Ruthenium Catalyzed N-Alkylation of Cyclic Amines with Primary Alcohols

Article abstract of DOI:10.1002/ejoc.202000167

A robust alcohol amination protocol using common saturated amines and primary alcohols as starting materials is described. The reactions are catalyzed by combination of dichloro(p-cymene)ruthenium(II) dimer precatalyst with triphenylphosphine ligand, with

Full text of DOI:10.1002/ejoc.202000167

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Ruthenium Catalyzed N-Alkylation of Cyclic Amines with Primary
Alcohols
Authors: Risto Savela, Dieter Vogt, and Reko Leino
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000167
Link to VoR: https://doi.org/10.1002/ejoc.202000167
01/2020

10.1002/ejoc.202000167
European Journal of Organic Chemistry
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Ruthenium Catalyzed N-Alkylation of Cyclic Amines with Primary
Alcohols
Risto Savela*,[a] Dieter Vogt,[b] Reko Leino[a]]
[a]
Dr. R. Savela, Prof. Dr. R. Leino
Laboratory of Molecular Science and Technology
Åbo Akademi University
Biskopsgatan 8, FI-20500 Åbo, Finland
E-mail: risto.savela@abo.fi
[b]
Prof. Dr. D. Vogt
Laboratory of Industrial Chemistry, Department of Biochemical and Chemical Engineering
Technical University of Dortmund
Emil-Figge-Str. 66, D-44227 Dortmund, Germany
Supporting information for this article is given via a link at the end of the document.
Abstract: A robust alcohol amination protocol using common
saturated amines and primary alcohols as starting materials is
described. The reactions are catalyzed by combination of dichloro(p-
cymene)ruthenium(II) dimer precatalyst with triphenylphosphine
ligand, with the excess alcohol substrate or toluene functioning as the
solvent. The catalyst and ligand residues can be precipitated from the
reaction media by addition of hexane or cold diethyl ether, followed by
precipitation and isolation of the product as a hydrochloride salt.
One of the most common ways to form carbon-nitrogen bonds is
by reaction between an organic halide and an amine, in the
presence of an inorganic or organic base. While this reaction often
is both highly efficient and convenient to operate, it also generates
significant amounts of waste. In contrast, the application of
catalytic borrowing hydrogen7 (or hydrogen shuttling) for N-
alkylation using alcohols only produces water as the byproduct,
although typically suffers from high reaction temperatures or
sensitive catalysts. The borrowing hydrogen reaction of a model
primary alcohol followed by amination with secondary amine via
enamine to a tertiary amine is illustrated in Scheme 1.
Introduction
HNR2
Cyclic amines are common structural elements in agrochemicals,1
as well as in naturally occurring and synthetic pharmaceutically
relevant compounds,2 including antibiotics, anticancer, analgesic,
antidepressant, anti-HIV and anti-HCV agents. Many such
compounds are in regular clinical use, with selected examples
illustrated in Figure 1. Especially piperidine,3 piperazine,4
morpholine,5 and pyrrolidine6 moieties and their close analogues
are frequently occurring motifs in these structures.2d
R
R
OH
NR2
H2
HNR2
-H2O
R
NR2
R
O
Scheme 1. Amination of primary alcohols with secondary amines under
borrowing hydrogen conditions.
OH
N
O
N
O
N
F
In recent years, various homogeneous and heterogeneous8
catalytic methods have emerged in the borrowing hydrogen field.
For homogenous applications, different transition metal catalysts
based on iridium,9 copper,10 nickel,11 iron,12 cobalt,13
manganese,14 rhodium15 and ruthenium16-19 have been employed.
Especially the ruthenium-based systems have been widely and
successfully applied to a large variety of amines16-18 and nitriles.19
The primary aim of this investigation was to develop a borrowing
hydrogen method utilizing a variety of saturated cyclic amines. An
important secondary goal was to minimize the waste produced in
the purification of the products, i.e., simple removal of catalyst
complex and purification of products without the need of
Procyclidine
HO
Fenpropimorph
Melperone
CF3
S
N
Lomitapide
O
O
N
O
O
HN
N
H
O
CF3
Raloxifene
H
N
N
N
OH
N
N
N
OH
O
N
O
Cl
O
O
Cyclizine
Cetirizine
Ranolazine
chromatographic separation. Here, we describe
triphenylphosphine ligated dichloro(p-cymene)ruthenium(II)
dimer catalyzed methodology for alkylation of cyclic amines with
a robust
Figure 1. Pharmaceutically active compounds containing saturated cyclic
amine motifs.
1
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10.1002/ejoc.202000167
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primary alcohols, while simultaneously minimizing the necessary
purification operations.
Table 1. Screening of ligands for N-alkylation of morpholine with 1-butanol
under 10 bar of argon[a]
L
Yield[b]
(%)
Entry
1
Ligand(L)
XANTPHOS
XANTPHOS
DPPF
(mol-%)
Results and Discussion
0.52
0.26
0.52
0.26
1.04
0.52
1.04
1.04
1.04
0.52
0.26
0.52
0.26
0.52
0.26
0.52
0.26
0.52
0.26
0.52
0.26
-
17
16
53
54
30
20
2
[Ru(p-cymene)Cl2]2
O
L
O
3
OH
N
H2O
10 bar Argon
140 oC
N
H
DPPF
4
Ph3P
5
Scheme 2. N-Alkylation of morpholine with 1-butanol using dichloro(p-
cymene)ruthenium(II) dimer precatalyst in combination with phosphine ligands
Ph3P
6
[c]
P(2-OMePh)3
P(2,6-OMePh)3
P(2,4,6-OMePh)3
DPPE
-
7
The N-alkylation of morpholine with 1-butanol, illustrated in
Scheme 2, was selected as a model reaction, based on the good
availability of the reactants. This allowed the reactions to be
performed at close to one gram scale in the preliminary screening,
carried out in stainless steel reactors at elevated pressure and
temperature.
[c]
-
8
[c]
-
9
[c]
-
10
11
12
13
14
15
16
17
18
19
20
21
22
DPPE
38
44
53
51
57
58
52
12
10
DPPP
DPPP
PPh2
Ph2P
PPh2
n
O
Fe
O
DPPB
PPh2
PPh2
PPh2
PPh2
PPh2
DPPB
DPEphos
XANTPHOS
DPPF
n = 1 DPPE
DPPP
n = 2
n = 3 DPPB
DPEphos
DPEphos
cataCXium® PCy
cataCXium® PCy
Triphos
PPh2
R1
R2
P
N
Ph
P
P
R3
3
PPh2
R1 = R2 = R3 = H: Ph3P
TriPhos
cataCXium Pcy
[c]
R1 = OMe; R3 = R2 = H: P(2-OMePh)3
R1 = R3 = OMe; R2 = H: P(2,6-OMePh)3
R1 = R3 = R2 = OMe: P(2,4,6-OMePh) 3
-
Triphos
48
18
-
Figure 2. Ligands used in the reaction screening.
[a] General Conditions: At 140 °C for ~ 21 h, Morpholine 0.7 mL (8.0 mmol), 1-
Butanol 4 mL, [RuCl2(p-cymene)]2 6 mg (0.01 mmol; 0.13 mol-%), 10 bar of
argon. [b] GC-Yield against tetradecane internal standard. [c] Product barely
detectable from the baseline.
Based on prior art,16-18 a selection of phosphine ligands illustrated
in Figure 2 were tested. Results from the ligand screening are
summarized in Table 1. As expected, the bidentate ligands DPPF,
DPPB and DPEphos in combination with dichloro(p-
cymene)ruthenium(II) dimer provided good results even at 0.13
mol-% catalyst loading within 21 hours (Table 1, Entries 4, 15 and
17). Tridentate Triphos ligand provided acceptable results in the
same reaction setting (Table 1, Entry 21). Also, a number of
monodentate ligands, cataCXium®PCy, triphenylphosphine
(Ph3P) and methoxy derivatized triphenylphosphines were
investigated. All monodentate ligands resulted in relatively poor
GC-based yields for N-butyl morpholine, or in no reaction at all. In
cases of bidentate ligands, having excess of ligand to ruthenium
center (above 1:1 ratio) had minimal to no benefits with respect to
the overall yield of N-butyl morpholine. Furthermore, under these
conditions, in the absence of ligand, some alkylation was
observed albeit in low GC-based yield (Table 1, Entry 22).
Unfortunately, the absence of ligand resulted in heterogenous
mixture interfering with the work-up procedures.
Following the initial ligand screening under 10 bar of argon, the
reactions with DPPB, DPPF, DPEphos, Triphos and Ph3P ligands
were repeated under atmospheric argon pressure. The results are
collected in Table 2. For reaching similar GC-yield of N-butyl
morpholine as obtained under 10 bar, a four-fold increase in
catalyst loading was required with the same reaction time.
Surprisingly, unlike the reactions carried out under 10 bar of argon,
the Ph3P ligand here yielded very similar results as compared to
the other ligands. Both the Triphos and DPPF ligands were
excluded from further investigation due to their high cost and
minimal benefits over the more common ligands such as
DPEphos and Ph3P.
Table 2. N-butylation of morpholine under atmospheric pressure.[a]
Entry
Ligand
Yield[b] (%)
1
2
Triphos
DPPB
52
43
2
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10.1002/ejoc.202000167
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3
4
5
DPPF
DPEphos
Ph3P
48
55
48
Unsaturated substrates, such as citronellol, yielded complex
unseparable product mixtures. Benzylic 1-phenyl ethanol only
gave minor amounts of the N-alkylated morpholine derivative, as
detected by gas chromatography utilizing both flame ionization
detector and mass spectrometry. In contrast, the reactions with
benzyl alcohol derivatives as substrates resulted in 32 to 93%
isolated yields of the corresponding N-benzylated morpholines
(Table 4, Entries 6-10). The amination of anisyl alcohol with
morpholine was also upscaled to 40 mmol scale to yield 4-[(4-
methoxyphenyl)methyl]morpholine hydrochloride in comparable
yield and purity as in 8 mmol scale. In cases where conjugated
systems could be formed, for example with 2-phenyl ethanol as
the substrate, small amounts of unsaturated enamine derivative
was detected in the product (Table 4, Entry 11). Secondary
alcohols, such as 2-octanol and 1,2-tetradecanediol, reacted in
approx. 30% conversion of the starting material with prolonged
reaction times not improving the conversion. Also these
substrates resulted in heterogeneous mixtures and were,
consequently, not investigated further. While the use of 1,2-
tetradecanediol as starting material failed, 1-phenyl-1,2-
ethanediol was successfully and selectively aminated with
morpholine, resulting in 50% isolated yield of compound 13 by
crystallization of the product from the crude mixture (Table 4,
Entry 13). The use of 1,4-butanediol under these conditions
resulted in an unseparable mixture of 1,4-di(morpholin-1-
yl)butane with the corresponding conjugated diene. By extending
the distance between the two primary alcohol groups, diamination
of the terminal diol was achieved in 70% isolated yield for the 1,6-
hexanediol substrate (Table 4, Entry 14). Substrates containing
tertiary amine functionalities reacted in full conversion of the
starting material in 24 hours, but only mediocre (20-38%) isolated
yields were obtained (Table 4, Entries 16, 17 and 20). The
reaction should be further optimized if these types of substrates
are desired, for example, compound 20 was only obtained in 50%
GC-based yield with almost full conversion of the alcohol used.
Also, the general purification protocol is not fully suitable for all of
the compounds investigated. Both sulfur and oxygen containing
heterocycles were also investigated as substrates. While the
benzothiophene based substrate resulted in 92% isolated yield of
the compound 18 as hydrochloride (Table 4, Entry 18), the
tetrahydrofurfuryl alcohol starting material gave compound 19 in
a significantly lower isolated yield of 45% (Table 4, Entry 19) and
furfuryl alcohol produced a very thick, black fluid-like mixture
making purification impossible. Finally, fluorene-based substrates
were also tested. Similar to 1-phenyl ethanol, the secondary
alcohol fluorenol only showed a minute amount of the aminated
product by GC analysis. 9-Fluorenemethanol, in turn, gave a
significant amount of side products with barely detectable amount
of the corresponding aminated compound after 24 hours at 140
ºC.
[a] General Conditions: At 140 °C in closed 10 mL stainless steel reactor for ~
21 h; Morpholine 0.7 mL (8.0 mmol), 1-Butanol 4 mL, [RuCl2(p-cymene)]2 24.5
mg (0.04 mmol; 0.5 mol-%), Ligand 0.08 mmol (Ph3P 0.32 mmol). [b] GC-yield
against tetradecane as internal standard.
For purification purposes, after removal of Ph3P-ligated ruthenium
complex with hexane, the N-butyl morpholine was precipitated
from butanol/hexane solution as a hydrochloride salt by addition
of trimethyl silyl chloride to the reaction mixture. The obtained
powderous N-butyl morpholine hydrochloride was essentially free
of catalyst traces (verified by 1H-NMR spectroscopy) after
washing with hexane. In comparison, the hydrochloride salt of the
product obtained from the reaction using DPEphos-ligated
ruthenium complex was visibly contaminated with catalyst traces
after washing of the powderous product with hexane. The
optimized conditions used for substrate scope screening are
illustrated in Scheme 3.
Table 3. N-butylation of morpholine in a glass reactor.[a]
[RuCl2(p-cymene)]2
L
Entry
Ligand(L)
Yield[c] (%)
(mol-%)[b]
(mol-%)
1
2
3
4
5
6
1
1
0.5
0.25
1
Ph3P
Ph3P
Ph3P
4
2
2
1
2
1
> 95
> 95
86
39
> 95
Ph3P
DPEphos
DPEphos
0.5
> 95
[a] a General Conditions: At 140 °C in closed 9 mL sealed thick walled glass
reactor for ~ 24 h; Morpholine 0.7 mL (8.0 mmol), 1-Butanol 4 mL. [b] [RuCl2(p-
cymene)]2; 2.0 mol-%: 98 mg, 1.0 mol-%: 49 mg, 0.5 mol-%: 25 mg, 0.25 mol-%:
13 mg. [c] GC-Yield against tetradecane as internal standard.
[RuCl2(p-cymene)] 2 1.0 mol-%
Ph3P 4.0 mol-%
N
O
H2O
HN
O
R
OH
R
Alcohol as solvent
140 o
C
Scheme 3. Optimized reaction conditions obtained from screening.
After the initial screening of reaction conditions, utility of the
method was investigated also with other alcohols. Typically,
simple unbranched primary alcohols yielded N-alkylated
morpholines in 60-80% isolated yields (Table 4, Entries 1, 2, 5
and 12), while β-substituted primary alcohols (Table 4, Entries 4,
11, 15-25) resulted in 20-80% isolated yield of the N-alkylated
product. The β-trimethyl silyl substituent was labile under the
investigated conditions, producing the corresponding alkane most
likely by hydrolysis of the Si-C bond (Table 4, Entry 3).
Table 4. Substrate scope for N-alkylation of morpholine with Ph3P ligated ruthenium catalyst.[a]
Entry
Substrate
Solvent
Product
Yield (%)[b]
81[c]
-
1
1
3
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Tol[d]
2
3
66[c]
2
Tol[d]
87[c]
3
-
4
65
4
-
5
79[c]
5
-
Tol[d]
Tol[d]
Tol[d]
-
6
91[c]
6
7
86[c]
7
8
85[c]
8
9
32[g]
9
10
11
12
13
92(99)[c],[h]
10
11
12
13
-
86[c]
-
80[c]
Tol[d]
50[f]
Tol[e]
14
70
14
-
15
16
17
78
38
30
15
16
17
Tol[d]
Tol[d]
4
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Tol[d]
18
19
20
92[c]
18
Tol[d]
Tol[d]
45
19
20
20
[a] General Conditions: 4 mL alcohol, 8 mmol morpholine, [RuCl2(p-cymene)]2 49 mg (0.08 mmol; 1.0 mol-%), Ph3P (2eq/Ru, 84 mg) at 140 °C for 24 hour. [b]
Isolated yield. [c] Purified as HCl salt. [d] 8 mmol of alcohol and 2.7 mL of toluene [e] 4 mmol of diol and 2.7 mL of toluene. [f] 2 mol-% of catalyst. [g] Purified using
flash chromatography. [h] Isolated yield in parentheses for reaction done at 40 mmol scale.
achieved without any detectable side products but the
Following the alcohol substrate screening, also different cyclic
amines were tested. Simple unhindered compounds, such as
piperidine and pyrrolidine, produced the corresponding tertiary
amines in high yields (Table 5, Entries 1 and 7). The addition of
one α-methyl group as steric hindrance around the amine moiety
had minimal effect on the reaction outcome according to GC-
analysis of the crude mixture; yielding 75% GC-based yield, but
only 51% isolated yield of compound 22 was obtained. (Table 5,
Entry 2). Significant steric hindrance around the amine moiety,
such as in 2,2,6,6-tetramethyl piperidine, resulted only in barely
detectable amounts of the corresponding aminated product by
GC analysis. Under slightly modified conditions, selective
monoalkylation of piperazine was achieved. Based on GC-
analysis of the crude mixture, full conversion of piperazine was
monoalkylated piperazine 23 was only obtained in 26% isolated
yield (Table 5, Entry 3). By increasing the catalyst loading and
extending the reaction time, dialkylation of piperazine could be
achieved in 48% isolated yield (Table 5, Entry 4). In contrast, pre
N-derivatized pipezarines, N-methyl piperazine and N-Boc-
piperazine, yielded the corresponding alkylated piperazines in
excellent yields (Table 5, Entries 5 and 6). Also, both indoline and
1,2,3,4-tetrahydroisoquinoline gave the expected alkylated
products in 50-80% yields (Table 5, Entries 8 and 9). In case of
indoline, both alkylated indole and indoline were detected after
the reaction, with the alkylated indoline obtained in 52% isolated
yield and the alkylated indole in 23% isolated yield after
chromatographic purification.
Table 5. N-alkylation of saturated cyclic amines with 1-octanol.[a]
Entry
1
Substare
Solvent
-
Product
Yield (%)[b]
80[c]
21
22
-
51
2
-
-
-
26[d]
48[e]
91
3
4
5
23
24
25
Tol[f]
80[g]
92
6
7
8
9
26
27
28
29
-
Tol[f]
-
52[g],[h],[i]
79[i]
[a] General Conditions: 4 mL 1-octanol, 8 mmol cyclic amine, [RuCl2(p-cymene)]2 49 mg (0.08 mmol; 1.0 mol-%), Ph3P 84 mg (0.32 mmol, 4 mol-%) at 140 °C for
24 hour. [b] Isolated yield. [c] Purified as HCl salt. [d] 6 mmol of piperazine used. [e] 48 hour reaction time with [RuCl2(p-cymene)]2 98 mg (0.16 mmol; 2.0 mol-%),
Ph3P 164 mg (0.64 mmol, 8.0 mol-%). [f]8 mmol of octanol in 2.7 mL of toluene. [g] Purified using flash chromatography. [h] Additional 1.9 mmol of respective indole
(Yield: 23 %). [i] 48 hour reaction.
5
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10.1002/ejoc.202000167
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precipitation as hydrochloride salt followed by toluene trituration
or simple acid-base extraction. Limitations arise from sterically
hindered amines, secondary alcohols and aliphatic 1,2-diols, as
well as from olefin containing compounds. Also, aromatic
substituents at β–carbon, such as in 2–phenyl ethanol and
indoline, may result in stable enamine derivatives that may be
difficult to separate from the product. Currently, our attempts are
directed to expansion of the methodology towards possible
enantioselective applications, using secondary alcohols and
diversely β–substituted primary alcohols as substrates.
Based on previously reported mechanisms for similar catalyst
ligand combinations,16b,28 it is very likely that the reaction
proceeds via formation of a catalytically active ruthenium(0)
species by chloride abstraction and dissociation of p-cymene.
Also, a half-sandwich type [Ru(PPh3)2(p-cymene)Cl]Cl would
require an additional inorganic base in order to generate a free
coordination site to become catalytically active. Thus, a tentative
catalytic cycle is presented in Scheme 4, where Ln symbolizes
triphenylphosphine and/or possible amine ligands.
[Ru(p-cymene)Cl2]2
Experimental Section
2 PPh3
General Considerations: Chemicals, solvents, ruthenium complex and
ligands were bought from Merck, TCI or ABCR and used as such unless
otherwise noted. 99.996 % Argon was used in ligand and pressure
screening, combined liquids were degassed by argon bubbling. Solvents
and liquid reagents used in experiments involving glass reactors were
dried and degassed and stored in a glovebox. The reaction was followed
utilizing GC-Fid, equipped with HP-1 column: (30m × 320 μm × 0.25 μm),
and H2 as carrier gas, using the following temperature program: injector
220 °C, oven T initial = 50 °C (4 min), rate 20 °C/min, T final = 300 °C, hold
5 min. The NMR spectra were recorded using a 500 MHz NMR
spectrometer. The measured NMR spectra were calibrated using residual
solvent signal as internal standard.21 The NMR signals assignments were
based on 2D NMR (COSY, HSQC, H2BC, INADEQUATE and HMBC) and
1D-TOCSY. Elemental analysis was performed with FLASH 2000 CHNS-
analyzer. Infrared spectra were recorded on a FTIR Fourier Transform
Infrared Spectrometer. High resolution mass spectroscopy (HRMS) was
carried out with micrOTOF spectrometer (Electrospray (ESI)), with a time
of flight (TOF) mass analyser. Flash column chromatography was carried
out on automated purification system using RediSep Rf Gold columns with
20-40 µm silica particle size.
OH
2 RNH
R
O
2 RNH2Cl
R
O
R
N
LnRu0
R
OH
H
H
LnRu
O
H
O
RuLn
H
O
N
or
N
R
R
R
RuLn
H
H
O
LnRu
H
N
O
R
R
u
nR
L
H
H
H
H
Ligand screening: Into ~ 10 mL stainless steel reactor with magnetic
stirrer was measured dichloro(p-cymene)ruthenium(II) dimer (6 mg, 0.01
mmol) and respective amount of desired (di)phosphine ligand. Reactor
was closed and placed under argon atmosphere. Into the reactor was
added n-butanol (4 mL, 44 mmol), morpholine (0.70 mL, 8 mmol) and
tetradecane (0.05 mL, 0.2 mmol). Reactor was pressurized with argon to
10 bar and then set to 140 °C in an aluminum heating block for ~ 21 hours.
After cooling down to r.t. the gained solution was analyzed by GC-Fid.
LnRu
O
HN
-H2O
O
O
R
N
R
Scheme 4. Proposed catalytic cycle for ruthenium catalyzed borrowing
hydrogen reaction.
Low pressure experiments: Into ~ 10 mL stainless steel reactor with
magnetic stirrer was measured dichloro(p-cymene)ruthenium(II) dimer (25
mg, 0.04 mmol) and respective amount of desired (di)phosphine ligand
(Ph3P 0.32 mmol, 84 mg; Triphos 0.08 mmol 43 mg; DPPB 0.08 mmol 34
mg; DPPF 0.08 mmol 44.5 mg; DPEphos 0.08 mmol 44 mg). Reactor was
closed and placed under argon atmosphere. Into the reactor was added n-
butanol (4 mL, 44 mmol), morpholine (0.70 mL, 8 mmol) and tetradecane
(0.05 mL, 0.2 mmol). Reactor was set to 140 °C in an aluminum heating
block for ~ 21 hours. After cooling down to r.t. the gained solution was
analyzed by GC-Fid.
Conclusion
To conclude, we have developed a simple to operate N-alkylation
protocol applicable to a variety of cyclic amines with primary
alcohols via borrowing hydrogen reaction. Significant advantages
of the presented method are the absence of external inorganic
base and the concentration ranges close to those commonly
required for industrial fine chemical processes. Also, the waste
associated with purification procedures was minimized by use of
triphenylphosphine ligated ruthenium precatalyst. The in-situ
generated catalyst can be mostly precipitated from the reaction
mixture followed by simple washing procedures to achieve the
pure product. For example this could not be done when utilizing
DPEphos as ligand. The methodology can be applied to a
number of commercially available cyclic amines and primary
alcohols. In most cases, the catalyst can be readily precipitated
from the reaction media by simple addition of hexane or cold
diethyl ether, followed by purification of the product by
Glass reactor experiments: Into 9 mL thick walled glass reactor with
magnetic stirrer was measured dichloro(p-cymene)ruthenium(II) dimer and
respective amount of desired (di)phosphine ligand. The reactor was taken
into a glove box followed by addition of n-butanol (4 mL, 44 mmol),
morpholine (0.70 mL, 8 mmol) and tetradecane (55 μL , 0.2 mmol). Reactor
was sealed with screw cap, taken outside and heated to 140 °C for 24
hours.
General method A: Into 9 mL thick walled glass reactor with magnetic
stirrer was measured dichloro(p-cymene)ruthenium(II) dimer (49 mg; 0.08
mmol) and Ph3P (84 mg; 0.32 mmol). The reactor was taken into a glove
6
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10.1002/ejoc.202000167
European Journal of Organic Chemistry
FULL PAPER
box followed by addition suitable alcohol (4 mL) and respective cyclic
amine (8.0 mmol). Reactor was sealed with screw cap, taken outside and
heated to 140 °C for 24 hours.
MHz, 25 °C): δ. 3.69 (t, J = 4.6 Hz, O-(CH2-CH2)2-N, 4 H), 2.37 (b, O-(CH2-
CH2)2-N, 4H), 2.17-2.09 (m, CH-CH2-N, 2H), 1.51-1.42 (m, CH-CH2-N,
1H), 1.42-1.20 (m, CH3(CH2)4- and CH3CH2CH, 8H), 0.89 (t, J = 6.9 Hz,
CH3(CH2)4-, 3H), 0.85 (t, J = 7.5 Hz, CH3CH2CH 3H). 13C NMR (CDCl3,
125.76 MHz, 25 °C): δ 67.3 (O-(CH2-CH2)2-N), 63.6 (CH-CH2-N), 54.4 (O-
(CH2-CH2)2-N), 35.9 (CH-CH2-N), 31.5 (CH3(CH2)2CH2CH), 29.1
(CH3(CH2)2CH2CH), 24.7 (CH3CH2CH), 23.3 (CH3(CH2)2CH2CH), 14.3
(CH3(CH2)4-), 10.9 (CH3CH2CH). νmax (film)/cm-1: 2926, 1456, 1271, 1118,
1015, 865. HRMS–ESI: m/z [M+H]+ calcd for C12H26NO: 200.2009; found:
200.2011.
General method B: Into 9 mL thick walled glass reactor with magnetic
stirrer was measured dichloro(p-cymene)ruthenium(II) dimer (49 mg; 0.08
mmol) and Ph3P (84 mg; 0.32 mmol). The reactor was taken into a glove
box followed by addition of toluene, (2.7 mL) suitable alcohol (8 mmol) and
respective cyclic amine (8.0 mmol). Reactor was sealed with screw cap,
taken outside and heated to 140 °C for 24 hours.
N-octyl morpholine hydrochloride (5). General method A with general
purification method yielding white powder. Yield: Crop 1: 1.32 g, Crop 2:
0.18 g; 79 %. 1H NMR (D2O, 500.13 MHz, 25 °C): δ 4.13 (bd, J = 12.6 Hz,
N-CH2-CH2-O, 2H), 3.83 (bt, J = 12.5 Hz, , N-CH2-CH2-O, 2H), 3.54 (bd,
J = 12.8 , N-CH2-CH2-O, Hz, 2H), 3.21-3.16 (m, N-Bu-CH2-N, N-CH2-CH2-
O, 4H), 1.78-1.71 (m, CH3-(CH2)5-CH2-CH2-N, 2H), 1.42-1.24 (m, CH3-
(CH2)5-(CH2)2-N, 10H), 0.87 (t, J = 7.0 Hz, CH3-(CH2)7-N, 3H). 13C NMR
(D2O, 125.76 MHz, 25 °C): δ 63.8 (N-CH2-CH2-O), 57.4 (CH3-(CH2)6-CH2-
N), 51.5 (N-CH2-CH2-O), 31.0 (CH3-(CH2)4-(CH2)3-N), 28.10 (CH3-(CH2)4-
(CH2)3-N), 28.07 (CH3-(CH2)4-(CH2)3-N), 25.6 (CH3-(CH2)4-CH2-(CH2)2-N),
23.0 (CH3-(CH2)5-CH2-CH2-N), 22.0 (CH3-(CH2)4-(CH2)3-N), 13.4 (CH3-
(CH2)7-N). νmax (solid)/cm-1: 2931, 2866, 2535, 2432, 1454, 1409, 1381,
1266, 1120, 1088, 1016, 975, 906, 873, 752, 698, 623, 576, 511, 471, 440.
Anal. Calcd. for C12H26ClNO: C, 61.13; H, 11.11; N, 5.94. Found: C, 61.02;
H, 11.29; N, 6.08.
General purification method. After cooling to room temperature, the
mixture was poured into hexane (10 mL) and filtered. Chlorotrimethylsilane
(1.6 mL) was added slowly and the mixture was stirred for 2 hours, filtered
and washed with small amount of hexane. Solid powder was triturated in
small amount of toluene; the liquor was placed into freezer for approx. 12
hours, filtered and triturated in small amount of toluene.
General method for removal of hydrochloride salt. Hydrochloride salt
of the amine was suspended into 15 mL of saturated aqueous sodium
carbonate and 15 mL of diethyl ether followed by vigorous stirring for two
hours. Layers were separated and the aqueous phase was extracted with
additional 15 mL of diethyl ether. The organics were combined, dried with
sodium sulphate.
N-butyl morpholine hydrochloride (1). General method A with general
purification method yielding off white powder. Yield: 1.16 g, 81 %. 1H NMR
(D2O, 500.13 MHz, 25 °C): δ 4.13 (bd, J = 12.6 Hz, N-CH2-CH2-O, 2H),
3.83 (bt, J = 12.2 Hz, , N-CH2-CH2-O, 2H), 3.55 (bd, J = 12.6 , N-CH2-
CH2-O, Hz, 2H), 3.25-3.11 (m, N-Bu-CH2-N, N-CH2-CH2-O, 4H), 1.76-1.70
(m, CH3-CH2-CH2-CH2-N, 2H), 1.44-1.36 (m, CH3-CH2-(CH2)2-N, 2H), 0.94
(t, J = 7.4 Hz, CH3-(CH2)3-N, 3H). 13C NMR (D2O, 125.76 MHz, 25 °C): δ
63.8 (N-CH2-CH2-O), 57.1 (CH3-CH2-CH2-CH2-N), 51.6 (N-CH2-CH2-O),
25.0 (CH3-CH2-CH2-CH2-N), 19.1 (CH3-CH2-CH2-CH2-N), 12.7 (CH3-CH2-
CH2-CH2-N). νmax (solid)/cm-1: 2967, 2466, 1447, 1413, 1109, 1065, 974,
912, 867, 621, 472. Anal. Calcd. for C8H18ClNO: C, 53.47; H, 10.10; N,
7.80. Found: C, 53.53; H, 10.32; N, 7.99.
N-benzyl morpholine hydrochloride (6). General method
A with
modified purification method, utilizing diethyl ether instead of hexane
yielding white powder. Yield: 1.55 g, 91 %. 1H NMR (D2O, 500.13 MHz,
25 °C): δ 7.59-7.50 (m, 5H), 4.38 (s, 2H), 4.11 (bm, 2H), 3.78 (bm, 2H),
3.44 (bd, J = 12.5 Hz, 2H), 3.26 (dt, J = 12.5 Hz; 12.5 Hz; 3.4 Hz, 2H). 13
C
NMR (D2O, 125.76 MHz, 25 °C): δ 131.2, 130.3, 129.3, 127.9, 63.6, 60.9,
51.2.
All analytical data were in good accordance with reported data.22
4-[(4-chlorophenyl)methyl]-morpholine hydrochloride (7). General
method B with modified purification method, utilizing diethyl ether instead
4-(2-ethoxyethyl)-morpholine hydrochloride (2). General method B
with modified purification method, utilizing combination of
chlorotrimethylsilane and ethanol (2 mL) followed by crystallization from
acetone yielding white needles. Yield: 1.04 g, 66 %. m.p. = 127-135 °C. 1H
NMR (CDCl3, 500.13 MHz, 25 °C): δ 4.08-4.00 (b, N(CH’’CH’’)2O 2H),
3.89-3.83 (b, N(CH’CH’)2O, 2H), 3.83-3.79 (m, EtOCH2CH2-N, 2H), 3.59
(q, J = 7.0 Hz, CH3CH2O, 2H), 3.56-3.49 (b, N(CH’’CH’’)2O, 2H), 3.41-3.38
(m, EtOCH2CH2N, 2H), 3.25-3.22 (b, N(CH’CH’)2O, 2H) .1.23 (t, J = 7.0
Hz, CH3CH2O, 3H). 13C NMR (CDCl3, 125.76 MHz, 25 °C): δ 67.8
(CH3CH2O), 64.8 (N(CH2CH2)2O), 64.6 ((EtOCH2CH2-N), 57.9
(EtOCH2CH2-N), 53.5(N(CH2CH2)2O), 15.3 (CH3CH2O). νmax (solid)/cm-1:
2974, 2868, 2450, 1450, 1403, 1379, 1356, 1287, 1139, 1125, 1083, 1066,
1040, 1011, 954, 917, 860, 599, 461, 409. Anal. Calcd. for C8H18ClNO2: C,
49.10; H, 9.27; N, 7.16. Found: C, 49.02; H, 9.31; N, 7.33.
of hexane and addition of
2 mL of ethanol prior to addition of
chlorotrimethylsilane. After trituration in toluene the product was
crystallized from ethanol at -18 ºC yielding yellow needles. The needles
crystallized contained approx. 1 wt-% of ethanol. Yield: 1.72 g, 86 %. m.p.:
190-195 °C, sublimation; 220-225 ºC decomposition. 1H NMR (MeOD,
500.13 MHz, 25 °C): δ 7.60 (d, J = 8.4 Hz, Cl-CAr(CArH-CArH)2-CAr-CH2-N,
2H), 7.50 (d, J = 8.4 Hz, Cl-CAr(CArH-CArH)2-CAr-CH2-N, 2H), 4.39 (s, -CH2-
N-(CH2-CH2)2-O, 2H), 4.10-3.75 (b, -N-(CH2-CH2)2-O, 4H), 3.40-3.15 (b, -
N-(CH2-CH2)2-O, 4H). 13C NMR (MeOD, 125.76 MHz, 25 °C): δ 137.4 (Cl-
CAr), 134.3 (Cl-CAr(CArH-CArH)2-CAr-CH2-N), 130.4 (Cl-CAr(CArH-CArH)2-
CAr-CH2-N), 128.5 (CAr-CH2-N), 64.8 (-N-(CH2-CH2)2-O), 60.9 (-CH2-N-
(CH2-CH2)2-O), 52.8 (-N-(CH2-CH2)2-O). HRMS–ESI: m/z [M-Cl]+ calcd for
C11H15N1O1Cl: 212.0837; found: 212.038. νmax (solid)/cm-1: 2532, 2474,
1602, 1498, 1450, 1403, 1349, 1262, 1123, 1095, 1083, 1023, 974, 909,
863, 809, 797, 718, 669, 525, 467, 411.
Ethyl morpholine hydrochloride (3). General method B utilizing 2-
trimethyl silyl ethanol, with general purification method yielding pale yellow
powder. Yield: 1.05 g, 87 % 1H NMR (CDCl3, 500.13 MHz, 25 °C): δ 4.06
(dd, J = 3.6 Hz, 13.0 Hz, O-(CH’-CH’)2-N, 2H), 3.86-3.80 (m, O-(CH’’-
CH’’)2-N 2H), 3.50 (d, J = 13.0 Hz, O-(CH’-CH’)2-N, 2H), 3.23 (q, J = 7.3
Hz, N-CH2CH3 2H), 3.12 (dt, J = 2.9 Hz, 12.2 Hz, O-(CH’’-CH’’)2-N, 2H)
1.38 (t, J = 7.3 Hz, N-CH2CH3, 3H). 13C NMR (CDCl3, 125.76 MHz, 25 °C):
δ 65.1 O-(CH2-CH2)2-N, 53.6 (N-CH2CH3), 52.6 O-(CH2-CH2)2-N, 9.3 (N-
CH2CH3). νmax (solid)/cm-1: 2927, 2462, 1697, 1449, 1255, 1107, 1050,
1022, 922, 860, 822, 601, 450. Anal. Calcd. for C6H14ClNO: C, 47.53; H,
9.31; N, 9.30. Found: C, 47.38; H, 9.31; N, 9.30
4-[(2,4-dichlorophenyl)methyl]-morpholine hydrochloride (8). General
method B with modified purification method, utilizing diethyl ether instead
of hexane and addition of
2 mL of ethanol prior to addition of
chlorotrimethylsilane. Yielding title compound as pale yellow powder after
trituration in toluene. Yield: 1.91 g; 85 %. 1H NMR (MeOD, 500.13 MHz,
25 °C): δ 7.80 (d, J = 8.4 Hz, ClCAr-CArH-CArH-CAr-, 1H), 7.67 (d, J = 2.0
Hz, CAr(Cl)-CArH-CAr(Cl), 1H), 7.51 (dd, J = 2.0 Hz, 8.4 Hz, ClCAr-CArH-
CArH-CAr-, 1H), 4.56 (s, -CH2-N-(CH2-CH2)2-O, 2H), 4.10-3.80 (b, (-N-(CH2-
CH2)2-O, 4H), 3.40 (b, (-N-(CH2-CH2)2-O, 4H). 13C NMR (MeOD, 125.76
MHz, 25 °C): δ 138.4 (-CArH-CAr(Cl)-CAr-), 137.9 (ClCAr-CArH-CArH-CAr-),
136.2 (ClCAr-CArH-CArH-CAr-), 131.1 (CAr(Cl)-CArH-CAr(Cl)), 129.3 (ClCAr-
CArH-CArH-CAr-), 126.9 ClCAr-CArH-CArH-CAr-, 64.8 (-N-(CH2-CH2)2-O),
57.9 (-CH2-N-(CH2-CH2)2-O), 43.2 (-N-(CH2-CH2)2-O). νmax (solid)/cm-1:
4-(2-ethylhexyl)-morpholine (4). General method A followed by general
purification method and removal of hydrochloride salt. The evaporation of
solvents yielded yellow oil. Yield: 1.03 g, 65 %. 1H NMR (CDCl3, 500.13
7
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000167
European Journal of Organic Chemistry
FULL PAPER
2309, 1588, 1479, 1437, 1405, 1261, 1117, 1082, 1054, 976, 907, 865,
821, 800, 746, 699, 659, 613, 562, 493, 459, 419. Anal. Calcd. for
C11H14Cl3NO: C, 46.75; H, 4.99; N, 4.96. Found: C, 46.92; H, 5.20; N, 5.02.
2.73 (t, J = 7.6 Hz, 2H), 2.14-2.07 (m, 2H). 13C NMR (MeOD, 125.76 MHz,
25 °C): δ 141.4, 129.7, 129.4, 127.5, 65.0, 58.0, 53.1, 33.4, 26.4.
All analytical data were in good accordance with reported data.24
4-(4-morpholinylmethyl)-phenol (9). General method B. The gained
crude mixture was poured onto cold diethyl ether and filtered. After
evaporation of solvents the crude mixure was purified using flash
chromatography (gradient: hexane:EtOAc 0-100 %) yielding pale yellow
solid containing minor impurities. Yield: 0.50 g, 32 %. Rf: 0.11, (1:1
hexane:ethyl acetate). 1H NMR (CDCl3, 500.13 MHz, 25 °C): δ 7.12 (d, J
= 8.5 Hz, 2H), 6.66 (d, J = 8.5 Hz, 2H), 3.73 (t, J = 4.7 Hz, 4H), 3.45 (s,
2H), 2.49 (b, 4H). 13C NMR (CDCl3, 125.76 MHz, 25 °C): δ 155.6, 131.1,
128.2, 128.2, 115.6, 66.8, 63.0, 53.5.
1-Phenyl-2-morpholinoethanol (13). General method A utilizing double
amount of catalyst and ligand. The gained mixture was transferred to round
bottom flask with diethyl ether and placed cooled to -18 °C. Gained
precipitate was crystallized from 2-propanol followed by extraction into hot
hexane, decantation, evaporation and finally recrystallized from 2-
propanol to afford white needles. The purification cycle was repeated to
yield additional crops. Yield: Crop 1: 0.69 g, Crop 2: 0.14 g, 50 %. m.p.:
80-82 °C (lit: 85 °C).25 1H NMR (CDCl3, 500.13 MHz, 25 °C): δ 7.41-7.36
(m, 4H), 7.32-7.28 (m, 1H) 4.77 (dd, J = 10.5 Hz, 3.5 Hz, 1H), 3.90-4.00
(b, 1H), 3.82-3.74 (m, 4H), 2.82-2.72 (b, 2H), 2.60-2.45 (m, 4H). 13C NMR
(CDCl3, 125.76 MHz, 25 °C): δ 142.0, 128.5, 127.7, 126.0, 68.7, 67.2, 66.8,
53.6.
All analytical data were in good accordance with reported data.23
4-[(4-methoxyphenyl)methyl]-morpholine hydrochloride (10). General
method A with modified purification method, utilizing diethyl ether instead
of hexane. A pure white powder was obtained directly by washing of the
formed hydrochloride salt few times with cold diethyl. Yield: 1.76 g, 92 %.
1H NMR (MeOD, 500.13 MHz, 25 °C): δ 7.50 (d, J = 8.7 Hz, H3CO-
CAr(CArH-CArH)2-CAr-, 2H), 7.02 (d, J = 8.7 Hz, H3CO-CAr(CArH-CArH)2-CAr-,
2H), 4.31 (s, -CH2-N-(CH2-CH2)2-O, 2H), 4.10-3.70 (m, -N-(CH2-CH2)2-O
and OCH3, 7H), 3.40-3.10 (b, -N-(CH2-CH2)2-O, 4H). 13C NMR (MeOD,
125.76 MHz, 25 °C): δ 162.6 (H3CO-CAr-), 134.1 (H3CO-CAr(CArH-CArH)2-
CAr-, 121.4 (H3CO-CAr(CArH-CArH)2-CAr-), 115.6 (H3CO-CAr(CArH-CArH)2-
CAr-), 64.9 (-N-(CH2-CH2)2-O), 61.5 (-CH2-N-(CH2-CH2)2-O), 55.9 (OCH3),
52.5 (-N-(CH2-CH2)2-O). νmax (solid)/cm-1: 2450, 1611, 1516, 1437, 1404,
1302, 1252, 1185, 1122, 1081, 1059, 1031, 960, 944, 907, 866, 854, 835,
822, 795, 759, 569, 516, 461, 432. Anal. Calcd. for C12H18ClNO2: C, 59.14;
H, 7.44; N, 5.75. Found: C, 59.09; H, 7.56; N, 5.73.
All analytical data were in good accordance with reported data.26
1,6-di(morpholin-1-yl)hexane (14). General method B utilizing 1,6-
hexabediol (0.75 g, 4 mmol). Purification by general method, followed by
removal of hydrochloride salt. The solvent was evaporated to afford yellow
oil containing minor impurities Yield: 0.72 g, 70 %. 1H NMR (CDCl3, 500.13
MHz, 25 °C): δ 3.70 (t, J = 4.7 Hz, 8H), 2.41 (b, 8H), 2.33-2.29 (m, 4H),
1.53-1.42 (m, 4H), 1.32-1.29 (m, 4H). 13C NMR (CDCl3, 125.76 MHz,
25 °C): δ 67.1, 59.3, 53.9, 27.6, 26.7.
All analytical data were in good accordance with reported data. 27
N-(Cyclohexylmethyl)morpholine (15). General method A followed by
general purification method and removal of hydrochloride salt. The
evaporation of solvents yielded pale brown liquid. Yield: 1.16 g, 78 %. 1H
NMR (CDCl3, 500.13 MHz, 25 °C): δ 3.69 (t, J = 4.7 Hz, 4H), 2.37 (b, 4H),
2.10 (d, J = 7.2 Hz, 2H), 1.77-1.73 (m, 2H), 1.72-1.63 (m, 3H), 1.52-1.42
(m, 1H), 1.26-1.09 (m, 3H), 0.90-0.81 (m, 2H). 13C NMR (CDCl3, 125.76
MHz, 25 °C): δ 67.2, 66.3, 54.3, 34.8, 32.0, 26.9, 26.3.
4-[(4-methoxyphenyl)methyl]-morpholine hydrochloride (10). Into 30
mL thick walled glass reactor with magnetic stirrer was measured
dichloro(p-cymene)ruthenium(II) dimer (245 mg; 0.4 mmol) and Ph3P (420
mg; 1.6 mmol). The reactor was taken into a glove box followed by addition
4-methoxybenzyl alcohol (10 mL) and morpholine (3.50 mL, 40.0 mmol).
Reactor was sealed with screw cap, taken outside and heated to 140 °C
for 24 hours. After cooling to room temperature, the mixture was poured
into cold diethyl ether (30 mL) and filtered. Ethanol (2 mL) was added to
the mixture followed by slow addition of chlorotrimethylsilane (8.0 mL), the
mixture was stirred for 2 hours, filtered and washed with small amount of
diethyl ether. The off white powder was triturated toluene (30 mL) for
approx. 1.5 h; filtered and washed with diethyl ether to yield white powder
after drying under vacuum. Yield: 9.70 g, 99 %. All analytical data were in
good accordance with the previous experiment, vide supra.
All analytical data were in good accordance with reported data.28
4-[(1-methyl-3-piperidinyl)methyl]morpholine (16). General method B.
Ethanol (2 mL) and chlorotrimethylsilane (1.6 mL) were added slowly and
the mixture was stirred for 2 hours. Water (~ 10 mL) was added to the
mixture and stirred until two clear layers formed (~1 h). Layers were
separated and the organic layer extracted with H2O (~ 10 mL). Combined
aqueous fractions were extracted twice with toluene (2x 10 mL). To the
aqueous fraction were added 10 mL of saturated Na2CO3 and 15 mL of
diethyl ether. The biphasic system was stirred vigorously until two clear
layers could be separated (~ 1-2 h). Layers were separated and aqueous
fraction extracted with addition diethyl ether (10 mL). Organics were
combined, dried with sodium sulfate and evaporated to dryness yielding
red brown liquid containing minor impurities. Yield: 0.59 g, 38 %. 1H NMR
(CDCl3, 500.13 MHz, 25 °C): δ 3.70-3.63 (m, N-(CH2CH2)2-O, 4H), 2.90
(bd, J = 10.7 Hz, -CH2-N(Me)-CH’CH-, 1H), 2.75 (bd, J = 10.7 Hz, (-CH’-
N(Me)-CH2CH-, 1H), 2.44-2.28 (bm, N-(CH2CH2)2-O, 4H), 2.23 (s, N-CH3,
3H), 2.13 (d, J = 7.3 Hz, -CH2-N-(CH2CH2)2-O, 2H), 1.88-1.77 (m, -CH’’-
N(Me)-CH2CH- and -CH2-N(Me)-CH2CH- 2H), 1.73-1.61 (m, -CH’-CH2-
CH2-N(Me)- and -CH2-CH’-CH2-N(Me)-, 2H), 1.60-1.50 (m, -CH2-N(Me)-
CH’’CH- and -CH2-CH’’-CH2-N(Me)-, 2H), 0.88-0.78 (m, -CH’’-CH2-CH2-
N(Me)-, 1H). 13C NMR (CDCl3, 125.76 MHz, 25 °C): δ 67.1 (N-(CH2CH2)2-
O), 63.6 (-CH2-N-(CH2CH2)2-O), 61.2 (-CH2-N(Me)-CH2CH-), 56.6 (-CH2-
N(Me)-CH2CH-), 54.3 (N-(CH2CH2)2-O), 46.9 (N-CH3), 33.4 (-CH2-N(Me)-
CH2CH-), 29.1 (-CH2-CH2-CH2-N(Me)-), 25.4 (-CH2-CH2-CH2-N(Me)-).
HRMS–ESI: m/z [M+H]+ calcd for C11H12N2O1: 199.1805; found: 199.1809.
νmax (film)/cm-1: 2930, 2849, 2773, 1444, 1374, 1272, 1202, 1117, 1059,
1007, 909, 863, 835, 799, 778, 696, 629, 477.
4-(2-phenylethyl)-morpholine hydrochloride (11). General method A
with general purification method yielding off white powder containing tiny
amount of the styrene derivative (by NMR-analysis). Yield: Crop 1: 1.42 g,
Crop 2: 0.14 g, 86 %. 1H NMR (MeOD, 500.13 MHz, 25 °C): δ. 7.37-7.31
(m, -CarH-(CarH)2-(CarH)2-Car-, 4H), 7.29-2.24 (m, -CarH-(CarH)2-(CarH)2-
Car-, 1H), 4.06 (dd, J = 3.5 Hz, 13.0 Hz, -N-(CH’)2-(CH’)2-O, 2H), 3.89-3.54
(m, N-(CH’’)2-(CH’’)2-O, 2H), 3.57 (d, J = 13.0 Hz, N-(CH’)2-(CH’)2-O, 2H),
3.41-3.35 (m, Ph-CH2-CH2-N-, 2H), 3.21 (dt, J = 3.5 Hz, 12.3, -N-(CH’’)2-
(CH’’)2-O, Hz, 2H), 3.15-3.11 (m, Ph-CH2-CH2-N-, 2H). 13C NMR (MeOD,
125.76 MHz, 25 °C): δ 137.5 (CarH-(CarH)2-(CarH)2-Car-), 130.0 (CarH-
(CarH)2-(CarH)2-Car-), 129.9 (CarH-(CarH)2-(CarH)2-Car-), 128.2 (CarH-
(CarH)2-(CarH)2-Car-), 65.0 (-N-(CH)2-(CH)2-O), 59.3 (Ph-CH2-CH2-N-),
53.2 (-N-(CH)2-(CH)2-O), 30.9 (Ph-CH2-CH2-N-). νmax (solid)/cm-1: 2430,
1454, 1266, 1128, 1091, 980, 906, 871, 753, 698, 630, 576, 511, 469, 440.
HRMS–ESI: m/z [M-Cl]+ calcd for C17H35N2O2: 192.1383; found: 192.1410.
4-(3-phenylpropyl)-morpholine hydrochloride (12). General method A
with modified purification method, utilizing diethyl ether instead of hexane,
yielding white powder. Yield: 1.54 g, 80 %. 1H NMR (MeOD, 500.13 MHz,
25 °C): δ 7.31-7.24 (m, 4H), 7.23-7.18 (m, 1H), 4.02 (dd, J = 3.3 Hz, 13.1
Hz, 2H) 3.84-3.78 (m, 2H), 3.48 (d, J = 12.8 Hz, 2H), 3.18-3.08 (m, 4H),
8
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000167
European Journal of Organic Chemistry
FULL PAPER
4-[(1-methyl-2-piperidinyl)methyl]-morpholine (17). General method B.
Ethanol (2 mL) and chlorotrimethylsilane (1.6 mL) were added slowly and
the mixture was stirred for 2 hours. Water (~ 10 mL) was added to the
mixture and stirred until two clear layers formed (~1 h). Layers were
separated and the organic layer extracted with H2O (~ 10 mL). Combined
aqueous fractions were extracted twice with toluene (2x 10 mL). To the
aqueous fraction were added 10 mL of saturated Na2CO3 and 15 mL of
diethyl ether. The biphasic system was stirred vigorously until two clear
layers could be separated (~ 1-2 h). Layers were separated and aqueous
fraction extracted with addition diethyl ether (10 mL). Organics were
combined, dried with sodium sulfate and evaporated to dryness yielding
dark yellow oil with minor impurities of the respective enamine. Yield: 0.46
g, 30 %. 1H NMR (CDCl3, 500.13 MHz, 25 °C): δ 3.69-3.62 (m, N-
(CH2CH2)2-O, 4H), 2.82-2.76 (m, -CH’’-N(Me)-CH-, 1H), 2.54 (dd, J = 4.8
Hz 12.0 Hz, -CH’-N-(CH2CH2)2-O, 1H), 2.39 (b, -N-(CH2CH2)2-O, 4H), 2.29
(m, N-CH3, 3H), 2.14 (dd, J = 12.0 Hz 18.4 Hz, -CH’’-N-(CH2CH2)2-O, 1H),
2.04 (dt, J = 3.5 Hz, 11.4 Hz, -CH’-N(Me)-CH-, 1H), 2.01-1.95 (m, -CH2-
N(Me)-CH-, 1H), 1.84-1.77 (m, CH2-N(Me)CH-CH’-CH2, 1H), 1.72-1.66 (m,
-CH’-CH2CH2-N(Me), 1H), 1.60-1.46 (m, -CH2CH2-N(Me)-, 2H), 1.27-1.15
(m, -CH’’-CH2CH2-N(Me) and CH2-N(Me)CH-CH’’-CH2, 2H). 13C NMR
(CDCl3, 125.76 MHz, 25 °C): δ 67.2 (N-(CH2CH2)2-O), 63.1 (-CH2-N-
(CH2CH2)2-O), 61.1 (-CH2-N(Me)-CH-), 57.6 (-CH2-N(Me)-CH-), 54.7 (N-
(CH2CH2)2-O), 43.7 (N-CH3), 31.1 (CH2-N(Me)CH-CH2-CH2), 25.9 (-
CH2CH2-N(Me)-), 24.2 (-CH2-CH2CH2-N(Me)). HRMS–ESI: m/z [M+H]+
calcd for C11H12N2O1: 199.1805; found: 199.1799. νmax (film)/cm-1: 2929,
2581, 2778, 1445, 1372, 1276, 1204, 1116, 1070, 1031, 1008, 866, 801,
762, 634, 498.
separated and the organic layer extracted with H2O (~ 10 mL). Combined
aqueous fractions were extracted twice with toluene (2x 10 mL). To the
aqueous fraction were added 10 mL of saturated Na2CO3 and 15 mL of
diethyl ether. The biphasic system was stirred vigorously until two clear
layers could be separated (~ 1-2 h). Layers were separated and aqueous
fraction extracted with addition diethyl ether (10 mL). Organics were
combined, dried with sodium sulfate and evaporated to dryness yielding
red brown liquid containing minor impurities. Yield: 0.29 g, 20 %. 1H NMR
(CDCl3, 500.13 MHz, 25 °C): δ 3.67 (t, J = 4.6 Hz, N-(CH2CH2)2-O, 4 H),
3.05-3.01 (m, (-CH’-N(Me)-CH-, 1H), 2.51-2.40 (m, -N-(CH2CH2)2-O and -
CH’-N-(CH2CH2)2-O, 5H) 2.39 (s, N-CH3, 3H), 2.36-2.20 (m, (-CH2-N(Me)-
CH- and -CH’’-N-(CH2CH2)2-O, 2H), 2.20- 2.12 (m, -CH’’-N(Me)-CH-, 1H),
1.98-1.90 (m, -CH’-CH2-CH2-N(Me)-CH-, 1H), 1.79-1.62 (m, -CH2-CH2-
CH2-N(Me)-CH-, 2H), 1.56-1.49 (m, -CH’’-CH2-CH2-N(Me)-CH- 1H). 13C
NMR (CDCl3, 125.76 MHz, 25 °C): δ 67.1 (N-(CH2CH2)2-O), 64.5 (-CH2-N-
(CH2CH2)2-O), 62.6 (-CH2-N(Me)-CH-), 57.9 ((-CH2-N(Me)-CH-), 54.5 (N-
(CH2CH2)2-O), 41.7 (N-CH3), 30.9 (-CH2-CH2-CH2-N(Me)-CH-), 22.7 (-
CH2-CH2-CH2-N(Me)-CH-). HRMS–ESI: m/z [M+H]+ calcd for C10H21N2O:
185.1648 found: 185.1639. νmax (film)/cm-1: 2954, 2769, 1454, 1275, 1206,
1115, 1070, 1035, 1013, 910, 863, 796, 491.
N-octyl piperidine hydrochloride (21). General method A with general
purification method yielding white powder. Second crop was triturated first
in diethyl ether followed by toluene trituration. Yield: Crop1. 1.14 g, Crop
0.36 g, 80 %. 1H NMR (D2O, 500.13 MHz, 25 °C): δ 3.52 (bd, N-(CH2)2-
(CH2)2-CH2, 2H), 3.09-3.05 (m, , CH2-N-(CH2)2- , 2H), 2.94-2.88 (m, N-
(CH2)2-(CH2)2-CH2, 2H), 1.99-1.90 (m, N-(CH2)2-(CH2)2-CH2, 2H), 1.85-
1.79 (m, N-(CH2)2-(CH2)2-CH2, 1H), 1.77-1.66 (m, N-(CH2)2-(CH2)2-CH2,
CH2-CH2-N-(CH2)2-(CH2)2-CH2, 4H), 1.52-1.44 (m, N-(CH2)2-(CH2)2-CH2,
1H), 1.39-1.26 (m, CH3-(CH2)5-(CH2)2-N, 10H) 0.87 (t, J = 7.1 Hz, CH3-
(CH2)7-N, 3H). 13C NMR (D2O, 125.76 MHz, 25 °C): δ 57.0 (CH2-N-(CH2)2-),
53.1 (N-(CH2)2-(CH2)2-CH2), 31.0 (CH3-(CH2)5-(CH2)2-N), 28.13 (CH3-
(CH2)5-(CH2)2-N), 28.11 (CH3-(CH2)5-(CH2)2-N), 25.8 (CH3-(CH2)5-(CH2)2-
N), 23.3 (-CH2-CH2-N-(CH2)2-(CH2)2-CH2), 22.8 (N-(CH2)2-(CH2)2-CH2),
22.0 (CH3-(CH2)5-(CH2)2-N), 21.2 (N-(CH2)2-(CH2)2-CH2), 13.4 (CH3-
(CH2)7-N). νmax (solid)/cm-1: 2430, 1454, 1265, 1127, 1091, 979, 906, 871,
752. Anal. Calcd. for C13H28ClN: C, 66.78; H, 12.07; N, 5.99. Found: C,
66.39; H, 12.05; N, 5.90.
4-(benzothiophene-2-ylmethyl)morpholine
hydrochloride
(18).
General method B with modified purification method, utilizing diethyl ether
instead of hexane and addition of ethanol (2 mL) prior to addition of
chlorotrimethylsilane (1.6 mL). Yielding title compounds as light brown
powder after trituration in toluene. Yield: 1.99 g, 92 %. 1H NMR (MeOD,
500.13 MHz, 25 °C): δ 7.85-7.95 (m, CAr-CArH-CArH-CArH-CArH-CAr-S, 2H),
7.70 (s, -CAr-CH-C(CH2-)-S-CAr-, 1H), 7.40-7.45 (m, CAr-CArH-CArH-CArH-
CArH-CAr-S, 2H), 4.73 (s, -CH2-N-(CH2-CH2)2-O, 2H) 4.10-3.90 (bm, -CH2-
N-(CH2-CH2)2-O, 4H), 3.53-3.23 (bm, -CH2-N-(CH2-CH2)2-O, 4H). 13C
NMR (MeOD, 125.76 MHz, 25 °C): δ 142.5 (-CAr-CH-C(CH2-)-S-CAr-),
140.5 (-CAr-CH-C(CH2-)-S-CAr-), 131.2 (-CAr-CH-C(CH2-)-S-CAr-), 131.0 (-
CAr-CH-C(CH2-)-S-CAr-), 127.0 (CAr-CArH-CArH-CArH-CArH-CAr-S), 126.2
(CAr-CArH-CArH-CArH-CArH-CAr-S), 125.5 (CAr-CArH-CArH-CArH-CArH-CAr-S),
123.4 (CAr-CArH-CArH-CArH-CArH-CAr-S), 64.9 (-CH2-N-(CH2-CH2)2-O),
56.0 (-CH2-N-(CH2-CH2)2-O), 52.7 (-CH2-N-(CH2-CH2)2-O). νmax (solid)/cm-
1: 2961, 2529, 2451, 1532, 1457, 1433, 1409, 1346, 1303, 1258, 1198,
1146, 1124, 1079, 1060, 1016, 986, 956, 903, 867, 831, 743, 725, 707,
621, 567, 500, 443, 416. Anal. Calcd. for C13H16ClNOS: C, 57.88; H, 5.98;
N, 5.19; S, 11.88. Found: C, 57.70 H, 6.03; N, 5.06; S, 11.64.
N-octyl 2-methyl piperidine (22). General method A with modified
purification method, using
4 hours of stirring after addition of
chlorotrimethylsilane, yielding white solid in two crops. The crops were
combined and the hydrochloride salt removed according to the general
method. The solvent was evaporated to afford yellow oil. Yield: 0.86 g,
51 %. 1H NMR (CDCl3, 500.13 MHz, 25 °C): δ 2.86-2.82 (m, -(CH(CH3)-N-
CH’-CH2-CH2-, 1H), 2.64-2.60 (m, CH3-(CH2)6-CH’-N, 1H), 2.34-2.28 (m,
CH3-(CH2)6-CH’’-N 1H), 2.26-2.20 (m, N-CH(CH3)-CH2, 1H), 2.14-2.09 (m,
-(CH(CH3)-N-CH’’-CH2-CH2-, 1H), 1.67-1.49 (m, N-CH(CH3)-CH’,
(CH(CH3)-N-CH2-CH2-CH2-, -(CH(CH3)-N-CH2-CH2-CH’-, 4H), 1.49-1.36
(m, N-CH2-CH2-(CH2)5-CH3, 2H) 1.32-1.16 (m, N-CH(CH3)-CH’’,
-
4-[(Tetrahydro-2-furanyl)methyl]morpholine (19). General method B.
After cooling to room temperature, the mixture was poured into hexane (10
mL) and filtered. Ethanol (2 mL) and chlorotrimethylsilane (1.6 mL) were
added to the mixture was stirred for 2 hours at room temperature. The
excess solvents were evaporated and the thick black oil was taken into
small amount of acetone and allowed to stand at -18 ºC for few days. The
white to pale yellow solid was separated and the procedure repeated for
the liquor. Hydrochloride salt was removed from combined solids by the
general method. The solvent was evaporated to afford pale yellow brown
liquid. Yield: 0.62 g; 45 %. 1H NMR (CDCl3, 500.13 MHz, 25 °C): δ 4.06-
4.01 (m, 1H), 3.90-3.86 (m, 1H), 3.76-3.69 (m, 5H), 2.55-2.38 (m, 6H),
2.02-1.95 (m, 1H), 1.93-1.80 (m, 2H), 1.53-.45 (m, 1H). 13C NMR (CDCl3,
125.76 MHz, 25 °C): δ 76.5, 68.3, 67.0, 63.9, 54.4, 30.4, 25.5.
-
(CH(CH3)-N-CH2-CH2-CH’’-, -N-(CH2)2-(CH2)5-CH3, 12H), 1.04 (d, J = 6.3
Hz, piperidine-CH3, 3H), 0.87 (t, J = 7.0 Hz, CH3-(CH2)7-N, 3H). 13C NMR
(CDCl3, 125.76 MHz, 25 °C): δ 55.9 (N-CH(CH3)-CH2), 54.4 (CH3-(CH2)6-
CH2-N), 52.4 (-(CH(CH3)-N-CH2-CH2-CH2-), 34.9 (N-CH(CH3)-CH2), 31.9
(CH3-(CH2)5-(CH2)2-N), 29.8 (CH3-(CH2)5-(CH2)2-N), 29.4 (CH3-(CH2)5-
(CH2)2-N), 28.0 (CH3-(CH2)5-(CH2)2-N), 26.4 (-(CH(CH3)-N-CH2-CH2-
CH2-), 25.3 (N-CH2-CH2-(CH2)5-CH3), 24.3 (-(CH(CH3)-N-CH2-CH2-CH2-),
22.8 (CH3-(CH2)5-(CH2)2-N), 19.4 (piperidine-CH3), 14.2 (CH3-(CH2)7-N).
νmax (film)/cm-1: 2923, 2853, 1466, 1371, 1076. HRMS–ESI: m/z [M+H]+
calcd for C14H30N: 212.2373; found: 212.2405.
N-octyl piperazine (23). General method A, utilizing piperazine (0.53 g; 6
mmol), followed by general purification method. Gained red brown paste
was extracted with hot acetone and the whole mixture was placed in
freezer after cooling to rt, precipitating white to pale red solid. The
hydrochloride was removed with the general method .The solvent was
evaporated to afford red brown liquid. Yield: 0.31 g, 26%. 1H NMR (CDCl3,
500.13 MHz, 25 °C): δ 2.87 (t, J = 4.9 Hz, 4H), 2.38 (b, 4H), 2.29-2.26 (m,
All analytical data were in good accordance with reported data.29
4-[(1-methyl-2-pyrrolidinyl)methyl]morpholine (20). General method B.
Ethanol (2 mL) and chlorotrimethylsilane (1.6 mL) were added slowly and
the mixture was stirred for 2 hours. Water (~ 10 mL) was added to the
mixture and stirred until two clear layers formed (~1 h). Layers were
9
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000167
European Journal of Organic Chemistry
FULL PAPER
2H), 1.58 (b, 1H), 1.49-1.44 (m, 2H), 1.30-1.25 (m, 10H), 0.86 (t, J = 6.9
Hz, 3H). 13C NMR (CDCl3, 125.76 MHz, 25 °C): δ 59.7, 54.9, 46.3, 32.0,
29.7, 29.4, 27.8, 26.8, 22.8, 14.2.
layer extracted with H2O (~ 10 mL). Combined aqueous fractions were
extracted twice with toluene (2x 10 mL). To the aqueous fraction were
added 10 mL of saturated Na2CO3 and 15 mL of diethyl ether. The biphasic
system was stirred vigorously until two clear layers could be separated (~
1-2 h). Layers were separated and aqueous fraction extracted with addition
diethyl ether (10 mL). Organics were combined, dried with sodium sulfate
and evaporated to dryness yielding colorless oil with minor solvent
impurities. Yield: 1.35 g, 92 %. 1H NMR (CDCl3, 500.13 MHz, 25 °C): δ.
2.50-2.43 (m, 4H), 2.42-2.36 (m, 2H), 1.78-1.71 (m, 4H), 1.56-1.45 (m, 2H),
1.35-1.17 (m, 10H), 0.86 (t, J = 9.2 Hz, 3H). 13C NMR (CDCl3, 125.76 MHz,
25 °C): δ. 56.9, 54.4, 32.0, 29.7, 29.4, 29.3, 27.9, 23.5, 22.8, 14.2.
All analytical data were in good accordance with reported data. 30
N,N-dioctylpiperazine (24). Into 9 mL thick walled glass reactor with
magnetic stirrer was measured dichloro(p-cymene)ruthenium(II) dimer (98
mg; 0.16 mmol), Ph3P (168 mg; 0.64 mmol) and piperazine (0.35 g, 4
mmol). The reactor was taken into glove box followed by addition octanol
(4 mL). Reactor was sealed with screw cap, taken outside and heated to
140 °C for 48 hours. After cooling to room temperature the mixture was
purified following the general purification method and removal of the
hydrochloride salt. The solvent was evaporated to afford red brown liquid.
Yield: 0.60 g, 48%. 1H NMR (CDCl3, 500.13 MHz, 25 °C): δ 2.47 (b, N-
[(CH2)2-]2-N, 8H), 2.23-2.28 (m, N-CH2-(CH2)6CH3, 4H), 1.50-1.45 (m, N-
CH2-CH2-(CH2)5CH3, 4H), 1.31-1.19 (m, N-(CH2)2(CH2)5CH3, 20H), 0.87 (t,
J = 7.0 Hz, N-(CH2)7CH3, 6H). 13C NMR (CDCl3, 125.76 MHz, 25 °C): δ
59.1 (N-CH2-(CH2)6CH3), 53.5 (N-[(CH2)2-]2-N), 32.0 (N-(CH2)2(CH2)5CH3),
29.7 (N-(CH2)2(CH2)5CH3), 29.4 (N-(CH2)2(CH2)5CH3), 27.8 (N-
All analytical data were in good accordance with reported data.32
N-octyl-Indoline (28). General method B with 48 hour reaction time. After
cooling to room temperature, the mixture was poured into hexane (10 mL)
and filtered. Solvents were evaporated followed by two subsequent
purifications by flash chromatography (gradient: petrol ether:EtOAc 0-
100 %) yielding two products: Indoline derivative as pale yellow liquid.
Yield: 0.96 g, 52 %, Rf: 0.67 (Toluene); Indole derivative as pale green
liquid. Yield: 0.43 g, 23 %, Rf: 0.88 (Toluene).
(CH2)2(CH2)5CH3),
27.1
(N-CH2-CH2-(CH2)5CH3),
23.0
(N-
(CH2)2(CH2)5CH3), 14.2 (N-(CH2)7CH3). νmax (film)/cm-1: 2922, 2853, 2806,
1464, 1375, 1270, 1159, 1117, 1012, 825, 721. HRMS–ESI: m/z [M+H]+
calcd for C20H43N2: 311.3421; found: 311.3511.
1
N-octyl-Indoline: H NMR (CDCl3, 500.13 MHz, 25 °C): δ 7.09-7.04 (m,
2H), 6.63 (t, J = 7.3, Hz, 1H), 6.47 (d, J = 7.7 Hz, 1H), 3.34 (t, J = 8.3 Hz,
2H), 3.05 (t, J = 7.4 Hz, 2H), 2.96 (t, J = 8.3 Hz, 2H), 1.64-1.56 (m, 2H),
1.39-1.29 (m, 10H), 0.91 (t, J = 7.1 Hz, 3H). 13C NMR (CDCl3, 125.76 MHz,
25 °C): δ 152.9, 130.1, 127.4, 124.5, 117.3, 107.0, 53.2, 49.5, 32.0, 29.6,
29.5, 28.7, 27.5, 27.4, 22.8, 14.3.
1-Methyl-4-octyl-piperazine (25). General method A. After cooling to
room temperature, the mixture was poured into hexane (10 mL) and
filtered. Chlorotrimethylsilane (1.6 mL) was added slowly and the mixture
was stirred for 2 hours. To the mixture was added water (~ 10 mL) and
stirred until two clear layers formed (~1 h). Layers were separated and the
organic layer extracted with H2O (~ 10 mL). Combined aqueous fractions
were extracted twice with toluene (2x 10 mL). Into the aqueous fraction
were added 10 mL of saturated Na2CO3 and 15 mL of diethyl ether. The
biphasic system was stirred vigorously until two clear layers could be
separated (~ 1-2 h). Layers were separated and aqueous was extracted
with addition diethyl ether (10 mL). Organics were combined, dried with
sodium sulfate and evaporated to dryness. The gained cloudy yellowish oil
was further taken into hexane and kept at -18 °C for 1 hour before filtering
thru thin pad of cellite and evaporated to yield colorless oil. Yield: 1.55 g,
91 %. 1H NMR (CDCl3, 500.13 MHz, 25 °C): δ 2.80-2.32 (b, 8H), 2.31-2.28
(m, 2H), 2.26 (s, 3H), 1.49-1.44 (m, 2H), 1.30-1.17 (m, 10H), 0.85 (t, J =
7.0 Hz, 3H). 13C NMR (CDCl3, 125.76 MHz, 25 °C): δ 59.0, 55.3, 53.4, 46.2,
31.9, 29.7, 29.4, 27.8, 27.1, 22.8, 14.2.
All analytical data were in good accordance with reported data.33
N-octyl-Indole: 1H NMR (CDCl3, 500.13 MHz, 25 °C): δ. 7.65 (d, J = 7.9
Hz, 1H), 7.38-7.35 (m, 1H), 7.24-7.21 (m, 1H), 7.14-7.08 (m, 2H), 6.51 (dd,
J = 3.1 Hz, 0.7 Hz, 1H), 4.13 (t, J = 7.2 Hz, 2H), 1.89-1.82 (m, 2H), 1.38-
1.21 (m, 10H) 0.90 (t, J = 7.0 Hz, 3H). 13C NMR (CDCl3, 125.76 MHz,
25 °C): δ. 136.1, 128.7, 127.9, 121.4, 121.1, 119.3, 109.5, 100.9, 46.6,
31.9, 30.4, 29.4, 29.3, 27.2, 22.8, 14.2.
All analytical data were in good accordance with reported data.34
N-octyl Tetrahydroquinoline (29). General method A, using 48 hour
reaction time, followed by general purification method and removal of
hydrochloride salt. Evaporation of solvent yielded a red brown liquid. Yield:
1.55 g, 79 %. 1H NMR (CDCl3, 500.13 MHz, 25 °C): δ. 7.14-7.08 (m, 3H),
7.03-7.01 (m, 1H), 3.63 (s, 2H), 2.91 (t, J = 5.9 Hz, 2H), 2.73 (t, J = 5.9 Hz,
2H), 2.50, (t, J = 7.7 Hz, 2H), 1.64-1.57 (m, 2H), 1.34-1.28 (m, 10H), 0.89
(t, J = 6.9 Hz, 3H). 13C NMR (CDCl3, 125.76 MHz, 25 °C): δ. 135.1, 134.5,
128.8, 126.7, 126.1, 125.6, 58.8, 56.4, 51.2, 32.0, 29.7, 29.4, 29.3, 27.8,
27.4, 22.8, 14.3.
All analytical data were in good accordance with reported data.31
4-Octyl-1-(tert-butoxycarbonyl)piperazine (26). General method B.
After cooling to room temperature, the mixture was poured into hexane (10
mL) and filtered. Solvents were evaporated followed by flash purification
(Gradient: Petrol ether:EtOAc 0-100 %) yielding red brown oil. Yield: 1.91
g, 80 %. Rf = 0.33 (Hexane:EtOAc 3:1). 1H NMR (MeOD, 500.13 MHz,
25 °C): δ 3.43 (b, (CH2)2-N-Boc ,4H), 2.42 (t, (CH2)2-N-octyl ,4H), 2.35 (m,
CH3(CH2)5CH2CH2-N ,2H), 1.55-1.50 (m, CH3(CH2)5CH2CH2-N, 2H), 1.45
(s, OC(CH3)3, 9H), 1.36-1.10 (m, CH3(CH2)5CH2CH2-N, 10H), 0.90 (t, J =
7.0 Hz, CH3(CH2)5CH2CH2-N, 3H). 13C NMR (MeOD, 125.76 MHz, 25 °C):
δ 156.4 (-CO2-C(CH3)3), 81.2 (-CO2-C(CH3)3), 59.8 (CH3(CH2)5CH2CH2-N),
54.0 ((CH2)2-N-octyl) 44.8-43.8 ((CH2)2-N-Boc), 33.0 ((CH3(CH2)5CH2CH2-
N)), 30.6 (CH3(CH2)5CH2CH2-N), 30.4 (CH3(CH2)5CH2CH2-N), 28.6
(CO2C(CH3)3, CH3(CH2)5CH2CH2-N), 27.5 (CH3(CH2)5CH2CH2-N), 23.7
(CH3(CH2)5CH2CH2-N), 14.4 (CH3(CH2)5CH2CH2-N). νmax (film)/cm-1: 2925,
1697, 1416, 1364, 1242, 1170, 1004, 867, 768. HRMS–ESI: m/z [M+H]+
calcd for C17H35N2O2: 299.2693; found: 299.2695.
All analytical data were in good accordance with reported data. 35
Acknowledgements
Funding from Academy of Finland, Waldemar von Frenckells
Foundation, Gust. Kompa Foundation and Svenska Tekniska
Vetenskapsakademien i Finland.
Keywords: Catalysis • Amination • Borrowing hydrogen • Cyclic
amines • Ruthenium
N-octyl pyrrolidine (27). General method A. After cooling to room
temperature, the mixture was poured into hexane (10 mL) and filtered.
Chlorotrimethylsilane (1.6 mL) was added slowly and the mixture was
stirred for 2 hours. Water (~ 10 mL) was added to the mixture and stirred
until two clear layers formed (~1 h). Layers were separated and the organic
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10.1002/ejoc.202000167
European Journal of Organic Chemistry
FULL PAPER
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This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000167
European Journal of Organic Chemistry
FULL PAPER
Borrowing hydrogen
[RuCl2(p-cymene)] 2 1.0 mol-%
Ph3P 4.0 mol-%
N
X
H2O
HN
X
R
OH
R
Alcohol or toluenet
140 o
C
Total of 29 examples
R = Alkyl or aryl; X = O, CH2, NH, or NR
A robust alcohol amination protocol using common saturated amines and primary alcohols as starting material is described with total
of 29 examples. The reactions are catalyzed by combination of dichloro(p-cymene)ruthenium(II) dimer precatalyst with
triphenylphosphine ligand. The catalyst residues can be precipitated from the reaction media by addition of hexane or cold diethyl ether,
followed by precipitation and isolation of the product as a hydrochloride salt without the need of chromatographic purification in most
cases.
12
This article is protected by copyright. All rights reserved.