Fast continuous alcohol amination employing a hydrogen borrowing protocol

Article abstract of DOI:10.1039/c8gc03328e

A continuous flow method for the direct conversion of alcohols to amines via a hydrogen borrowing approach is reported. The method utilises a low loading (0.5%) of a commercial catalyst system ([Ru(p-cymene)Cl₂]₂ and DPEPhos), reagent grade solvent and is selective for primary alcohols. Successful methylation of amines using methanol and the direct dimethylamination of alcohols using commercial dimethylamine solution are reported. The synthesis of two pharmaceutical agents Piribedil (5) and Buspirone (25) were accomplished in good yields employing these new methods.

Full text of DOI:10.1039/c8gc03328e

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Fast continuous alcohol amination employing a
hydrogen borrowing protocol†
Cite this: Green Chem., 2019, 21, 59
a
Ricardo Labes, a Carlos Mateos, *b Claudio Battilocchio, ‡a Yiding Chen,
Received 23rd October 2018,
Accepted 12th November 2018
b
Paul Dingwall, §a Graham R. Cumming, b Juan A. Rincón,
Maria José Nieves-Remacha b and Steven V. Ley
*
a
DOI: 10.1039/c8gc03328e
rsc.li/greenchem
A continuous flow method for the direct conversion of alcohols to resents excellent atom efficiency and generates only water as
amines via hydrogen borrowing approach is reported. The by-product during the overall conversion of alcohol to amine.
a
method utilises a low loading (0.5%) of a commercial catalyst Reported first in 19812–4 and recently reviewed,5 direct alcohol
system ([Ru(p-cymene)Cl2]2 and DPEPhos), reagent grade solvent amination through a variety of alcohol amination systems gen-
and is selective for primary alcohols. Successful methylation of erally consists of an oxidation phase to generate a carbonyl
amines using methanol and the direct dimethylamination of alco- species using a suitable hydrogen atom catalytic carrier, fol-
hols using commercial dimethylamine solution are reported. The lowed by rapid imine formation and final return of hydrogen
synthesis of two pharmaceutical agents Piribedil (5) and Buspirone to effect formation of the product amine (Scheme 1).
(25) were accomplished in good yields employing these new
Many advances in this field have been made with varying
degrees of success. All these approaches strive to obtain a
robust practical sequence in terms of catalyst loading, reaction
time and scalability.6–14 For example, an attractive application
of hydrogen borrowing method was reported by Pfizer, using
an Iridium catalyst originally developed by Fujita15 to prepare
a GlyT1 inhibitor on kilogram scales.16 In the same report, the
authors describe that the reaction works best in a pressurized
vessel, heating above the boiling point of the reaction mixture
suggesting its suitability for continuous flow development.16
In other work, the method was extended for other pharmaceu-
tically relevant substrates, where potential catalyst poisoning
can be a undesired side effect.17
methods.
Nitrogen containing compounds constitute the majority of
pharmaceutical and agrochemical agents and feature in a vast
range of natural products and chemical building blocks used
for synthesis. As a consequence, their preparation is important
as is the discovery of new, more sustainable routes to these
types of molecules. The community is fairly well served with
classical alkylation and arylation methods to form substituted
amines, which are particularly relevant in an industrial set-
tings.1 However, to convert alcohols to amines usually requires
multiple steps via activation through halides or sulfonates fol-
lowed by nucleophilic displacement with amines, or alterna-
tively via oxidation and reductive amination. These multistep
methods, although successful, often use quite aggressive
reagents, produce excessive waste and are not always amenable
to scale.
Our recent findings on the efficient use of ruthenium cata-
lysed continuous transfer hydrogenation reactions18,19 led us
to study the benefits of these hydrogen borrowing methods
in similar systems. Continuous flow hydrogen-borrowing
As an alternative approach, a hydrogen borrowing tech-
nique is becoming increasingly attractive. This process rep-
aInnovative Technology Centre, Department of Chemistry, University of Cambridge,
Lensfield Road, Cambridge, CB2 1EW, UK. E-mail: svl1000@cam.ac.uk
bCentro de Investigación Lilly S.A., Avda. de la Industria 30,
Alcobendas-Madrid 28108, Spain. E-mail: c.mateos@lilly.com
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8gc03328e
‡Current
address:
Syngenta
Crop
Protection,
Process
Research,
Schaffhauserstrasse 101, Stein, CH-4332, Switzerland.
§Current address: Queen’s University Belfast, University Rd, Belfast, BT7 1NN,
UK.
Scheme 1 Alcohol amination via hydrogen borrowing.
Green Chem., 2019, 21, 59–63 | 59
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methods have been reported in the past, but not always that DPEPhos and DPPF were the best performing phosphines.
without issues, for example, low space–time yield and catalyst At 250 °C triphenylphosphine was also active, furnishing the
leaching.20,21 Nevertheless there is still scope to develop product in 74%. Interestingly, more hindered tri-o-tolylpho-
greater process windows (high temperatures and pressures) sphine resulted in only 12% conversion (see ESI†).
and provide a practical continuous method that can deliver
the product quickly and safely on a reasonable scale (higher a design of experiment (DoE) study was performed (see ESI†).
process intensification). The catalyst loading demonstrated the strongest effect, fol-
To better optimize and understand the reaction parameters
Previous studies have concentrated mainly on the multistep lowed by time and then temperature. An increase in concen-
discovery of novel catalysts, however here we choose to focus tration marginally improved the reaction.
on the use of a catalytic system that has well-recognised sub-
A selection of these DoE experiments is compiled in Table 1
strate compatibility and is commercially available. For this, the to illustrate the versatility of the method. Thus, if lower tem-
catalytic system developed by Williams and colleagues ([Ru(p- perature is required, higher catalyst loading and time can be
cymene)Cl2]2 and DPEPhos in toluene) was selected, as it is used (Table 1, entry 1). If the catalyst loading was reduced, the
relatively inexpensive, air-stable and does not require extensive conditions can be adjusted to work as low as 0.3 mol% of cata-
downstream processing.22
lyst (Table 1, entry 2). On reducing the time scale, all other
To accommodate the anticipated high temperatures and parameters can be adjusted to complete the reaction within
pressures needed for the reaction, a Phoenix flow reactor was 1 min (Table 1, entry 3). As expected, no reaction was observed
selected. This device operates at up to 450 °C and 300 bar and without addition of the catalyst system (Table 1, entry 4).
has interchangeable 8 and 35 mL stainless steel flow coils.23
One potential problem of hydrogen borrowing methods is
The initial evaluation began by flowing a solution of benzyl that polar compounds, commonly encountered in pharma-
alcohol and morpholine similar to Williams’ original con- ceutical and agrochemical candidates, can suffer from low
ditions but with 0.5 mol% of the ruthenium catalyst instead of solubility in toluene/xylene, which constrains the applicability
2.5 mol%,22 and varying the residence time and temperature of the method. We therefore screened for alternative solvents
of the reactor (Fig. 1). We were surprised by the strong positive with higher polarity and were pleased to find that the reaction
effect the temperature had over the reaction turnover. In only worked equally well in trifluorotoluene(CF3Ph), CPME and
10 minutes of residence time in the reactor the product was THF (see ESI†). Here again non-anhydrous and non-degassed
obtained in 60% yield at 200 °C and fully converted at 250 °C, solvents were used to conform with the desired practicality.
while only 12% of product was observed at 150 °C (Fig. 1). In Differential Scanning Calorimetry (DSC) was conducted to
the original work, the reaction mixture required reflux for 24h confirm the reaction safety generating amines in THF at high
in the presence molecular sieves to obtain 84% yield.22 Here, temperatures (see ESI†).
non-dried and non-degassed toluene was used with no
decrease in conversion. Interestingly at 250 °C no by-products, next investigated if this could be applied more generally to
for example esters, were observed. other alcohol amination processes. The results of this brief
The equivalents of alcohol and phosphine were also varied reaction scope study are shown in Table 2.
With a successful, robust and clean protocol in hand we
and our results were in agreement with the original findings
The method suggests that high yields can be obtained with
benzylic and aliphatic alcohols, while allylic alcohols suffered
from additional reduction of the double bond, with decreased
overall yield (13). Heterocycles such as morpholine (1, 3, 7, 15),
piperidine (10), indole (7 & 11), methylenedioxy (5 & 8) and
Table 1 Evaluation of the influence of parameters
Temp.
(°C)
Res. time
(min)
Cat. load
(mol%)
Conc.
Yielda
(%)
Entry
(mol L−1
)
1
2
3
4
150
250
250
250
30
8
1
2.5
0.3
2.5
0
3
Neat
3
2
75
>99
>99
0
8
Fig. 1 Comparison of yield in different temperatures and residence
time.
a NMR yield using trimethoxybenzene as internal standard.
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Table 2 Alcohol amination via hydrogen borrowing
by using methanol in toluene useful reactivity was observed
(Table 3).
Methylation of morpholine gave 93% yield of the corres-
ponding N-methylmorpholine (16). Interestingly 2,4-dichloro-
aniline lead to the monomethylated product even when using
2.2 equivalents of methanol, while no substitution of chlorine
observed (17). At the same time ester (19) was obtained with
no significant transesterification with methanol. We believe
that under the studied conditions the oxidation to formal-
dehyde is fast enough to avoid transesterification.
To complement these studies and further respond to the
needs of industry, since dimethylamino derivatives occur in a
range of bioactive materials, we chose to study the direct
alcohol amination with dimethylamine as source of amine
(Table 4). For this, different from previous reports,22 we used a
commercial solution of dimethylamine in THF, which greatly
improves the practicality of the method.
These illustrative examples show how these alcohols can be
coupled with dimethylamine using the Phoenix flow reactor to
afford the corresponding aminated products.
Finally, to demonstrate wider functional group tolerances
we reacted the alcohol (23) with amine (24) to lead to the
anxiolytic drug Buspirone (25) directly in 76% yield
(Scheme 2). In doing so, we improved the synthesis from the
commercial route by reducing the sequence by one step, avoid-
Reactions conditions are shown in the scheme. Yields are for the
isolated compound. a 0.5 mol L−1, 2.5 mol% [Ru(p-cymene)Cl2]2,
5 mol% DPEPhos. b 1.1 equiv. of alcohol, 0.5 mol L−1 in THF, 1 mol%
[Ru(p-cymene)Cl2]2, 2 mol% DPEPhos. c 1.3 equiv. of benzylamine,
1 mol L−1, 1 mol% [Ru(p-cymene)Cl2]2, 2 mol% DPEPhos. d 0.5 mol
Table 3 Amine methylation using methanol
L−1 in CPME. e 0.5 mol L−1 f 1 mol L−1 g 1 mol L−1 in THF. h 2.5 mol%
. .
[Ru(p-cymene)Cl2]2, 5 mol% DPEPhos. i NMR yield using trimethoxy-
benzene as internal standard.
piperazine (the anti-Parkinson agent Piribedil 5 & 8) were all
compatible, but thiazole 12 resulted in poor yield, although no
further decomposition was observed and starting material was
recovered in 83%, even using a higher 2.5 mol% loading of
catalyst. tert-Butylamine (4) and aniline (14) required a higher
catalyst loading to afford the corresponding benzylated pro-
ducts in higher yields. Cyclization of 1,5-pentanol afforded the
piperidine 6 in 76% yield. Remarkably ester-containing pro-
ducts (10) were successfully reacted with benzyl alcohol
without damage to the ester functionality. Phenolic substrate
also remained unchanged in the process (15). We noticed too
that with secondary alcohols, such as 1-phenylethanol (2), no
amination occurred and starting material was recovered.
Reactions conditions are shown in the scheme. Yields are for the
isolated compound. a 2 mol L−1 solution. b 1 mol L−1 solution. c 2.2
equivalents of methanol.
Table 4 Alcohol dimethylamination using Me2NH in THF
From the above results we speculated that this hydrogen
borrowing method could be usefully applied to the direct
methylation (or dimethylation) of amines with methanol. This
would constitute an attractive greener approach towards
certain active pharmaceutical ingredients (APIs). In an initial
experiment using only methanol as solvent we noticed a
colour change but no chemical reactivity. On the other hand,
Reactions conditions are shown in the scheme. Yields are for the
isolated compound.
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Scheme 2 Synthesis of Buspirone.
The authors are grateful to Eli Lilly & Co. (RL) and the EPSRC
(SVL, grants EP/K009494/1, EP/M004120/1 and EP/K039520/1)
for financial support. This work was supported by Eli Lilly &
Co. through the Lilly Research Award Program (LRAP).
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