Multistep synthesis of amides from alcohols and amines in continuous flow microreactor systems using oxygen and urea hydrogen peroxide as oxidants

Article abstract of DOI:10.1039/c3gc40407b

By integrating a heterogeneous oxidation step, gas-liquid separation, and an oxidative amidation reaction to form a continuous system, a multistep synthetic protocol has been demonstrated to produce amides under mild conditions using alcohols and amines as the starting materials. The use of inexpensive oxygen and urea hydrogen peroxide as the only oxidants affords an economical and adaptable synthetic route for amides.

Full text of DOI:10.1039/c3gc40407b

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Multistep synthesis of amides from alcohols and
amines in continuous flow microreactor systems using
oxygen and urea hydrogen peroxide as oxidants†
Cite this: DOI: 10.1039/c3gc40407b
Xiaoying Liu and Klavs F. Jensen*
By integrating a heterogeneous oxidation step, gas–liquid separation, and an oxidative amidation reac-
tion to form a continuous system, a multistep synthetic protocol has been demonstrated to produce
amides under mild conditions using alcohols and amines as the starting materials. The use of inexpensive
oxygen and urea hydrogen peroxide as the only oxidants affords an economical and adaptable synthetic
route for amides.
Received 27th February 2013,
Accepted 28th March 2013
DOI: 10.1039/c3gc40407b
www.rsc.org/greenchem
The amide linkage is an important functional group due to its to regenerate the catalyst in order to render the process cataly-
extensive presence in natural products, pharmaceutical com- tic, usually produces gaseous hydrogen as a by-product or
pounds, and synthetic polymers. Compared to the general syn- employs sacrificial hydrogen accepting reagents. This aspect
thetic methods based on the reaction between activated forms poses additional challenges on system design to handle H2 or
of carboxylic acids and amines, the synthesis of amides on product isolation.
directly from alcohols and amines would be a desirable chemi-
A strategy to overcome the close “coupling” of the two oxi-
cal transformation.1,2 It would afford a highly economical syn- dation steps is to design two separate reactions to achieve the
thetic route due to the availability and stability of the starting same net transformation. Such “decoupling” would allow each
materials.
oxidation step to be carried out independently and therefore
Only a limited number of systems have been developed so create more possibilities to improve the overall reaction, such
far to achieve this transformation, which are promoted by as increase selectivity, improve efficiency, and lower environ-
homogeneous or heterogeneous catalysts.1–3 Ru- or Rh-based mental impact. In addition, the relatively large number of well-
transition metal complexes,4–8 Ag- or Au-based supported cata- established processes to convert alcohols into aldehydes12 and
lysts9,10, and Cu salt11 have been used to directly convert alco- aldehydes (with amines) into amides13 provides a considerably
hols and amines into amides. These synthetic protocols share wider design space to develop processes that would cover a
a common underlying mechanism that involves three main broader range of substrates. However, the added complexity in
consecutive steps: (1) activation—the oxidation of alcohols to multistep batch reactions, as compared with one-pot pro-
form aldehydes; (2) bond construction—the coupling of alde- cesses, can make such development efforts time-consuming
hydes with amines to produce hemiaminals as reactive inter- and less efficient.
mediates; (3) dehydrogenation—subsequent oxidation of
The use of continuous flow microreactors provides a valu-
hemiaminals to amides through H2 liberation or H transfer to able platform for the development of multistep syntheses by
a hydrogen acceptor. Since alcohols are less reactive and an integrating multiple unit operations into one single network
increase in their oxidation level is required for this type of and eliminating the handling of intermediate species.14–16 The
transformation, the synthetic strategies would involve oxidative streamlined operation renders continuous scanning of reaction
activation of the alcohols. Another key feature of such strat- parameters and therefore enables fast screening of catalysts and
egies is that both oxidation steps, (1) and (3), are necessarily rapid optimization of reaction conditions. At the same time, the
catalyzed by the same catalyst, making catalyst development modular nature of multistep syntheses in flow allows for the
extremely challenging. Additionally, the last step, which needs reaction parameters to be individually adjusted for each step
and makes it possible to access a substantially larger operating
space. Furthermore, microreactors use minimum amounts of
Department of Chemical Engineering, Massachusetts Institute of Technology,
materials, which can be particularly beneficial when the
77 Massachusetts Avenue, Cambridge, MA 02139, USA. E-mail: kfjensen@mit.edu;
systems involve expensive catalysts or reagents. Additionally, the
Fax: (+1) 617-258-8992
temperature and pressure can be precisely controlled, leading to
enhanced safety and higher selectivity.
†Electronic supplementary information (ESI) available: Experimental setup and
product isolation. See DOI: 10.1039/c3gc40407b
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We present here a multistep synthetic protocol developed in
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continuous flow microreactor systems to directly convert aro-
matic alcohols and secondary amines into amides. The reac-
tion system consists of three micro-system devices: (i) a
packed-bed microreactor to catalytically oxidize alcohols into
aldehydes using O2 as the oxidant and Ru/Al2O3 as the catalyst;
(ii) a membrane separator to extract the residual O2 out of the
system; (iii) a spiral-channel microreactor to convert aldehydes
and amines into amides using urea hydrogen peroxide (UHP)
as the oxidant without any catalyst or promoter. The use of the
membrane separator to remove the predominant gas phase
allows for control of residence time for the spiral-channel
reactor. Our system is continuously operated under mild con-
ditions with a total residence time of 45 min. The use of
widely available alcohols and amines as starting materials and
inexpensive oxidizing agents (O2 and UHP) offers an economi-
cal synthetic route to amides.
Scheme 1 Oxidation of benzyl alcohol to form benzaldehyde as a probe reac-
tion for catalyst screening with the packed-bed microreactor using molecular
oxygen as the oxidant.
concentrations of starting materials, back pressure, and resi-
dence time were varied in the optimization process. Specifi-
cally, using the catalytic oxidation of benzyl alcohol to form
benzaldehyde as a probe reaction (Scheme 1), we studied a
range of supported Pt-, Pd-, Au- and Ru-based catalytic
materials and identified Ru/Al2O3-5 wt% (Alfar Aesar)20 to be
the most efficient catalyst without any additives/promoters. A
stable conversion of 95% was successfully obtained with the
reaction running continuously for 24 h at 80 °C. For the mem-
brane separator, pressure control is crucial to achieve good
separation.16,18 The back pressure at the outlet for the liquid
phase was controlled by a stainless steel vessel that is con-
nected to a high-pressure nitrogen cylinder and the pressure
difference between the two outlets was provided by a pressure
drop tubing (100 μm ID). The liquid stream was fed into the
spiral-channel microreactor where the aldehyde merged with
urea hydrogen peroxide (UHP) and amine to produce amide
(Scheme 2). The use of UHP is an improvement over our pre-
vious work13 using aqueous H2O2, which decomposes over
time to generate gas bubbles. UHP makes the process more
stable, controllable, and adaptable.
The substrate scope of this multistep methodology was
determined by investigating different types of alcohols and
amines to produce the corresponding amides. We have found
that our strategy is suitable to prepare a wide range of amides
starting from aromatic alcohols (Table 1). The reactions with
morpholine were performed under mild conditions with the
temperature for the packed-bed reactor at 80 °C and that for
the spiral-channel reactor at 90–130 °C. Functional groups on
the phenyl ring do not significantly affect the reaction (entries
1–9). Excellent conversion was achieved with yields ranging
from 69 to 94%. The main by-product is the corresponding
aldehyde, with yields in the range of 2–15%. Our synthetic pro-
tocol can be extended to heterocyclic aromatic alcohols
(entries 10–12) under similar reaction conditions with good to
excellent yields toward the corresponding amides. Allylic alco-
hols were also investigated as potential substrates and lower
yield was obtained. For example, although 95% of cinnamyl
alcohol was converted into cinnamaldehyde, the amidation
step was less efficient, resulting in the amide yield of 67%.
The experimental setup (Fig. 1) consists of three micro-
system devices: a packed-bed microreactor, a membrane
separator, and
a spiral-channel microreactor. The first
reactor17 is a silicon-Pyrex microreactor with a single-channel
(27 × 8 × 0.6 mm3). An array of pillars was fabricated down-
stream of the reactor with 25 μm intervals as a weir to hold the
catalytic materials inside the channel. The stainless steel
packaging chuck allows the device to be heated and pressur-
ized. The separator18 is constructed of two stainless steel
chucks with a single channel (20 × 2 × 1 mm3) on each piece. A
piece of a Zefluor membrane (Pall, 0.5 μm pore size) is sand-
wiched between the two pieces that are compressed together.
It operated at ambient temperature in our experiments. The
third device is a silicon-Pyrex microreactor (220 μL in total
volume) with a spiral channel.19 The mixing and reaction
zones are separated by a halo etched region.
Each of the three unit operations—heterogeneous catalysis,
separation, and amidation—was studied and optimized before
forming a continuous network. Reaction parameters and vari-
ables, including catalytic material, reaction temperature,
Fig. 1 Diagram of the experimental setup for multistep synthesis of amides
from alcohols and amines. Photos of the three micro-system devices (a packed-
bed microreactor, a gas–liquid membrane separator, and a spiral-channel micro-
reactor) are also shown.
Scheme 2 Amidation of aromatic aldehydes by secondary amines to form
amides in the spiral-channel microreactor using urea hydrogen peroxide (UHP)
as the oxidant. Ar: aromatic groups.
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Table 1 Multistep synthesis of amides in continuous flow microreactor systems
from aromatic alcohols and morpholine using O2 and urea hydrogen peroxide
as oxidantsa
Fig. 2 Amides synthesized with the multistep continuous flow system utilizing
piperidine, pyrrolidine, or 1,2,3,4-tetrahydroisoquinoline. The reaction tempera-
ture for the amidation step is 110 °C with the other conditions being the same
as those for morpholine.
Entry
1
Alcohol
T
b (°C)
Conversionc (%)
95
Yieldd (%)
86
100
110
gas–liquid separation was achieved through the process. The
obtained product mixture underwent extraction, concen-
tration, column chromatography, and solvent evaporation to
yield 4-(4-chlorobenzoyl)morpholine with the yield of 84% (see
ESI† for details).
The underlying reaction mechanism involves aldehyde as
an intermediate species that couples with amine to form
amide with the assistance of H2O2 that is released from the
urea hydrogen peroxide adduct under our reaction conditions.
This coupling step is a direct adaption of our previous
method13 for oxidative amidation of aromatic aldehydes, with
H2O2 being replaced by urea hydrogen peroxide, further
demonstrating the versatility of this continuous multistep syn-
thetic strategy.
In summary, the integration of a heterogeneous oxidation
step, gas–liquid separation, and an oxidative amidation reac-
tion represents an effective protocol for amide synthesis under
mild conditions using alcohols and amines as the starting
materials. The use of inexpensive oxygen and urea hydrogen
peroxide as the only oxidants affords a more economical and
adaptable synthetic route. It also clearly shows the major
advantage of continuous multistep systems to allow chemical
or reaction parameters to be independently adjusted, hence
providing a larger design space for developing chemical reac-
tions or systems. Despite sharing the same general mechanis-
tic features, this approach differs considerably from previous
and current research efforts on developing catalysts that pro-
motes both the activation of alcohols and amidation of the
resultant aldehydes in one pot. By decoupling the key reaction
steps, such continuous systems provide new opportunities for
organic synthesis in general, building upon the extensive
literature on conversion of various functional groups.
2
3
4
5
86
>99
>99
97
81
90e
94
88
100
120
130
6
110
>99
79
7
130
130
110
97
>99
96
79
89
69
8f
9f
10
120
>99
97
11
12
90
>99
>99
79
81
120
a Reaction conditions are as follows. Packed-bed microreactor: 5 μL
min−1 flow rate for alcohol (0.1 M in acetonitrile), 200 μL min−1 flow
rate for gaseous oxygen, 80 °C. The estimated residence time based on
the total flow rate is 19 s. Spiral-channel microreactor: 2.5 μL min−1
flow rate for both morpholine (4 M in acetonitrile) and UHP (2 M in
dimethyl sulfoxide), 90–130 °C, 22 min residence time, unless
otherwise indicated. b Reaction temperature for the spiral-channel
microreactor. c GC conversion. d GC yield. e Isolated yield: 84% (see
ESI† for details). f Initial reagent concentrations: 8 M for morpholine
and 4 M for UHP.
The authors thank the Novartis-MIT Center for Continuous
Manufacturing for support of this work.
Aliphatic alcohols, however, are not compatible with our
system. In addition, this process can be applied to other sec-
ondary amines, including piperidine, pyrrolidine, and 1,2,3,4-
tetrahydroisoquinoline, to form amides under similar con-
ditions (Fig. 2).
For the purpose of establishing a workup protocol for our
multistep synthesis to determine the isolated yield toward the
amide products, 32 samples were collected and combined
within a total reaction period of 24 h using 4-chlorobenzyl
alcohol and morpholine as the starting materials (Table 1,
entry 3). No catalyst deactivation was observed and quantitative
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