Continuous-Flow Synthesis and Derivatization of Aziridines through Palladium-Catalyzed C(sp3)?H Activation

Article abstract of DOI:10.1002/anie.201602483

A continuous-flow synthesis of aziridines by palladium-catalyzed C(sp³)?H activation is described. The new flow reaction could be combined with an aziridine-ring-opening reaction to give highly functionalized aliphatic amines through a consecutive process. A predictive mechanistic model was developed and used to design the C?H activation flow process and illustrates an approach towards first-principles design based on novel catalytic reactions.

Full text of DOI:10.1002/anie.201602483

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201602483
German Edition: DOI: 10.1002/ange.201602483
Flow Reactions
Continuous-Flow Synthesis and Derivatization of Aziridines through
3
ꢀ
Palladium-Catalyzed C(sp ) H Activation
Jacek Zakrzewski, Adam P. Smalley, Mikhail A. Kabeshov, Matthew J. Gaunt,* and
Alexei A. Lapkin*
Abstract: A continuous-flow synthesis of aziridines by palla-
a relatively small number of examples.[5] Part of the reason for
this deficiency is the limited mechanistic understanding of
these complex reactions, which frequently are heterogeneous
under operating conditions; this characteristic can preclude
3
ꢀ
dium-catalyzed C(sp ) H activation is described. The new
flow reaction could be combined with an aziridine-ring-
opening reaction to give highly functionalized aliphatic
amines through a consecutive process. A predictive mechanis-
ꢀ
industrial applications of either batch or continuous C H
activation processes.
ꢀ
tic model was developed and used to design the C H activation
flow process and illustrates an approach towards first-princi-
ples design based on novel catalytic reactions.
Recently, one of our groups reported a new palladium-
3
ꢀ
catalyzed C(sp ) H activation reaction on hindered aliphatic
amines to give aziridines (Scheme 1a).[6] Having performed
some initial mechanistic studies on this transformation,[7] we
considered the possibility of utilizing this reaction as a plat-
C
ontinuous flow processes represent a paradigm shift in the
manufacture of fine chemicals, specialties, and pharmaceut-
icals owing to the demonstrable gains in efficiency and
product quality.[1] A crucial aspect of realizing this ideal is the
effective crossover from fundamental chemistry advances to
process engineering. It is noticeable that the transition of
novel catalytic transformations of potential industrial interest
into continuous flow processes is often slow owing to the
inherent complexity of the reaction systems. With often
limited mechanistic understanding of new reactions, it is
rarely straightforward to determine the best reactor config-
uration or predict their behavior at scale, which can make the
design of an optimal process difficult regardless of whether it
is batch, semibatch, or continuous. The ultimate desired target
for process chemistry is a fully predictive process model that
accounts for a wide range of operating conditions and scale
effects. However, the development of such models for
complex reactions represents a significant methodological
challenge.[2,3]
ꢀ
form for a C H activation reaction in flow. Given the
prevalence of aliphatic amines in biologically active mole-
3
ꢀ
cules, a flow-based C(sp ) H activation process on these
molecules would represent an important advance. There are
3
ꢀ
very few examples of flow processes for C(sp ) H activa-
tion,[8] and no flow C(sp ) H activation reactions have been
conducted on a gram scale.
3
ꢀ
Herein we report the successful translation of first-
3
ꢀ
principles mechanistic understanding of a C(sp ) H activa-
tion reaction for the formation of aziridines into a practical
flow process. A predictive process model was used to explore
in silico the behavior of a semibatch and a flow reactor prior
to testing of the reactors at microreactor and gram scales
(Scheme 1b–c). Additionally, we show that the aziridine
products can be used directly as part of a sequential flow
A central field in modern synthetic organic chemistry is
ꢀ
transition-metal-catalyzed C H activation. The last 15 years
have seen tremendous advances in the use of many different
ꢀ
metal catalysts to functionalize traditionally unreactive C H
bonds; palladium salts, in particular, have enjoyed a great deal
of success in effecting C H activation reactions.[4] Despite the
ꢀ
potential of these seemingly ideal strategic bond-forming
ꢀ
reactions, the uptake of C H activation in pharmaceutical
and agrochemical processes and manufacture is limited to
[*] J. Zakrzewski, Prof. A. A. Lapkin
Department of Chemical Engineering and Biotechnology
University of Cambridge
Pembroke Street, Cambridge, CB2 3RA (UK)
E-mail: aal35@cam.ac.uk
A. P. Smalley, Dr. M. A. Kabeshov, Prof. M. J. Gaunt
Chemistry Department, University of Cambridge
Lensfield Rd, Cambridge, CB2 1EW (UK)
E-mail: mjg32@cam.ac.uk
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201602483.
ꢀ
Scheme 1. Towards a C H activation process in flow.
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ꢀ
process, thus enabling the rapid synthesis of complex aliphatic
amines with minimal purification.
lead to C H bond cleavage involving an external acetate
ligand. However, we found that this pathway was kinetically
unfavorable (Gibbs activation energy 38 kcalmolꢀ1; TS E).
Instead, we found that protonation of the amine 1 with acetic
acid to give 1·HOAc was energetically beneficial by 0.8 kcal
molꢀ1. Therefore, we believe that acetic acid protonates the
free amine 1 to give 1·HOAc, thereby reducing the free-amine
concentration, which in turn reduces the concentration of the
off-cycle bis(amine)–Pd complex A. Thus, palladium is
maintained in the catalytic cycle instead of being held in the
off-cycle complex A.
During our previous studies, we discovered that the
addition of acetic acid to the reaction mixture for the
ꢀ
palladium-catalyzed C H activation to form aziridines
resulted in a significant rate enhancement.[7] We chose these
conditions from which to develop a predictive kinetic model
that would facilitate the transfer from batch to flow processes.
ꢀ
A proposed catalytic cycle for the C H activation, accounting
for the influence of acetic acid, is shown in Figure 1a. We
began our studies by examining this pathway by quantum-
mechanical and kinetic approaches.
ꢀ
Therefore, the mechanism of the acid-accelerated C H
We focused on the turnover-limiting step, which was
activation reaction was reduced to a kinetic model incorpo-
rating three equilibria (K0, K1, and K2) and one irreversible
reaction (k3; Figure 1a). The elementary steps following the
turnover-limiting step were ignored in setting up the model. A
set of unique, kinetically controlled experiments was designed
and performed to build a dataset for parameter estimation.
Values of kinetic parameters for equilibria at 708C were
ꢀ
believed to be C H bond cleavage. This assumption was
supported by experimental kinetic isotope effect (KIE)
studies,[7] which gave a value of 3.9. Calculations performed
at the density functional theory (DFT) level by the use of
Gaussian09 (Figure 1b) showed that the bis(amine) complex
A was the catalyst resting state, as it was thermodynamically
the most stable species in the reaction mixture.[9] The key
reactive intermediate (mono(amine)–Pd complex B) was
found to be less stable by 6.2 kcalmolꢀ1. Cyclopalladation
from the (mono)amine–Pd complex B to form intermediate D
was characterized as a single elementary step (through
concerted metalation–deprotonation, CMD)[10] with a barrier
of 22.9 kcalmolꢀ1. We also considered that the higher acetate
concentration resulting from the addition of acetic acid may
found
to
be
K0 = 3.14
[Lmolꢀ1 minꢀ1],
K1 =
2963160.29 [Lmolꢀ1 minꢀ1], K2 = 7415.93 [Lmolꢀ1 minꢀ1],
and for the turnover-limiting step (708C), k3 = 9.23 [minꢀ1].
Kinetic parameters were fitted to the experimental data using
gPROMS ModelBuilder. The values obtained from parame-
ter estimation are in very good agreement with the values
predicted by DFT calculations (see the Supporting Informa-
tion). The weighted residual was found to be smaller than the
Figure 1. a) Working model for the reaction mechanism. Kinetic parameters corresponding to the reactions preceding the rate-limiting step are
marked “k”. The region in the box illustrates the difference between the mechanism under the original reaction conditions and the mechanism
under the new fully optimized conditions described herein. b) Energy profile of cyclopalladation proceeding through a CMD mechanism. Values
of the kinetic parameters for equilibria at 708C: K0 =3.14 Lmolꢀ1 minꢀ1, K1 =2963160.29 Lmolꢀ1 minꢀ1, K2 =7415.93 Lmolꢀ1 minꢀ1; and for the
turnover-limiting step (708C): k3 =9.23 minꢀ1
.
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c2 value corresponding to the 95% confidence region, thus
could not be higher than 1208C owing to the thermal
indicating that the mechanism shown in Figure 1a is a good
representation of the reaction pathway. Small correlations
between most of the kinetic parameters (see the Supporting
Information) proved their independence. The larger correla-
tion between K0 and K2 can be explained by their competitive
nature with respect to the starting material.
instability of palladium acetate,[13] and full conversion must
be reached within 10 min for a large space–time yield to be
attained. The model was used to select operating conditions
that fulfilled both these requirements, while also considering
that high acid concentrations may lead to degradation of the
aziridine product (see Scheme 1b).[7] Optimization in silico by
using the process model was performed with respect to the
concentration of the starting material (amine 1), Pd(OAc)2,
and AcOH, and with respect to the temperature. The results
led us to several possible sets of conditions, which were then
tested experimentally. Our final process allowed a reduction
of the catalyst loading to 0.5 mol% with a residence time of
10 min (Figure 3). We did not notice any by-product forma-
tion over this time period.
A fully predictive kinetic model allows the selection of
optimal conditions to maximize conversion and yield as well
as minimize by-product formation, with a minimum of
experimental work. The model also helps to predict the
behavior of the reaction system on previously untested scales.
All of these factors can result in the faster design of
a continuous process. Before transition to the flow setup, we
further tested the kinetic model to assess its accuracy under
dynamic conditions of a semibatch process. We found that the
kinetic model accurately predicted the results for two differ-
ent semibatch experiments, in which a batch reactor was fed
continuously with the starting material, and ideal mass and
energy transfer were assumed (Figure 2). A slight deviation of
the model from the experimental data was observed in the
early stages of the experiment. This deviation can be
explained by the fact that the semibatch reactions were
performed without preheating of the reaction mixture, and
subsequently the reactor operated at lower temperature until
the system reached thermal equilibrium. The good agreement
between the experimental data and the predicted kinetics
provides further support for the model as an accurate
representation of the molecular processes.
The kinetic model was used to design a process model on
the assumption that an ideal plug flow reactor was used. We
defined two restrictive parameters: The reaction temperature
Figure 3. Results of continuous-flow experiments under optimal con-
ditions; CSM =0.05 molLꢀ1, CCat =2.5 10ꢀ4 molLꢀ1, CAcOH =0.5 molLꢀ1
.
Concentrations were measured at the outlet of the reactor for different
residence times in order to find the optimal residence time and
compare experimental results with the process model.
Following optimization of the flow reaction, the design of
a suitable process involving a purification method was
undertaken. The aim was a gram-scale synthesis characterized
by a large space–time yield and the design of a convenient
separation method for both the product and the catalyst (if
possible, also suitable for catalyst recycling). The whole
process should operate autonomously to be desirable for
large-scale applications. Since the catalytic system in batch is
homogeneous, the same approach was initially applied to the
flow process. We first tested the reaction on the microscale by
using a temperature-controlled custom-made silicon-glass
microfluidic reactor. The use of a homogenous catalyst is
beneficial in providing well-defined active sites and, given
effective mixing, rapid diffusivity to the catalyst. However, an
efficient way of separating the catalyst from the products is
required. Owing to the nature of the reaction system,
a biphasic separation model was not possible. Furthermore,
the most powerful, acid-based, metal scavengers were not
suitable for separating the Pd(OAc)2 from the reaction
mixture because they would scavenge both the catalyst and
Figure 2. Comparison of the kinetic model with experimental results
for two different semibatch reactions. Reaction conditions:
C
Cat0 =0.005 molLꢀ1, CCatfeed =0 molLꢀ1, F=0.02 mLminꢀ1, T=708C;
Reaction A: CSM0 =0.05 molLꢀ1; CSMfeed =0.1 molLꢀ1; Reaction B:
C
SM0 =0 molLꢀ1, CSMfeed =0.025 molLꢀ1; SM: starting material; Cat:
palladium acetate; 0: concentration in reactor before reaction start;
feed: concentration in the feeding stream. Time “0” corresponds to
when the pumping started.
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the aziridine product. It was found that
commercially available QuadraSil AP
(with a pendant primary amine)[11] suc-
cessfully coordinated only to the palla-
dium species, thus enabling removal of
the catalyst from the spent reaction
mixture. In a second separation step,
the amine product could be separated
from the reaction mixture by the use of
a silica gel functionalized with strongly
acidic groups. In this study we used the
Isolute SCX-3 gel (with pendant sulfonic
acid groups)[12] as a successful amine
scavenger (Figure 4a). The product can
be washed on the gel and subsequently
removed by the use of an eluent with
a high pH value. Implementation of this
“catch and release” technique yielded
a product of high purity (Figure 4b).
Following the successful develop-
ment and optimization of a small-scale
process, we further tested the reaction
on a larger scale by using a Vapourtec R-
Series system[14] equipped with a 10 mL,
thermostated poly(tetrafluoroethylene)
(PTFE) tubular reactor. Full conversion
was achieved with a flow rate equal to
1 mLminꢀ1, which produced 4.68 mmol
(771.9 mg) of aziridine product per hour,
thus resulting in a space–time yield of
0.463 [kgL(reactor)ꢀ1 hꢀ1]. The Vapour-
tec R-Series is designed to operate
autonomously, and the operational time
is only limited by the capacity of the
scavenger columns. This limitation can
be easily overcome with a setup includ-
ing two sets of columns: one operational
and one in a stand-by mode. To the best
ꢀ
of our knowledge, no C H activation of
amines has been carried out previously
ꢀ
ꢀ
Figure 4. a) Flow process for the aziridination C H activation reaction. Flow reactor: silicon-
glass microfluidic reactor or PTFE tubular reactor. The first column separates the catalyst from
the spent mixture; the second column separates the product. Reactants were pumped by:
pump A (starting material, oxidant), pump B (catalyst, acetic acid, acetic anhydride). A 6 bar
pressure regulator was fitted. b) Elution of the product from the “catch” column. c) Aziridine
ring opening and elution from the “catch” column to give functionalized morpholinones.
in a flow system, and no C H activation
process has been performed on a multi-
gram scale.[15] Both experimental designs
resulted in very good yields (isolation of
products in 90% yield), high purity of
1
products (> 90% according to H NMR
spectroscopy of the crude product
against an internal standard), and, on
the basis of inductively coupled plasma optical emission
spectroscopy (ICP OES), concentrations of palladium in the
mixture leaving the scavenger column below 1 ppm.
procedure suitable for opening aziridines with weak nucleo-
philes and reagents that could be potentially hazardous when
used in batch.
ꢀ
To extend the synthetic utility of this flow C H activation
In our previous study, the ring-opening reaction required
the action of either a strong Brønsted or Lewis acid to activate
the aziridine. In the current system, we questioned whether
the strong sulfonic acid scavenging resin might also function
as an activating agent for aziridine ring opening, thereby
reducing the number of chemical operations and streamlining
the overall transformation. The first step towards this goal
was achieved by retaining the aziridine on the “catch” Isolute
ꢀ
procedure, we investigated the coupling of the C H activa-
tion step to a subsequent reaction in a single flow process. It
had been previously shown that the aziridine products could
be functionalized through ring-opening reactions with various
nucleophiles, such as carboxylic acids, azides, thiols, and
halogens.[6,16] To further highlight the benefits of translating
this batch process into flow, we aimed to develop a robust
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SCX-3 column. While on the column, the aziridine is
In summary, as a result of extensive kinetic and mecha-
immobilized by sulfonic acid protonation, which makes it
susceptible to nucleophilic attack: heating to just 608C is
required to facilitate such a reaction. When a nucleophile—
water, methanol, or hydrazoic acid generated in situ—was
pumped through the resulting column (Figure 4c), the
derivatized products 3a–c were obtained in good yields
(Figure 5). The use of a solid-state support significantly
facilitated the reaction procedure, minimized the number of
purification steps, and shortened the reaction time consid-
erably.
nistic investigations involving DFT studies, we have success-
fully performed a two-step continuous-flow synthesis of
ꢀ
substituted morpholinones on the basis of C H activation.
By designing the process from first principles, we significantly
shortened the overall reaction time and increased the space–
time yield, while also reducing the number of purification
steps. A thorough understanding of the reaction system
allowed us to shorten the optimization time and efficiently
design the flow process. Novel aspects of the process include
3
ꢀ
the implementation of a C(sp ) H activation reaction in
a continuous-flow system and its performance on a multigram
scale. Our study further illustrates the utility of flow chemistry
as a tool for functionalization through consecutive reactions.
A further highlight is the nucleophilic opening of immobilized
aziridines in flow.
Acknowledgements
We are grateful to the Department of Chemical Engineering
and Biotechnology (J.Z.) and the EPSRC (A.P.S.) for student-
ships, and to the ERC and EPSRC (EP/100548X/1) for
fellowships (M.J.G.). Mass spectroscopy data were acquired at
the EPSRC UK National Mass Spectroscopy Facility at
Swansea University.
ꢀ
Keywords: aziridines · C H activation ·
continuous-flow synthesis · palladium catalysis · ring opening
Figure 5. Scope of the aziridine-ring-opening reaction. Yields are given
for the isolated product after the two-step synthesis.
Although several reactions have been described previ-
ously for aziridine ring opening in continuous flow,[17] to the
best of our knowledge, none have been performed by using an
immobilization–activation strategy. The high purity of the
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crude mixture (> 90%, H NMR) allows direct transforma-
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were
observed
with
polymer-bound
dichlorobis-
(triphenylphosphine)palladium(II); ICP OES measurements
of the spent reaction mixture showed palladium leaching
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Received: March 10, 2016
Revised: April 28, 2016
Published online: && &&, &&&&
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 7
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Flow Reactions
J. Zakrzewski, A. P. Smalley,
M. A. Kabeshov, M. J. Gaunt,*
A. A. Lapkin*
&&&& — &&&&
Continuous-Flow Synthesis and
Keep up with the flow! A predictive
combined with ring opening of the aziri-
Derivatization of Aziridines through
mechanistic model was developed and
dine in flow to give highly functionalized
aliphatic amines in a consecutive process
involving the capture and release of the
aziridine intermediate (see scheme).
3
ꢀ
ꢀ
Palladium-Catalyzed C(sp ) H Activation
used to design a flow process for C H
activation. The resulting continuous-flow
synthesis of aziridines through palla-
3
ꢀ
dium-catalyzed C(sp ) H activation was
Angew. Chem. Int. Ed. 2016, 55, 1 – 7
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7
These are not the final page numbers!