci. 2013, 4, 3578-3582.
2
mmol, 70 mg), 20% Pd(OH) /C (10 wt% w.r.t. substrate, 7.0 mg) and
MeOH (1 ml). The flask was connected with a hydrogen balloon (~1 bar)
and the reaction was stirred at ambient temperature overnight. After full
conversion of the substrate was observed by TLC, the reaction mixture
was filtered and the solvent was evaporated under vacuum. Purification
by flash column chromatography gave product 10e as colorless liquid
[14] E. Hartmann, D. J. Vyas, M. Oestreich Chem. Commun. 2011, 47,
7917-7932.
[
[
15] a) L. Zhu, T. Kitanosono, P. Xu, S. Kobayashi Beilstein J. Org. Chem
015, 11, 2007; b) L. Zhu, T. Kitanosono, P. Xu, S. Kobayashi Chem.
2
(
Yield: 86%, 44 mg).
Commun. 2015, 51, 11685-11688.
Typical procedure for the synthesis of compound 9: A solution of 3-
16] L. E. Eijsink, S. C. P. Perdriau, J. G. de Vries, E. Otten Dalton Trans.
benzyloxybutanenitrile (70 mg, 0.4 mmol) in methanol containing HCl
2016, 45, 16033-16039.
2
(~1.25M, 2 mL) was treated with 20% Pd(OH) /C (10 wt% w.r.t. substrate,
[17] S. W. Kohl, L. Weiner, L. Schwartsburd, L. Konstantinovski, L. J. W.
7
mg). The reaction was stirred under hydrogen (~5 bar) at ambient
Shimon, Y. Ben-David, M. A. Iron, D. Milstein Science 2009, 324, 74-77.
[
[
18] Catalyst 1 was freshly prepared in-situ from the aromatic hydrido-
chloride precursor (PNP)Ru(H)(Cl)(CO) by treatment with 1.0 eq of
KOtBu in THF.
temperature overnight. Then the reaction mixture was filtered and the
solvent was evaporated under vacuum. After washing the residue with
Et
8%, 22 mg).
Synthesis of compound 11e: A solution of 5e (61 mg, 0.2 mmol) in
methanol containing HCl (~1.25M, mL) was treated with 20%
Pd(OH) /C (10 wt% w.r.t. substrate, 6.1 mg). The reaction was stirred
2
O and pentane, 4-aminobutan-2-ol was obtained as its HCl salt (Yield:
19] a) S. Gomez, J. A. Peters, T. Maschmeyer Adv. Synth. Catal. 2002,
8
3
44, 1037-1057; b) D. B. Bagal, B. M. Bhanage Adv. Synth. Catal. 2015,
57, 883-900.
3
1
[20] Y. Monguchi, M. Mizuno, T. Ichikawa, Y. Fujita, E. Murakami, T. Hattori,
2
T. Maegawa, Y. Sawama, H. Sajiki J. Org. Chem. 2017.
[
[
21] a) J. G. Verkade Acc. Chem. Res. 1993, 26, 483-489; b) J. G. Verkade
Coord. Chem. Rev. 1994, 137, 233-295; c) J. K. Puri, R. Singh, V. K.
Chahal Chem. Soc. Rev. 2011, 40, 1791-1840.
under hydrogen (~5 bar) at ambient temperature overnight Then the
reaction mixture was filtered and the solvent was evaporated under
2
vacuum. After washing the residue with a Et O:pentane (1:10) solvent
22] a) Y. Kim, Y. Han, J.-W. Hwang, M. W. Kim, Y. Do Organometallics
mixture, pure 11e (36 mg, yield 87%) was obtained.
2002, 21, 1127-1135; b) A. M. Kirillov, Y. Y. Karabach, M. Haukka, M. F.
C. G. da Silva, J. Sanchiz, M. N. Kopylovich, A. J. L. Pombeiro Inorg.
Chem. 2008, 47, 162-175; c) T. N. Hooper, S. K. Langley, S. Gomez-
Coca, G. Lorusso, E. Ruiz, K. S. Murray, M. Evangelisti, E. K. Brechin
Acknowledgements
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ChemCatChem
10.1002/cctc.201800509
FULL PAPER
Dalton Trans. 2017, 46, 10255-10263; d) Y. H. Wen, H. M. Zhang, P.
Qian, H. T. Zhou, P. Zhao, B. L. Yi, Y. S. Yang Electrochim. Acta 2006,
1, 3769-3775; e) K. Gong, F. Xu, J. B. Grunewald, X. Ma, Y. Zhao, S.
5
Gu, Y. Yan ACS Energy Lett. 2016, 1, 89-93; f) Z. Boulsourani, G. D.
Geromichalos, K. Repana, E. Yiannaki, V. Psycharis, C. P.
Raptopoulou, D. Hadjipavlou-Litina, E. Pontiki, C. Dendrinou-Samara J.
Inorg. Biochem. 2011, 105, 839-849.
[
[
23] a) H. J. Li, L. Wang Eur. J. Org. Chem. 2006, 2006, 5099-5102; b) D.
Wang, D. Kuang, F. Zhang, S. Tang, W. Jiang Eur. J. Org. Chem. 2014,
2014, 315-318.
24] a) S. Zhu, M. Heppenstall-Butler, M. F. Butler, P. D. A. Pudney, D.
Ferdinando, K. J. Mutch J. Phys. Chem B 2005, 109, 11753-11761; b)
S. Zhu, P. D. A. Pudney, M. Heppenstall-Butler, M. F. Butler, D.
Ferdinando, M. Kirkland J. Phys. Chem B 2007, 111, 1016-1024; c) M.
M. Fiume, B. Heldreth, W. F. Bergfeld, D. V. Belsito, R. A. Hill, C. D.
Klaassen, D. Liebler, J. James G. Marks, R. C. Shank, T. J. Slaga, P.
W. Snyder, F. A. Andersen Int. J. Toxicol. 2013, 32, 59S-83S.
[
[
25] a) F. Renaud, C. Decurnex, C. Piguet, G. Hopfgartner J. Chem. Soc.,
Dalton Trans. 2001, 1863-1871; b) R. A. Franich, B. K. Nicholson, H. W.
Kroese, S. S. Gallagher, R. Meder, J. R. Lane, B. D. Kelly Polyhedron
2011, 30, 2884-2889.
26] R. Malacea, C. Fischmeister, C. Bruneau, J.-L. Dubois, J.-L. Couturier,
P. H. Dixneuf Green Chem. 2009, 11, 152-155.
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