Ruthenium-Catalyzed Deaminative Hydrogenation of Amino Nitriles: Direct Access to 1,2-Amino Alcohols

Article abstract of DOI:10.1002/chem.201900531

A new approach for the efficient and highly selective synthesis of 1,2-amino alcohols by direct reductive hydrolysis of N-formyl-protected α-amino nitriles is reported. The commercially available RuHCl(CO)(PPh₃)₃ complex was found to be a suitable catalyst for this operationally simple protocol, in which no stoichiometric amounts of undesired metal waste are generated. The deaminative hydrogenation is performed at 55 bar of H₂, using a 6:1 mixture of 1,4-dioxane/water as solvent. In addition, hydroxymethyl alcohols were prepared from cyanoketones under very similar conditions.

Full text of DOI:10.1002/chem.201900531

A Journal of
Accepted Article
Title: Ruthenium-Catalyzed Deaminative Hydrogenation of Amino
Nitriles: Direct Access to 1,2-Amino Alcohols
Authors: Pilar Calleja, Martin Ernst, A. Stephen K. Hashmi, and
Thomas Schaub
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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To be cited as: Chem. Eur. J. 10.1002/chem.201900531
Link to VoR: http://dx.doi.org/10.1002/chem.201900531
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10.1002/chem.201900531
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Ruthenium-Catalyzed Deaminative Hydrogenation of Amino
Nitriles: Direct Access to 1,2-Amino Alcohols
Pilar Calleja,[a] Martin Ernst,[b] A. Stephen K. Hashmi,[a,c] and Thomas Schaub*[a,b]
We dedicate this paper to the memory of Dr. Friedhelm Balkenhohl
Abstract: A new approach for the efficient and highly selective
synthesis of 1,2-amino alcohols by direct reductive hydrolysis of N-
formyl protected α-amino nitriles is reported. The commercially
available RuHCl(CO)(PPh3)3 complex was found to be a suitable
catalyst for this operationally simple protocol, in which no
stoichiometric amounts of undesired metal waste are generated. The
deaminative hydrogenation is performed at 55 bar of H2, using a 6:1
mixture of 1,4-dioxane/water as solvent. In addition, hydroxymethyl
alcohols were prepared from cyanoketones under very similar
conditions.
(AMP) is a widely used organic base for neutralizing and
solubilizing applications.[10] It is also used in cosmetics and in hair
sprays, as a dispersing agent for powders and pigments, as well
as a wetting agent. Technically, it is produced by nitration of
alkanes, followed by a Henry reaction with formaldehyde and
reduction to the amino alcohol (Scheme 1b). Unfortunately, this
protocol is not suitable for the preparation of more complex amino
alcohols and it suffers from several drawbacks, such as the low
selectivity in the nitration of the alkane or the safety risks of
handling nitroalkanes.
Therefore, the development of more efficient, low-cost, safe
and sustainable protocols for the direct access to these valuable
molecules is still an important challenge.
Introduction
1,2-Amino alcohols (ß-amino alcohols) are a versatile class of
compounds with diverse applications covering synthetic,
medicinal, coordination and materials chemistry.[1] These
compounds are a very common structural motif in a range of
natural and unnatural products,[2] and are also frequently used in
asymmetric synthesis as chiral auxiliaries or chiral catalysts.[3]
Thus, extensive efforts have been devoted towards the
development of new strategies for the synthesis of vicinal amino
alcohols. Typical methods for their preparation include
nucleophilic cleavage of epoxides/aziridines,[4] reduction of
carbonyl, imino or nitro compounds,[5] coupling reactions,[6] as well
as amino-hydroxylation of olefins (Scheme 1a).[7] Another
approach that has attracted much attention in recent years is the
intra-[8] and intermolecular late stage functionalization of C(sp3)-H
bonds.[9] However, many of the above-mentioned procedures
require the use of expensive reagents and catalysts, exhibit low
regio/stereoselectivity or involve the generation of stoichiometric
amounts of waste, which are limiting factors for a successful
industrial application.
a)
Classical Methods
OH
X
or
NO2
Y
Reduction reactions
X
Ring opening of
epoxides/aziridines
Aminohydroxylation
HO
DG
NH2
X
H
O
X = O,N
NR
Late stage C(sp3)-H
functionalization
Cross coupling
Industrial Process for the Preparation of AMP
b)
NO2
O2N
HNO3
Me
HCHO
[Red]
H2N
OH
OH
Me
Me
Me
Me Me
Me Me
From a purely industrial perspective, substituted ß-amino
alcohols are extremely valuable compounds, useful in a wide
range of applications. As an example, 2-amino-2-methyl propanol
via Henry reaction
c)
This Work:
R3HN
R1
CN
R2
Direct Reductive Hydrolysis
H2N
R1 R2
OH
[a]
[b]
[c]
Dr. P. Calleja, Prof. Dr. A. S. K. Hashmi, Dr. T. Schaub
Catalysis Research Laboratory (CaRLa)
Im Neuenheimer Feld 584, 69120 Heidelberg (Germany)
E-mail: Thomas.schaub@basf.com
Dr. M. Ernst, Dr. T. Schaub
Synthesis and Homogeneous Catalysis
BASF SE
Scheme 1. Common Synthetic Strategies for the Preparation of 1,2-Amino
Alcohols.
Results and Discussion
Carl-Bosch-Str. 38, 67056 Ludwigshafen (Germany)
Prof. Dr. A. S. K. Hashmi
Organisch-Chemisches Institut
Karls-University Heidelberg Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Based on our recent studies on the transition metal catalyzed
deaminative hydrogenation of nitriles to form primary
alcohols,[11,12] we were intrigued by the possibility of accessing
these important motifs by direct reductive hydrolysis of α-amino
nitriles, as an alternative to the current protocols (Scheme 1c). A
Supporting information for this article is given via a link at the end of
the document.
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number of α-amino nitriles can be easily synthesized via Strecker
reaction involving the condensation of a carbonyl group with
ammonia and hydrogen cyanide (or equivalents).[13] This is one of
the simplest and most economical methods for the preparation of
α-amino acids for both laboratory and industrial scales.[14]
However, in our initial investigations for the direct conversion of
free α-amino nitriles, only hydrolysis in a reverse Strecker reaction
was observed (Scheme 2, see also Supporting Information).
(entry 6), although the use of higher catalyst loading or higher H2
pressure did not result in an increment of the overall yield (entries
5 and 6 vs. 4). Since it was previously demonstrated that small
amounts of oxygen were well tolerated for this transformation,[11]
all the reagents could be handled under air and the system was
only purged with nitrogen prior to pressurization. In contrast to
what was observed for the reductive hydrolysis of simple
nitriles,[11] no product was formed when the reaction was run in
alcohol-type solvents (entries 7 and 8).
Three different ligands were also screened in the presence of
catalyst A. The addition of Xantphos or tridentate Triphos ligand
resulted in a decrease in its selectivity (Table 1, entries 9 and 11),
while the presence of dppe ligand completely inhibited its activity
(entry 10). Other Ru(II)-complexes bearing pincer-type ligands (B
and C), as well as Ru-MACHO® (D) or (Triphos)-Ru(CO)H2 (E),
which are frequently used for selective hydrogenation reactions,
were also evaluated.[16] However, none of them gave comparable
results to those achieved with Ru(II)-complex A (entries 12-15 vs.
4-6). In the presence of non-precious metal-based
Co(BF4)2•6H2O/Triphos system,[17] no product was formed albeit
the starting material was completely consumed (entry 17). Further
studies in the assessment of catalyst stability and recyclability are
currently underway in our laboratory.
RuHCl(CO)(PPh3)3 turned to be the most suitable catalyst for
this transformation, showing the perfect compromise between
reactivity and selectivity. According to the proposed mechanism
for the reductive hydrolysis of N-formyl protected α-amino nitriles
1, the nitrile group was hydrogenated to give imine 4, which was
then converted into aldehyde 5 in the presence of water and
further hydrogenated to the corresponding primary alcohol 2
(Scheme 4, path A). Final reduction of N-formyl group of protected
amino alcohol 2 was found to be slower and could only be
completed at higher H2 pressures (see also below). When more
active hydrogenation catalysts were used (Table 1, entries 11, 12
and 15), competitive processes such as formyl deprotection prior
nitrile reductive hydrolysis as well as reduction of imine 4 to give
primary amines 6 or 7 (Scheme 4, paths B and C) could not be
avoided, giving rise to complex mixtures of oligomers.
H2 (10 bar)
O
H2N
Me
CN
Me
RuHCl(CO)(PPh3)3 (1 mol%)
HCN
NH3
1,4-dioxane/H 2O (1:1)
140 °C, 18 h
Me
Me
Scheme 2. Hydrolysis of Free α-Amino Nitriles via Reverse Strecker Reaction
under Reductive Hydrogenation Conditions.
In order to improve the stability of the substrate towards
hydrolysis, the formyl group was selected for the protection of the
amino functionality. We reasoned that this amino protecting group
would also meet the criteria for an industrial application: 1) easy
introduction, 2) high stability during the reductive hydrolysis of the
nitrile, 3) easy removal without the generation of undesired
byproducts, and 4) inexpensiveness.
We continued our studies on the reductive deaminative
hydrogenation of α-amino nitriles using 1a as model substrate,
which was prepared by reaction of acetone cyanohydrin with
formamide and AcOH at 125 °C (Scheme 3).[15] Based on our
original protocol,[11] we tested the influence of various solvents, H2
pressure, catalysts, catalyst loading, additives and temperature.
The most relevant results are listed in table 1.
O
CN
HO
HCONH2, AcOH
125 °C, 3 h
CN
Me
NH
Me
Me
Me
Scheme 3. Synthesis of N-Formyl Protected Amino Nitrile 1a from Acetone
Cyanohydrin.
A
O
O
O
O
cat.
H2
N
+ H2O
cat.
H2
HN
C
HN
HN
HN
Unfortunately, our first attempts to form amino alcohol 3a
using 1 mol% of RuHCl(CO)(PPh3)3 at 140 °C, under 10 bar of H2
and using a 1:1 mixture of 1,4-dioxane:water as solvent during
18 h showed no conversion (Table 1, entry 1). Increasing the
catalyst loading (entry 2), H2 pressure (entry 3) or temperature
(see also supporting information, Table S1) only led to the
isolation of complex mixtures, in which significant loss of mass
was detected. To avoid the loss or degradation of polar
compounds during the workup process, the solvent ratio was
modified from 1:1 to 6:1 and the crude mixture was directly
concentrated to dryness after the reaction was completed.
Under these conditions, the desired product was obtained in
89% overall yield as a 2.7:1 mixture of N-formyl protected (2a)
and free alkanolamine (3a) (Table 1, entry 4). Larger amounts of
free amino alcohol 3a were detected when the reaction was
performed using 5 mol% of catalyst A under 55 bar of H2 pressure
NH
OH
O
- NH3
R1 R2
R1 R2
R1 R2
R1 R2
1
4
5
2
cat. H2
cat. H2
O
cat. H2
B
N
C
H2N
C
H2N
cat.
H2
H2N
R1 R2
NH2
OH
HN
R1 R2
R1 R2
R1 R2
NH2
7
6
+ H2O
Hydrolysis
(Scheme 2)
1,2-Amino
Alcohols (3)
Oligomers
Oligomers
Scheme 4. A) Proposed Path towards 1,2-Amino Alcohols via Reductive
Hydrolysis of N-Formyl Protected α-Amino Nitriles. B) Competitive Reduction of
N-formyl Group. C) Hydrogenation of Amino Nitriles to Form Primary Amines
and Oligomers as Possible Side Products.
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Table 1. Evaluation of Conditions for the Reductive Deaminative Hydrogenation of 1a.
Entry[a]
Catalyst
Ligand/Additive
Solvent
H2.
[bar]
Conc.
[mol/L]
Conv.
[%][b]
NMR yield [%][b]
2a
<1
<1
<1
65
56
42
<1.
<1
46
<1
29
24
6
3a
<1
<1
<1
24
16
32
<1
<1
<1
<1
7
Overall
<1
1
A (1 mol%)
A (5 mol%)
A (5 mol%)
A (3 mol%)
A (3 mol%)
A (5 mol%)
A (3 mol%)
A (3 mol%)
A (5 mol%)
A (5 mol%)
A (5 mol%)
B (5 mol%)
C (5 mol%)
D (5 mol%)
E (5 mol%)
F (5 mol%)
A (3 mol%)
-
-
1,4-dioxane/water (1:1)
1,4-dioxane/water (1:1)
1,4-dioxane/water (1:1)
1,4-dioxane/water (6:1)
1,4-dioxane/water (6:1)
1,4-dioxane/water (6:1)
MeOH
10
0.5
<1
2
10
0.07
0.07
0.14
0.14
0.14
0.14
0.14
0.14
0.14
0.14
0.14
0.14
0.14
0.14
0.14
0.14
>99
>99
>99
>99
>99
>99
<5%
90
<1
3
45
<1
4
-
-
-
45
89
5
55
72
6
55
74
7
45
<1
8
EtOH
45
<1
9
Xantphos (10 mol%)
1,4-dioxane/water (6:1)
1,4-dioxane/water (6:1)
1,4-dioxane/water (6:1)
1,4-dioxane/water (6:1)
1,4-dioxane/water (6:1)
1,4-dioxane/water (6:1)
1,4-dioxane/water (6:1)
1,4-dioxane/water (6:1)
1,4-dioxane/water (6:1)
50
46
10
11
12
13
14
15
17
18[c]
dppe (10 mol%)
50
<1
<1
Triphos (10 mol%)
50
>99
>99
46
36
-
50
<1
<1
<1
<1
<1
73[d]
24
-
50
6
-
50
85
10
<1
<1
8[d]
10
-
55
>99
>99
>99[d]
<1
Triphos (10 mol%)
-
50
<1
55 / 135
81[d]
[a] Reaction conditions: nitrile (0.5 mmol), catalyst, 1,4-dioxane and water were heated in a stainless steel autoclave at 140 °C under the indicated H2 pressure for
18 h. Reagents were handled under air and the reaction mixture was flushed with nitrogen (3-5X) and hydrogen (3-5X) prior to pressurization with hydrogen. [b]
Determined by NMR analysis using Cl2CH2CH2Cl2 or hexamethylbenzene as internal standard. [c] Nitrile (5 mmol), catalyst, 1,4-dioxane and water were heated in
a 160 mL stainless steel autoclave at 150 °C under 55 bar H2 pressure for 24 h. After cooling down to rt, the H2 pressure was increased to 135 bar. The mixture was
heated at 150 °C and it was stirred under these conditions for another 24 h. [d] Determined by GC analysis using diglyme as internal standard
We also studied the influence of various additives (see
Supporting Information, table S3). It was observed that the
catalytic activity was not affected by the presence of
stoichiometric amounts of inorganic salts, although the ratio
between protected and free amino alcohol was different in each
case.[18] Finally, it was possible to obtain free amino alcohol 3a on
a gram scale by increasing the H2 pressure stepwise (entry 18).[19]
To avoid the premature deprotection of the N-formyl group, the
reaction was initially conducted using the previously described
conditions under 55 bar of H2. After 24 hours, the hydrogen
pressure was increased to up to 135 bar to give our target
compound in 73% yield.
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Table 2. Catalytic Deaminative Hydrogenation of Formyl Protected Amino
This optimized deaminative hydrogenation protocol could also
be applied to a series of other substrates (Table 2). Most of the
required nitriles 1b-j could be easily synthesized from the
corresponding cyanohydrins using the same procedure as for the
preparation of our model substrate 1a (formamide, AcOH,
125 °C).[15,20] Alternatively, direct formyl protection of amino
nitriles by treatment with acetic-formic anhydride in THF at 22 °C
also afforded compounds 1b-j in excellent yields.[21] In contrast,
attempts to prepare N-formyl protected 2-amino-2,2-diphenyl
acetonitrile by using these methods, resulted in the recovery of
benzophenone.
Nitriles.
Entry[a]
Amino Nitrile 1
Amino Alcohol·HCl (3)
Yield (%)[b]
59
1
1a
3a
In general, the reactions proceeded cleanly to afford the
desired 1,2-aminoalcohols, which were isolated after hydrolysis of
the formyl group in good to excellent yields. Our model amino
alcohol 3a could also be isolated as the ammonium salt following
this procedure, albeit with a slight diminution in the overall yield
due to the isolation procedure (Table 2, entry 1 vs. Table 1, entry
6). Other formyl protected amino nitriles bearing two alkyl
substituents afforded the expected products in satisfactory yields
(Table 2, entries 2-4). Interestingly, 2-formyl-amino-2-
phenylacetonitrile 1e was successfully hydrogenated to the
corresponding amino alcohol 3e in 93% yield (entry 5). Cyclic
formyl protected amino nitriles were also excellent substrates for
the transformation, providing the desired products in very good
yields (entries 6-10).
O
2
3
4
88
86
82
1b
3b
NH CN
Me
O
Et
NH
CN
1c
1d
3c
3d
Me
O
iPr
NH CN
Et
Et
O
5
6
7
8
93
94
93
81
NH CN
1e
1f
3e
Table 3. Catalytic Deaminative Hydrogenation of Protected Amino Nitriles.
H
Ph
Cl
3f
H3N
OH
O
O
O
Entry[a]
Amino Nitrile
Amino alcohol
Yield (%)[b]
95
Cl
NH CN
NH CN
NH CN
H3N
1g
3g
OH
OH
OH
1
1k
1l
2k
[d]
2[c]
3[c]
4
-
BocHN
OH
Cl
2l
H3N
Me Me
1h
1i
3h
3i
[e]
-
1m
1n
1o
2m
2n
2o
Cl
9
81
71
H3N
91
[e]
Cl
5
-
10
H3N
OH
1j
3j
[a] Reaction conditions: nitrile (0.5 mmol), RuHCl(CO)(PPh3)3 (5.0 mol%),
1,4-dioxane and water (6:1) were heated in a premex autoclave at 140 °C
under 50 bar H2 pressure for 17 h. [b] Isolated yield on a 0.5 mmol scale. [c]
Reaction performed at 10 bar H2. [d] Decomposition of SM. [e] No
conversion.
[a] Reaction conditions: nitrile (0.5 mmol), RuHCl(CO)(PPh3)3 (5.0 mol%), 1,4-
dioxane and water (6:1) were heated in a Premex autoclave at 140 °C under 50
bar H2 pressure for 18 h. Hydrolysis step: collected reaction crude, HCl (conc,
1.2 equiv) and EtOH (1 mL) were stirred at 20 °C for 18 h. [b] Isolated yield over
2 steps on a 0.5 mmol scale.
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Other amino nitriles bearing different protecting groups were Conclusions
also examined (Table 3). Acetyl-protected amino nitriles 1k and
1n reacted under the same conditions to give N-protected amino
alcohols 2k and 2n, which could be isolated by flash
chromatography in excellent yields (entries 1 and 4). Despite
these remarkable results, the use of the formyl protecting group
is still preferred for the industrial application not only because of
its inexpensiveness, but also because it simplifies the purification
process. Tert-butyloxycarbonyl (boc) and benzyl (bn) protecting
groups were found to be incompatible with our optimized reaction
conditions (Table 3, entries 2, 3 and 5). While N-boc protected
amino nitrile 1l underwent complete decomposition, N-bn
protected amino nitriles 1m and 1o showed no conversion,
presumably due to an initial strong coordination with the
ruthenium center, resulting in the inhibition of the catalyst activity.
Apart from amino nitriles, cyanoketones 8 were converted into
hydroxymethyl alcohols 9 under very similar reaction conditions
(Scheme 5). In all the cases the carbonyl group was reduced to
give the corresponding secondary alcohol while the nitrile group
underwent reductive hydrolysis to give the corresponding primary
alcohol.
In summary, we have developed a novel method for the
synthesis of 1,2-amino alcohols from easily accessible N-formyl
protected amino nitriles using the commercially available
RuHCl(CO)(PPh3)3 complex as the catalyst. The required
precursors can be prepared in one step from cyanohydrins or free
α-amino nitriles in very good yields. This Ru-catalyzed
deaminative hydrogenation process offers a convenient synthetic
alternative to the existing methodologies for the preparation of this
class of compounds, and avoids the generation of stoichiometric
amounts of metal waste. A number of protected amino nitriles
were converted into the corresponding vicinal amino alcohols in
excellent yields, including industrially important 2-amino-2-methyl
propanol (AMP). Moreover, hydroxymethyl alcohols can also be
accessed from cyanoketones using very similar reaction
conditions.
Experimental Section
Hydroxymethyl alcohols 9 are a versatile class of compounds,
widely applied in polymer chemistry.[22] As an example, 5-
hydroxy-1,3,3-trimethyl-cyclohexanemethanol (9a) has been
reviewed as a suitable monomer for the preparation of injection
molded polyurethane objects.[23] Currently, the only method to
produce 9a is via the reduction of 5-hydroxy-1,3,3-trimethyl-
cyclohexanecarbonitrile to the corresponding amine using LiAlH4
followed by deamination using KOH at elevated temperatures,[24]
which so far prevented its synthesis on an industrial scale. Using
our methodology, it was possible to perform a five-fold scaling up
experiment starting from cyanoketone 8a without a significant loss
of product yield and maintaining the diastereoselectivity. This new
protocol represents a technically and economically advantageous
process for the production of this kind of compounds, in which no
stoichiometric amounts of undesired metal waste are generated,
and NH3 is formed as the sole by-product.
Caution: Hydrogen cyanide (HCN) and the cyanide ion CN- are extremely
poisonous substances. HCN is a liquid and boils at 25.6 °C. Proper safety
precautions need to be applied and appropriate safety equipment MUST
be used. For example, all the reactions involving the use of nitrile
derivatives were performed on small-scale (max. 2 mmol) using a cyanide
detector and personal protection equipment. Reactions must be carried
out in a well ventilated fume hood. After the reaction is completed, all
glassware must be rinsed with an alkaline bleach solution (pH of 10 or
higher) in the hood. If the pH is below 10, the reaction can evolve toxic
cyanogen chloride (CNCl) and hydrogen cyanide (HCN) gas. Alternatively,
the glassware can be rinsed with dilute sodium hydroxide solution (0.1 to
1 mM) in the hood. In all the cases, the rinse must be disposed of as
hazardous waste.
General Procedure for the Synthesis of 1,2-Amino Alcohols·HCl (3):
An approximately 40 mL Premex autoclave (equipped with a Teflon insert)
was charged with RuHCl(CO)(PPh3)3 (0.025 mmol, 23.8 mg), the
protected amino nitrile 1 (0.5 mmol), 1,4-dioxane (3.0 mL), and water (0.5
mL) under air. After closing the reaction vessel, the system was purged
first with nitrogen (5x) and then with hydrogen (3x). Finally, the autoclave
was pressurized with hydrogen (55 bar) and heated at 140ꢀ°C. The mixture
was then stirred at the specified temperature for 18 h. Note: At this
temperature the internal pressure rises up to 70 bar. Then, the reaction
was cooled-down on a water bath and depressurized carefully. The crude
mixture was collected in a round bottom flask and concentrated under
vacuum. Subsequently, it was dissolved in 1 mL of EtOH. To the solution
were added 55 µL of concentrated HCl (36%). The mixture was stirred at
23 °C for 18 hours. Then, the mixture was concentrated under reduced
pressure. The product was isolated by precipitation from CHCl3/Et2O.
R3
OH
R3
RuHCl(CO)(PPh3)3 (5 mol%)
O
H2 (45 bar)
CN
R1
R1
OH
n
1,4-dioxane/water (1:1)
140 °C, 18 h
n
R2
R2
n = 1,2
8
9
OH
OH
OH
OH
OH
OH
9a (80%, 3:1 dr)[b]
(69%, 3:1 dr)[c]
9b (40%)[b]
9c (82%, 3:1 dr)[b]
General Procedure for the Synthesis of Hydroxymethyl Alcohols (9):
An approx. 50 mL Parr autoclave was charged with RuHCl(CO)(PPh3)3
(47.6 mg, 0.05 mmol), cyanoketones 8 (1 mmol), 1,4-dioxane (12.0 mL)
and water (12.0 mL) under air. The mixture was degassed gently with
argon. After closing the reaction vessel, the system was purged first with
nitrogen (3x) and then with hydrogen (3x). Finally, the autoclave was
pressurized with hydrogen (45 bar), heated to 140 °C, and stirred under
these conditions for 22 h. Note: At this temperature the internal pressure
rises up to 55 bar. Then, the reaction was allowed to cool down to rt and
[a] Reaction conditions: nitrile (1.0 mmol), RuHCl(CO)(PPh3)3 (5.0 mol%), 1,4-
dioxane and water (1:1) were heated in a premex autoclave at 140 °C under 45
bar H2 pressure for 22 h. [b] Isolated yield on a 1.0 mmol scale. [c] Scale up:
Isolated yield on a 5.0 mmol scale.
Scheme 5. Catalytic Deaminative Hydrogenation of Cyanoketones to
Hydroxymethyl Alcohols.
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depressurized carefully. To the crude was added brine (10 mL) and the
organic phase was extracted with EtOAc (3x30 mL), washed with brine
and dried over Na2SO4. It was filtered through a short cotton pad and
concentrated under vacuum. The crude was purified by flash column
chromatography over SiO2 using Hexane/EtOAc/Acetone (1:1:0.1) or
petroleum ether/EtOAc as eluent.
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Acknowledgements
CaRLa (Catalysis Research Laboratory) is co-financed by the
Ruprecht-Karls-Universität Heidelberg (Heidelberg University)
and BASF SE.
Keywords: Nitriles • Deamination • Amino alcohols •
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This article is protected by copyright. All rights reserved.

10.1002/chem.201900531
Chemistry - A European Journal
FULL PAPER
FULL PAPER
Pilar Calleja, Martin Ernst, A. Stephen K.
Hashmi, Thomas Schaub*
Page No. – Page No.
Ruthenium-Catalyzed Deaminative
Hydrogenation of Amino Nitriles:
Direct Access to 1,2-Amino Alcohols
A new protocol for the reductive hydrolysis of protected α-amino nitriles using
RuHCl(CO)(PPh3)3 complex as the catalyst has been developed to afford 1,2-amino
alcohols, in which no stoichiometric amounts of undesired metal waste are
generated. This method is suitable for the preparation of industrially valuable
compounds, such as 2-amino-2-methyl propanol (AMP). In addition, hydroxymethyl
alcohols can also be accessed from cyanoketones under analogous conditions.
This article is protected by copyright. All rights reserved.