Continuous N-alkylation reactions of amino alcohols using γ-Al2O3 and supercritical CO2: Unexpected formation of cyclic ureas and urethanes by reaction with CO2

Article abstract of DOI:10.3762/bjoc.13.36

The use of γ-Al2O3 as a heterogeneous catalyst in scCO₂ has been successfully applied to the amination of alcohols for the synthesis of N-alkylated heterocycles. The optimal reaction conditions (temperature and substrate flow rate) were determined using an automated self-optimising reactor, resulting in moderate to high yields of the target products. Carrying out the reaction in scCO₂ was shown to be beneficial, as higher yields were obtained in the presence of CO₂ than in its absence. A surprising discovery is that, in addition to cyclic amines, cyclic ureas and urethanes could be synthesised by incorporation of CO₂ from the supercritical solvent into the product.

Full text of DOI:10.3762/bjoc.13.36

Continuous N-alkylation reactions of amino alcohols using
γ-Al2O3 and supercritical CO2: unexpected formation of
cyclic ureas and urethanes by reaction with CO2
Emilia S. Streng1, Darren S. Lee1, Michael W. George*1,2 and Martyn Poliakoff*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 329–337.
1School of Chemistry, University of Nottingham, University Park,
doi:10.3762/bjoc.13.36
Nottingham, NG7 2RD, UK and 2Department of Chemical and
Environmental Engineering, University of Nottingham Ningbo China,
Received: 02 December 2016
Accepted: 02 February 2017
Published: 21 February 2017
199 Taikang East Road, Ningbo 315100, China
Email:
Michael W. George* - mike.george@nottingham.ac.uk;
Martyn Poliakoff* - martyn.poliakoff@nottingham.ac.uk
This article is part of the Thematic Series "Automated chemical
synthesis".
*
Corresponding author
Guest Editor: I. R. Baxendale
Keywords:
© 2017 Streng et al.; licensee Beilstein-Institut.
License and terms: see end of document.
continuous flow; heterocycle; N-alkylation; self-optimisation;
supercritical CO2
Abstract
The use of γ-Al2O3 as a heterogeneous catalyst in scCO2 has been successfully applied to the amination of alcohols for the synthe-
sis of N-alkylated heterocycles. The optimal reaction conditions (temperature and substrate flow rate) were determined using an
automated self-optimising reactor, resulting in moderate to high yields of the target products. Carrying out the reaction in scCO2
was shown to be beneficial, as higher yields were obtained in the presence of CO2 than in its absence. A surprising discovery is
that, in addition to cyclic amines, cyclic ureas and urethanes could be synthesised by incorporation of CO2 from the supercritical
solvent into the product.
Introduction
N-alkylated amines are an important motif present in a range of ity issues. An approach that has received much attention
pharmaceutically and industrially useful chemicals; the alkyl- recently is the concept of hydrogen borrowing catalysis [5-19].
ation of amines is a commonly used reaction in process R&D The coupling of alcohols and amines is made possible by the
toward the synthesis of drug candidates [1-3]. Traditional catalysts ability to take two H atoms from the alcohol, oxidising
methods to produce such compounds frequently employ toxic it to an aldehyde. The aldehyde then reacts with the amine
alkylating agents or harsh reagents that can generate stoichio- affording an imine, which is subsequently reduced by transfer-
metric quantities of waste, e.g., boron salts from reductive ring two H atoms back from the catalyst. In this case the only
amination [4]. Hydrogenation offers a greener approach but is byproduct is water. Another approach to N-alkylation in which
often only applicable to simple substrates due to chemoselectiv- water is the only byproduct is the direct substitution of alcohols
329

Beilstein J. Org. Chem. 2017, 13, 329–337.
with amines. It is an attractive method; however, it requires sig- ucts we expected to see were a mixture of piperidine (2a),
nificant activation of the alcohol or amine to proceed effi- N-methylpiperidine (2b), N- and O-methylated 1, as well as
ciently, and often a heterogeneous catalyst at elevated tempera- oligomers. We chose to target 2b only for self-optimisation.
ture and/or pressure is employed [20-28]. As these reactions are
mostly carried out in high pressure systems, they are particular- We targeted N-methylpiperidine (2b) using the self-optimisa-
ly suitable for the use of supercritical solvents. Supercritical sol- tion approach with SNOBFIT as the optimising algorithm [47]
vents are highly compressed and/or heated gases that are and GC analysis as the analytical tool providing the responses
beyond the critical point (e.g., the critical point for CO2 is for the self-optimisation. This methodology allows high
3
1.1 °C and 73.9 bar); in this phase the gas exhibits unique yielding conditions to be found, minimising the formation of
properties and behaves both like a liquid and gas. Using inert byproducts. The temperature and the flow rate of the reaction
supercritical gases as reaction solvents is a greener alternative to were optimised in both the presence and absence of scCO2
using conventional flammable or toxic solvents; furthermore (Figure 1).
post-reaction separation is simplified as the gas/liquid phases
separate upon cooling. The use of supercritical methanol
(
[
scMeOH) for N-alkylation reactions has been reported before
29,30].
Our own investigations with heterogeneous catalysis in super-
critical carbon dioxide (scCO2) have mainly been focused on
continuous flow systems and the etherification of alcohols,
where alcohols are activated by heterogeneous catalysts [31-
3
8]. We have usually employed γ-alumina as the catalyst, as
this is a simple, readily available and environmentally benign
catalyst that is often overlooked and it is used merely as a
support for other catalysts [39-43]. The use of γ-alumina for the
methylation of aniline with dimethyl carbonate has been re-
ported [44]. In this paper, we chose to study the intramolecular
and intermolecular alkylation of amino alcohols using γ-Al2O3
with scCO2 as the solvent and employed self-optimisation
Figure 1: Simplified schematic demonstrating a self-optimising reactor
[34,35,37,44]. The reagents are pumped into the system where they
are mixed and then flowed through a reactor filled with catalyst. The
output of the reactor is analysed by an on-line GC. The response (e.g.,
yield) of this analysis is then sent to an optimising search algorithm
(
e.g., SNOBFIT), which then changes the conditions (e.g., flow rates
[
45,46] to explore the defined parameter space to effectively
and temperature) in order to maximise the response of the analysis.
identify the highest yielding and optimal conditions in a rela-
tively short timeframe.
The results of the optimisations are shown in Figure 2, and the
Results and Discussion
conditions with the highest yields of 2b are shown in Table 1.
To investigate our hypothesis that γ-Al2O3 with scCO2 could be During these experiments the parameter space was extensively
successfully applied to the amination of alcohols, we chose to studied and high yields were achieved at several different
employ a self-optimising reactor (Figure 1, see Supporting conditions. This provides confidence that our optimal yield was
Information File 1 for details) to streamline the optimisation the global optimum within the studied limits of the reaction. It
process using 5-amino-1-pentanol (1) as the model substrate can be seen from Figure 2 that, when the reaction was carried
and methanol as the alkylating agent (Scheme 1). For this reac- out in scCO2, high yields (up to 96%) for 2b were achieved
tion, self-optimisation is important as multiple products were (Figure 2a, Table 1, entries 1–3). In the absence of scCO2 the
identified that could form in parallel; from 1 the possible prod- percentage yield was good but the highest yields were ca.
8
–11% less (Figure 2b, Table 1, entries 4–6) compared to when
scCO2 was present. Clearly scCO2 is beneficial as a solvent in
the formation of 2b.
The optimal region for synthesising 2b turned out to be quite
broad, as high yields were obtained at a variety of conditions.
At lower flow rates (0.1 mL min–1) and hence longer residence
times, yields of 94% were observed at 310 °C (Table 1, entry
Scheme 1: Target reaction – intramolecular cyclisation of 1 followed
by N-methylation with methanol to yield 2b.
2
). Increasing the temperature by 30 °C led to an increase in the
330

Beilstein J. Org. Chem. 2017, 13, 329–337.
Figure 2: Result of the SNOBFIT optimisation for N-methylpiperidine (2b) with and without CO2 showing yields ≥70%. Figure a (left) shows the yields
for the experiment carried out in scCO2 at different temperatures and flow rates; Figure b (right) shows the results without CO2. Conditions: Tempera-
ture 250–350 °C, substrate flow (0.5 M solution in MeOH) 0.1–0.5 mL min−1, 100 bar, when applicable 0.5 mL min−1 CO2.
several different alcohols by flowing a starting mixture of 1
Table 1: The highest yields of 2b found by the optimisations carried
out with CO2 (entries 1–3) and without CO2 (entries 4–6).a
with the alcohol as the solvent (Table 2, entries 2–4). As might
be expected, the cyclisation to N-alkylated piperidines was ob-
served for the primary alcohols. The yield of the corresponding
N-alkylated piperidine falls as the longer chain alcohols are
reacted. When the secondary alcohol isopropanol was used as
the solvent, no N-alkylation was observed and piperidine 2a
was found as the major product. As this catalyst system has
been used previously for the etherification of alcohols [31-38],
it is possible that ethers of the alcohols could be formed. In the
case of 2d, dibutyl ether was the major byproduct, but in most
other cases only small amounts of the corresponding ethers
were observed. When the reaction with isopropanol was
Entry
T (°C)
Flow rate (mL min−1)
Yield 2b (%)b
1c
2c
3c
4d
5d
6d
340
310
330
350
350
350
0.3
0.1
0.15
0.4
0.3
0.5
94
94
96
86
85
83
a0.5 M solution of 1 in MeOH, 100 bar system pressure. bYields based
on GC analysis. cWith 0.5 mL min−1 CO2. dNo CO2 used.
rate of cyclisation and methylation which then allowed for
faster flow rates to be used under this operating temperature
whilst still maintaining the same yield of 2b (Table 1, entry 1).
Hence, three times the amount of material could be processed in
the same time using this elevated temperature, i.e., higher
productivity.
Table 2: Cyclisation and N-alkylation of 1 with different alcohols.a
Entry
R =
Yield (%)b,c
After optimisation with the model substrate 1 in methanol, the
application of these reaction conditions to a small range of dif-
ferent alcohols was studied. Initially we repeated the model
reaction to demonstrate that the approach is repeatable and that
the conditions found during the optimisation were indeed the
optimum (N.B. We chose the conditions that afforded the
highest yield). Pleasingly, full conversion of 1 was obtained and
an identical yield of 2b was observed (Table 2, entry 1). After
showing that the conditions were repeatable, we applied them to
1
2
3
4
Me 2b
Et 2c
94%
82%
n-Bu 2d
iPr 2e
73%
0% (2a 80%)
aConditions: 1 (0.5 M in ROH), 340 °C, substrate flow: 0.3 mL min−1,
CO2 flow: 0.5 mL min−1, 100 bar.; bDetermined by GC analysis of the
reaction mixture. cThe remaining materials are unidentified side prod-
ucts.
331

Beilstein J. Org. Chem. 2017, 13, 329–337.
repeated without scCO2 the same selectivity was observed. tion temperatures increased the selectivity and yield of 6 up to
However, when primary alcohols were run in the absence of 55%. This relatively modest yield could not be optimised
scCO2 the yields of the corresponding N-alkylated products further.
were lower and more piperidine 2a was observed. These results
suggest that the rate of intermolecular alkylation is faster in Ethanolamine 8 was used to explore the potential competition
scCO2, while the rate of intramolecular cyclisation is not signif- between the intra- and intermolecular etherification and amina-
icantly affected by the presence of scCO2 and thus proceeds tion. In this case we observed no azridine or N-methylaziridine,
faster than the intermolecular reaction.
which would be expected from the intramolecular closure of 8,
consistent with the results observed with bromoalkylamines
We also explored the cyclisation and N-alkylation of different [48], and suggesting the rate of closure for three-membered
amino alcohol substrates. Initially we investigated the effect of rings is slower than that of five- and six-membered rings. We
simply changing the alkane chain length. Starting with 4-amino- cannot rule out the formation of aziridine as an intermediate in
1
-butanol (3) under the model conditions afforded the desired the formation of the dimeric products that were observed. The
N-methylpyrrolidine (4) in 95% yield. Extending the alkyl chain reaction with ethanolamine yielded three products (Table 3),
using 6-amino-1-hexanol (5), however, favoured methylation N-methylmorpholine (9), 1,4-dimethylpiperazine (10) and the
over intramolecular cyclisation as only 20% of the cyclised fully N- and O-methylated ethanolamine 11. Under the stan-
product 6 was observed. The major product was 6-(dimethyl- dard conditions, 11 was the major product, and as the tempera-
amino)-1-methoxyhexane (7, Scheme 2), which was formed by ture was increased, the amount of 10 increased. When the pa-
both O- and N-methylation of the starting material. Self-optimi- rameter space was explored using the self-optimisation ap-
sation of the reaction of this substrate was performed in order to proach the selectivity to 10 was increased to 63%. The etherifi-
try and locate the optimal conditions for the highest yield of 6. cation/deamination pathway forming 9 could not be optimised
Within the parameters explored, it was found that higher reac- above 11% as the dehydration or methylated products were
Scheme 2: Cyclisation and N-alkylation of 1,4- and 1,6-amino alcohols.
Table 3: Reactions of ethanolamine.a
Entry
Flow rate (mL min−1)
Temperature (°C)
Conversion (%)
Selectivity (%)b
9
10
11
1
2
3
a
0.3
0.1
0.1
340
370
360
100
100
100
<1
11
5
13
48
63
72
0
c
c,d
3
aConditions: 8 0.5 M (or 1.0 M) solution in MeOH, 0.5 mL min−1 CO2, 100 bar; bBased on GC analysis of the reaction mixture, remaining material is a
mixture of unidentified side products; cSubstrate 1.0 M solution in MeOH; dAfter self-optimisation had been run targeting high yield of 10.
332

Beilstein J. Org. Chem. 2017, 13, 329–337.
present as the major products in all cases. These results over 13 (Table 4, entry 2). Indeed, when 13 was used as the
prompted us to explore the use of more functionalised amino starting material, the major product that was isolated was 14;
alcohols in an attempt to access these heterocycles more cleanly and this reactivity of 13 has been reported previously in batch
and to allow us to further examine the deamination reactivity reactions [49]. Increasing the residence time further (Table 4,
that produces 9.
entry 3) resulted in the oxazolidinone 13 not being detected and
4 was the major product together with a small quantity of
1
Diethanolamine 12 is expected to produce a cleaner cyclisation mono O-ethylated 14. Reducing the temperature gave a better
pathway to N-methylmorpholine (9) via intramolecular etherifi- selectivity to the oxazolidinone 13 (Table 4, entry 4) and
cation. When diethanolamine 12 in methanol was reacted using lowering the concentration, increased the conversion but gave a
the standard conditions (Table 1, entry 1), N-methylmorpholine poor selectivity (Table 4, entry 5). Increasing the pressure to
(
9) was obtained but only in 24% yield; however, when the 150 bar had a positive effect on the selectivity toward 13
conditions were changed in an attempt to optimise the yield, it (Table 4, entry 6) and increasing the concentration of 12 to 1 M
became apparent that the reactivity of 12 was more compli- gave the highest selectivity for 13 (Table 4, entry 7). Further in-
cated. Running the reaction at 380 °C and 0.3 mL min−1 creasing the temperature to 275 °C only served to increase the
resulted in 46% of 9 being obtained but, at lower temperatures, selectivity towards 14 (Table 4, entry 8). From these conditions,
different products were obtained. For example, when the reac- it appears that the incorporation of CO2 is fast but the rate of
tion was run at 250 °C (Table 4, entry 1), oxazolidinone 13 was conversion to 14 is dependent on the pressure of the system, the
observed as the major product (52%) together with 14, a dimer temperature of the reactor, the residence time and to some
of the starting material 12 as the main byproduct (42%).
extent the concentration of the amino alcohol in the alcohol. A
higher pressure of CO2 appears to slow the rate of conversion of
Formation of 13 involves incorporation of the CO2 solvent into 13 to 14, whilst elevated temperatures appear to accelerate the
the product. Despite the very large number of reactions studied rate. Increasing the residence time allows more time for 13 to be
in scCO2, there are relatively few examples of incorporation of converted into 14 and hence the higher selectivity for it and the
CO2 into the product. In this case, incorporation presumably appearance of trace amounts of mono- and bis-ethylated 14.
occurs via the formation of a carbamate intermediate. This
surprising formation of 13 suggests the incorporation of CO2 We have studied the incorporation of CO2 further by investigat-
into 12 with the dimer formation as a competing reaction. In ing the reaction of N-(2-aminoethyl)ethanolamine 15. The use
fact, when further conditions were studied, it became apparent of 15 as a starting material might be expected to produce high
that the dimer 14 could be formed from oxazolidinone 13 as in- selectivity for the corresponding imidazolidinone 16 via the in-
creasing the residence time led to an increase in selectivity of 14 corporation of CO2. The competing oxazolidinone formation
Table 4: Showing the effect of conditions on the reaction of diethanolamine 12 to form carbamate 13 and piperazine 14.a
Entry
Conc. (M)
T (°C)
P (bar)
Flow rate (mL min−1)
Conv. (%)b
Selectivity (%)b
13
14
1
2
3
4
5
6
7
8
0.5
0.5
0.5
0.5
0.2
0.2
1.0
1.0
250
250
250
240
250
250
250
275
100
100
100
100
100
150
150
100
0.3
0.2
0.1
0.3
0.3
0.3
0.2
0.2
53
52
20
0
42
65
61c
26
38
19
22
63d
98
100
48
69
42
65
73
8
80
73
56
100
a12 in ethanol, 0.5 mL min−1 CO2. bBased on GC analysis of the reaction mixture. c12% of mono-O-ethylated 14. dTrace of mono- and bis-ethylated
4.
1
333

Beilstein J. Org. Chem. 2017, 13, 329–337.
should be limited as the nucleophilicity of nitrogen is more than
that of the oxygen. Furthermore, the formation of dimers were
expected to be supressed as 16 does not contain a “CO2 unit”
that can serve as a leaving group. This was indeed the case as,
at 250 °C, 85% selectivity, 70% yield for 16 was observed
when the reaction was run in scCO2 (Scheme 3a). In the
absence of CO2 as a solvent the formation of imidazolidinone
1
6 was not observed. When the starting solution was pre-satu-
rated with CO2 and run in the absence of CO2 as a solvent, 16
was formed in 62% selectivity, 15% yield from 24% conver-
sion of the starting material. This poor conversion suggests that
CO2 is needed in an excess for the reaction to be successful, and
the use of CO2 as the solvent as well as a reagent in this case
provides the highest possible concentration of CO2. To estab-
lish whether any dimers are formed when 16 is exposed to the
catalyst bed for an extended time or to higher reaction tempera-
tures, a solution of 16 in iPrOH (0.5 M) was flowed at 250 and
Scheme 3: a) Reactions highlighting the incorporation of CO2 in to 16.
b) High temperature reaction of 15 yielding N,N’-dimethylpiperazine
(10).
2
75 °C, but no dimers were detected and unreacted 16 was the
main product observed. The reaction of 15 with CO2 could be Conclusion
supressed using higher temperatures, for example at 380 °C in Using a self-optimising reactor and a simple heterogeneous
methanol the intramolecular cyclisation is favoured and N,N’- catalyst, γ-Al2O3, moderate to high yields of several alkylated
dimethylpiperazine (10) is obtained as the major product in cyclic amines, formed in a two-step intramolecular cyclisation/
6
8% yield (Scheme 3b, 380 °C at 1 mL min−1), and no imidazo- N-alkyation reaction, using amino alcohols and simple alcohols
lidinone 16 was detected. has been achieved (Scheme 4).
Scheme 4: Summary of products obtained from the reactions of amino alcohols over γ-Al2O3 in scCO2.
334

Beilstein J. Org. Chem. 2017, 13, 329–337.
Using scCO2 as the solvent proved to be beneficial to the yield most surprising result as this occurred at lower temperatures
of cyclic N-alkylated amines, in particular for the N-alkylation compared to the cyclisation, however at higher temperatures
step which was arrested in the absence of scCO2. The intramo- intramolecular reactions were favoured. The formation of
lecular cyclisation of the amino alcohols was favoured at higher oxazolidinones was shown to be reversible releasing CO2 as
temperatures in both the presence and absence of scCO2. In- dimers are formed. Imidazolidinones were shown to be stable to
creasing the primary alcohol length led to slightly lower yields further reaction and no release of CO2 was observed under the
of the target products whereas secondary alcohols did not react conditions studied. Further optimisation and investigations into
with the amines at all. Varying the chain length of the amino the incorporation of CO2 are in progress.
alcohol produced the corresponding N-alkylated five- (4) and
seven-membered ring (6), three-membered aziridine rings were Experimental
not detected. Competing N- and O-alkylation was observed at CAUTION! The described reactions involve high pressures and
higher temperatures with ethanolamine (8) and 6-amino-1- require equipment (Figure 3) with appropriate pressure ratings.
hexanol (5), suggesting ring closure is slower in these cases.
Ethanolamine (8) produced dimers as the major products, All reagents and solvents were purchased from commercial
mainly via the amination pathway; however, some esterifica- sources and used as received. CO2 was supplied by BOC Gases
tion/deamination was observed as N-methylmorpholine (9) was (99.8%). The γ-alumina (PURALOX NWa155) was supplied by
also detected. CO2 incorporation in 12 and 15 was perhaps the SASOL. It was sieved before use, to obtain the desired particle
Figure 3: Diagram of the high pressure equipment used in the experiments.
335

Beilstein J. Org. Chem. 2017, 13, 329–337.
size (125–170 μm), which was used as the catalyst. Reaction the ITMC, RWTH Aachen, which prompted this work. We
mixtures were analysed using GC, GC–MS, 1H and 13C NMR. thank M. Guyler, P. Fields, R. Wilson, K. Hind, D. Litchfield
Compounds 1a–c, 4, 9, 10, 13, 14, 16 were obtained from and J. Warren for their technical support at Nottingham.
Aldrich and used as standards. 1d,e [50], 6 [51], 7 [52], and 11
[
53] were identified as previously described in the literature.
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Supporting Information
1
2
2
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