Visible Light-Promoted Beckmann Rearrangements: Separating Sequential Photochemical and Thermal Phenomena in a Continuous Flow Reactor

Article abstract of DOI:10.1002/ejoc.201900231

The Beckmann rearrangement of oximes to amides typically requires strong acids or highly reactive, hazardous electrophiles and/or elevated temperatures to proceed. A very attractive alternative is the in situ generation of Vilsmeier–Haack reagents, by means of photoredox catalysis, as promoters for the thermal Beckmann rearrangement. Investigation of the reaction parameters for this light-induced method using a one-pot strategy has shown that the reaction is limited by the different temperatures required for each of the two sequential steps. Using a continuous flow reactor, the photochemical and thermal processes have been separated by integrating a flow photoreactor unit at low temperature for the electrophile generation with a second reactor unit, at high temperature, where the rearrangement takes place. This strategy has enabled excellent conversions and yields for a diverse set of oximes, minimizing the formation of side products obtained with the original one-pot method.

Full text of DOI:10.1002/ejoc.201900231

A Journal of
Accepted Article
Title: Visible Light-Promoted Beckmann Rearrangements: Separating
Sequential Photochemical and Thermal Phenomena in a
Continuous Flow Reactor
Authors: Yuesu Chen, David Cantillo, and C. Oliver Kappe
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900231
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10.1002/ejoc.201900231
European Journal of Organic Chemistry
FULL PAPER
Visible Light-Promoted Beckmann Rearrangements: Separating
Sequential Photochemical and Thermal Phenomena in a
Continuous Flow Reactor
Yuesu Chen,[a,b] David Cantillo,[a,b] and C. Oliver Kappe*[a,b]
Abstract: The Beckmann rearrangement of oximes to amides
typically requires strong acids or highly reactive, hazardous
electrophiles and/or elevated tempertatures to proceed. A very
attractive alternative is the in situ generation of Vilsmeier-Haack
reagents, by means of photoredox catalysis, as promoters for the
thermal Beckmann rearrangement. Investigation of the reaction
parameters for this light-induced method using a one-pot strategy has
shown that the reaction is limited by the different temperatures
required for each of the two sequential steps. Using a continuous flow
reactor, the photochemical and thermal processes have been
separated by integrating a flow photoreactor unit at low temperature
for the electrophile generation with a second reactor unit, at high
temperature, where the rearrangement takes place. This strategy has
enabled excellent conversions and yields for a diverse set of oximes,
minimizing the formation of side products obtained with the original
one-pot method.
The accepted mechanism of the Beckmann rearrangement
(Scheme 1) involves migration of one of the imine C-substituents
to the nitrogen atom, and it is believed to be driven by the release
of the activated hydroxy group of the oxime (1). Strong protic
acids,[6] inorganic Lewis acids,[7] acyl chlorides,[2] acidic organic
chlorides[8] and other electrophilic reagents[9] (E+) have been
employed as mediators for the activation of the OH group by
forming a complex or an ester (3) (Scheme 1), which then
undergoes an exothermic rearrangement upon heating. Recent
studies have revealed that the mechanism can be self-
propagative (Scheme 2a).[10] Thus, the nitrilium cation 4 (the initial
intermediate of the rearrangement) can activate another molecule
of oxime via the complex 3A, which releases amide 2 and another
nitrilium ion to start a new turnover. This mechanism only requires
sub-stoichiometric amounts of electrophilic mediator to initiate the
reaction. Alternatively, when a tertiary amide (e.g., DMF[11,12] or
NMP [13]) is used as solvent and combined with an acid chloride,
the Vilsmeier-Haack (V-H) reagent 5 generated in situ is
responsible for the OH-activation (Scheme 2b), via the
intermediate 3B. As the V-H reagent is converted to the initial
tertiary amide after the rearrangement, the reaction is no longer
self-propagative. The reaction time can be relatively fast (< 1 h)
at ambient temperature,[12,13] although stoichiometric amounts of
acid chloride are used to regenerate the V-H reagent.
Introduction
The Beckmann rearrangement is an important and useful reaction
in organic synthesis that entails the conversion of ketoximes to
secondary amides. Since its discovery in 1886 by E. O.
Beckmann,[1] this transformation has found widespread
application in the synthesis of natural products[2] and the
preparation of drug molecules,[3] enabling the generation of amide
scaffolds in the target compounds.[4] An important industrial
application of the Beckmann rearrangement is the production of
Nylon monomers.[5]
a) Self-propagative Beckmann rearrangement
O
R2
R1
R1
N
OH
H
H
N
2
N
R2
R2
1
R1
R2
O
N
R1
N
R2
R1
N
R2
R1
4
nitrilium cation
4
3A
H
O
R1
R2
R1
R2
O+
E
E+
OH
N
H2O
R2
R1
N+ R2
R1
N
N
b) Vilsmeier-Haack (V-H) reagent promoted Beckmann rearrangement
- EOH
rearrangement
H
OH-activation
Cl
H2O
R1
OH
R2
2
4
1
2
3
R1
N
N
N
N
R2
- H+
1
R1
R2
O
N
N
Scheme 1. General mechanism for the Beckmann rearrangement.
Cl
O
tertiary amide
V-H reagent
Cl
5
3B
[a]
Y. Chen, Dr. D. Cantillo, Prof. Dr. C. O. Kappe
Center for Continuous Flow Synthesis and Processing (CC FLOW),
Research Center Pharmaceutical Engineering GmbH (RCPE),
Inffeldgasse 13, 8010, Graz (Austria)
Scheme 2. Activation of oxime hydroxy group in self-propagative (a) and
Vilsmeier-Haack reagent promoted (b) Beckmann rearrangements.
E-mail: oliver.kappe@uni-graz.at
Web: http://goflow.at
[b]
Y. Chen, Dr. D. Cantillo, Prof. Dr. C. O. Kappe
Institute of Chemistry, University of Graz, NAWI Graz,
Heinrichstrasse 28, 8010, Graz (Austria)
Apart from the well-established methods mentioned above,
many endeavors have been devoted to achieve Beckmann
rearrangements under more benign and controllable conditions.
These procedures include the use of boronic acid catalysts[14] or
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/chem.xxxxxx
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10.1002/ejoc.201900231
European Journal of Organic Chemistry
FULL PAPER
radical pathways induced by (NH4)2S2O8/DMSO.[15] Several
examples of photochemical Beckmann rearrangements were
reported in the 1960s and 1970s using UV-C irradiation.[16] Poor
yields and selectivities were described, probably due to
decomposition of the starting materials and/or products under the
relatively harsh conditions utilized. An attractive alternative to
avoid the drawbacks of UV light irradiation is a visible light
promoted Beckmann rearrangement,[17] in which the reaction is
promoted by a V-H reagent generated from CBr4 and DMF by
means of photoredox catalysis.[18] This synthetic strategy permits
the generation of the reactive V-H reagent under mild conditions,
and avoids the use of toxic or corrosive reagents such as POCl3,
SOCl2, COCl2 or t-BuCOCl.[11-13] Indeed, visible light induced V-H
reagent generation and its application for the dehydration of
aldoximes,[19] the preparation of carboxylic acid anhydrides,[20]
Lossen rearrangement,[21] Appel reaction[18] and carbonylations[22]
have been recently reported.
The visible light promoted Beckmann rearrangement
appears to be a promising protocol for the conversion of
ketoximes to amides under mild condition. However, a one-pot
procedure in which the V-H reagent is photochemically generated
and then promotes the thermal rearrangement can be considered
as suboptimal, often leading to unsatisfactory results (vide infra).
The two sequential processes taking place during the reaction
(photochemical vs thermal transformation) require different
reaction conditions for optimal results. With this in mind, we
envisaged a continuous flow strategy in which the active V-H
reagent is photochemically generated and then consumed under
different reaction conditions, by integrating the flow photoreactor
with a second reactor unit (Scheme 3). Thus, CBr4 and a
photocatalyst in DMF were pumped through a continuous flow
photochemical reactor. The V-H reagent solution generated was
immediately mixed with a second reaction stream containing the
oxime substrate before entering a second reactor unit, in which
the Beckmann rearrangement took place in the absence of light.
Using this strategy, the sequential photochemical and thermal
processes could be spatially separated and operated
independently, leading to excellent results. Indeed, while the V-H
reagent promoted Beckmann rearrangement required mild
heating, the photochemical reagent generation performed best at
low temperatures. The photochemical step, in addition, benefited
from the intense and uniform light irradiation achievable in a
microreactor.[23,24]
step photochemical Beckmann rearrangement. Initial attempts
using a one-pot strategy are also described. In addition, a detailed
study of the reaction mechanism is provided.
Results and Discussion
Initial Attempts Using a One-Pot Strategy
For the initial set of experiments a continuous flow setup as shown
in Figure 1 was utilized. For most experiments, a commercially
available coil-based flow photoreactor was used (Vapourtec
UV150). Experiments using green LED irradiation (515 nm, 50 W)
were carried out in a glass-chip reactor (see Supporting
Information for details). In addition, experiments using blue light
(455 nm) were carried out in both reactors for comparison (Table
1). The Beckmann rearrangement of acetophenone oxime 1a to
N-phenylacetamide (2a) was chosen as model for the reaction. In
a typical experiment, DMF as solvent was pumped through the
photoreactor with constant flow rate (initial experiments using
MeCN as solvent and substoichiometric amounts of DMF[17]
provided very poor results both in batch and flow). The solution of
reactants in DMF was degassed by gas sparging with Ar for 15
min. The reaction mixture was then introduced into the reactor
using a sample loop. A back pressure regulator (BPR) set at 3
bar[25] was installed at the reactor outlet to maintain the pressure
in the flow system, preventing the formation of gas (e.g., CO2)
bubbles. The reaction mixture was collected at the flow system
output in a volumetric flask containing 0.01 mmol of p-terphenyl
as internal standard. Samples were diluted to a total volume of 5
mL with acetonitrile for HPLC analysis.
injection
loop
pump
BPR
DMF
3 bar
N
OH
T, tR
photoreactor
0.2 M
H
N
1a
V = 2.0 mL
CBr4
photocatalyst
O
2a
Figure 1. Schematic diagram of the continuous flow photoreactor system for the
one-pot photochemical Beckmann rearrangements.
When organic dyes (Eosin Y and rose bengal) were employed as
photocatalysts no conversion was observed (Table 1, entries 1
and 2). Notably, discoloration of the reaction mixture could be
visually observed. The poor results could therefore be ascribed to
bleaching of the organocatalysts under the reaction conditions
used, due to the strong light irradiation and acidification of the
reaction mixture (HBr formation). Acidic conditions may promote
the formation of the lactone of Eosin Y, which does not absorb
light efficiently. Indeed, in our hands, replication of the reaction
conditions published in the literature[17] for this transformation
using Eosin Y in a batch reactor, resulted in insignificant amounts
of the desired amide (< 2%) (see Experimental Section for details).
Scheme 3. Concept for a two-step sequential flow process.
Herein, we present details on the continuous flow reactor,
optimization of the reaction conditions, and the scope of the two-
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10.1002/ejoc.201900231
European Journal of Organic Chemistry
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hv
Using Ru(bpy)3Cl2 as photocatalyst and 2 equiv of CBr4, formation
of the desired acetanilide 2a was observed along with
formamidine 6a and CO as side products (Table 1, entry 3).
Formamidine 6a is most likely formed by the reaction of 2a with a
second molecule of the V-H reagent,[26] indicating an excess of
the formation of the active species in the reaction mixture. In
addition, the release of CO gas could be confirmed by attaching
a CO detector to the reactor outlet. Thus, the amount of CBr4
loading was gradually reduced (Table 1, entries 4-6). The best
yield for 2a was achieved when 50 mol% of CBr4 was used (Table
1, entry 5), in agreement with the theoretical stoichiometry
required for the formation of 1 equiv of V-H reagent (Scheme 4).
Further reduction of the amount of CBr4 to 25 mol% resulted in
reduced conversion (Table 1, entry 6), excluding a self-
propagative mechanism (Scheme 2a). The reaction using 50
mol% CBr4 could be reproduced in the glass chip reactor in which
the experiments with 515 nm irradiation had been performed,
although a longer residence time was required to achieve
comparable conversion and yield (Table 1 entry 8). This initial set
of experiments was performed at 40 °C, which corresponds to the
temperature generated by the light source with air cooling.
Br
O
Ru
N
H
+
CO2
+ 2
2
CBr4
N
H
Br
5A
Scheme 4. Generation of the V-H reagent (5A) from CBr4 and DMF. 2 equiv of
the reactive species can be generated per mol of halide.
A series of control experiments was then performed using
Ru(bpy)3Cl2 and 50 mol% of CBr4 (Table 1, entry 5). It could be
demonstrated that the reaction is photocatalytic (Table 2), since
no product (2a) was detected when the reaction was performed
without photocatalyst (Table 2, entry 2), CBr4 (Table 2, entry 3) or
light (Table 2, entry 4). Importantly, even in the absence of
substrate (1a), 90% of CBr4 was consumed by the oxidative
quenching of the excited photocatalyst (Table 2, entry 5),
demonstrating that V-H reagent formation and the subsequent
Beckmann rearrangement are independent events. The reaction
became slower at lower concentration (Table 2, entry 6). As HBr
is formed during the reaction, the possibility that this protic acid
acts as catalyst for the Beckmann rearrangement was explored.
Thus, HBr instead of CBr4 was added to some of the reaction
mixtures processed in the absence of light. No conversion was
observed either at room temperature (Table 2, entry 7), or at
elevated temperatures (Table 2, entries 8-10). Indeed, heating at
100 °C only resulted in partial hydrolysis of 1a (Table 2, entry 10).
Additional experiments with varying reaction time and catalyst
loading showed that it is possible to reduce the catalyst loading
from 2 mol% to 1 mol% by increasing the residence time to 20
min (see Table S3 in the Supporting Information).
Table 1. Catalyst screening and optimization of CBr4 loading (Figure 1).[a]
Entry
photocatalyst
CBr4
[mol%]
Time
[min]
light
source
[nm]
Molar fraction [%][b]
[c]
1a
>99
>99
2
2a
0
CBr4
>99
94
39
21
3
1
2
3
4
5
6
7
8
Eosin Y
200
200
200
100
50
10
10
10
10
10
10
10
20
515[d]
515[d]
455
Rose Bengal
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
0
Table 2. Control experiments for the one-pot continuous photochemical
Beckmann rearrangement of 1a (Figure 1).[a]
45
53
79
8
455
4
455
6
25
455
88
39
8
0
50
455[d]
455[d]
47
68
9
Entry
Variation
standard condition
from
Molar fraction [%][b]
Remarks
Standard
50
0
[c]
1a
2a
79
0
CBr4
[a] The solution of reactants was degassed by Ar sparging for 15 min; 0.5 mL
was injected for each run; [b] Determined by HPLC at 254 nm using p-terphenyl
as internal standard. [c] Unconverted CBr4 in the reaction mixture. [d] Reactions
carried out in a glass chip reactor. A Vapourted UV150 coil-based system was
used for entries 3-6.
1
2
3
4
5
6
7
-
6
3
Without Ru(bpy)3Cl2
Without CBr4
Without light
Without substrate
0.1 M concentration
8 equiv HBr
> 99
> 99
> 99
-
> 99
0
-
0
> 99
10
1
-
14
67
0
> 99
-
No light
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We next investigated the influence of temperature in the
reaction using Ru(bpy)3Cl2 as photocatalyst and 50 mol% of CBr4
(Table 1, entry 5) (Figure 2). At temperatures above 40 °C the
Beckmann rearrangement of 1a was fast enough to complete
within 10 min. However, at lower temperatures lower conversion
of 1a was observed, the reaction becoming completely inhibited
at temperatures <10 °C. In contrast, the photochemical formation
of the V-H reagent (which can be monitored by the consumption
of CBr4) performed best at low temperatures, being quantitative
at 0 °C. This effect can likely be attributed to the longer lifetime of
the triplet state of Ru(bpy)32+ (Ru(II)*) at low temperatures.[27] This
was further confirmed in a quenching experiment without
substrate, in which CBr4 was consumed in a similar fashion and
temperature dependence as observed in Figure 2 (See Table S2
8
9
8 equiv HBr, 70 °C
99
98
0
0
-
-
No light
No light
4 equiv HBr, 80 °C,
50 min
10
4 equiv HBr, 100 °C,
50 min
77
0
-
No light, oxime
hydrolysis
[a] The solution of reactants was degassed by Ar bubbling for 15 min; 0.5
mL was injected for each run. [b] Determined by HPLC at 254 nm using p-
terphenyl as internal standard. [c] Unconverted CBr4 in the reaction mixture.
Some of the experiments collected in Table 1 resulted in good
conversions (>90%) (entries 3-5), but yields for the desired
product 2a were below 80% in all cases (HPLC analysis with p-
terphenyl as internal standard). GC-MS analysis of a crude
reaction mixture revealed the formation of several side-products
during the reaction (Scheme 5). A small amount of aniline (7a)
(3%), the hydrolysis product of formamidine 6a, could be detected
by HPLC even when using 50 mol% of CBr4. Indeed, larger
excess of CBr4 led to significant amounts of 7a (9% when 100
mol% CBr4 was used) due to the excessive V-H reagent formation.
A small amount of benzonitrile (9a) (1%) was also generated via
Beckmann fragmentation. This is a common side reaction in the
Beckmann rearrangement. The major side product observed was
isoxazolone 8a (16%), which is most likely generated by oxidation
of activated oxime 3a with a tribromomethyl radical following the
mechanism shown in Scheme 6. The tribromomethyl radical
(ꞏCBr3) is generated from the oxidative quenching of the excited
state of the photocatalyst (Ru(II)*) with CBr4. This radical then
abstracts one electron from the N-atom of activated oxime 3a,
forming the radical cation 10a and a tribromomethyl carbanion.
Deprotonation of the radical cation by the CBr3 anion generates
bromoform (CHBr3) and radical 11a. Intermediate 11a undergoes
5-exo-trig cyclization, deprotonation, and single electron oxidation
by Ru(III), recovering the catalyst and affording isoxazolone (8a).
Notably, generation of CHBr3 could be confirmed by GC-MS
analysis of the reaction mixture, supporting the radical
mechanism depicted in Scheme 6.
in the
Supporting Information). The variable temperature
experiments indicate that the light-induced Beckmann
rearrangement using the one-pot procedure is hampered by the
fact that the photochemical and thermal steps of the reaction
perform best in different temperature regimes. In addition, the
one-pot procedure combining light irradiation and exposure to
40 °C favors the formation of side-product 8a.
N
O
N
Ph
Ph
CBr4
3a
H
H
N
O
H
CHBr3
CBr3
N
CBr3
Ru(II)*
10a
H
hv
Ru(III)
Ph
N
O
N
11a
Ru(II)
Ph
Ph
N
N
O
O
N
- H+
Ph
N
N
O
N
Ph
Ph
excess
N
O
N
O
H2O
N
H
N
V-H reagent
H2O
- H+
NH2
Ph
Ph
N
N
O
O
Ph
2a
8a
7a
6a
Beckmann
rearrangement
minor
side product
Scheme 6. Postulated mechanism for the formation of isoxazolone 8a via
photocatalyzed oxidation of 3a.
observed by
GC-MS
N
N
H
OH
N
CBr3
V-H reagent
OH-activation
N
O
major
side product
O
H
Using continuous flow technology reactive intermediates
can be generated on demand by combining several reactor units.
This enabling technology has overcome the limitations of many
processes in which intermediates or reagents, too hazardous to
be generated or stored in large amounts, need to be generated
and immediately consumed. Although V-H reagents are highly
hygroscopic salts, they are relatively stable in solution if contact
with moisture is avoided.[28] In situ generation of a V-H reagent
using conventional protocols (DMF + POCl3) for the formylation of
Ph
Ph
O
oxidation
Ph
1a
3a
8a
N
N
Beckmann
fragmentation
N
minor
side product
O
Ph
9a
- MeBr, - DMF
Ph
Br
Scheme 5. Detected side products (highlighted with frames) and their formation.
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10.1002/ejoc.201900231
European Journal of Organic Chemistry
FULL PAPER
pyrrole has also been reported in the literature.[29] In the case of
the photochemical rearrangement described herein, a two-step
flow arrangement permits to separate the photochemical and the
thermal processes, avoiding undesired interactions of light or
photochemically generated short lived intermediates with the
substrate or the intermediates in the Beckmann rearrangement.
We envisaged that this strategy would minimize the formation of
side-products and permit the independent operation of the two
reaction steps (vide infra).
Notably, only insignificant amounts isoxazolone 8a could be
detected in the crude reaction mixture, since the reaction mixture
containing activated oxime 3a and Ru(bpy)3Cl2 was not exposed
to blue light irradiation and most of the CBr4 was consumed during
the V-H reagent formation before mixing with oxime 1a. Shorter
reaction time led to incomplete conversion of both CBr4 and 1a
(Table 3, entry 1); increasing the amount of CBr4 to 100 mol% did
improve the conversion to some extent, but amide 2a was partially
transformed into formamidine 6a under these conditions (Table 3,
entry 2).
N
OH
0.4 M
1a
stream 2
stream 1
DMF
DMF
R1
R2
BPR
M
3 bar
T2
tR2
V2 = 10 mL
T1 = 0 °C
tR1
H
N
CBr4
50 mol%
V
1 = 2.0 mL
Ru(bpy) Cl2 1 mol%
O
3
2a
Figure 3. Schematic view of the continuous flow reactor utilized for the two-step
photochemical Beckmann rearrangement a Vapourtec E-Series equipped with
a UV150 photoreactor was utilized.
Table 3. Optimization with photochemical V-H reagent generator (Figure 3).[a]
Figure 2. Effect of temperature on the one-pot photochemical procedure (molar
fractions were determined by HPLC at 254 nm using p-terphenyl as internal
standard).
Sequential Two-Step Flow Process
Entry
tR1
[min]
tR2
[min]
CBr4
[mol%]
Molar fraction [%][b]
Based on the considerations above, a second continuous flow
reactor system was constructed as shown in Figure 3. In this case,
the output of the continuous photochemical reactor (Vapourtec
UV150) was attached to a T-mixer, in which a second reaction
stream containing the oxime substrate 1a was introduced. The
resulting mixture of substrate and V-H reagent then entered a
second reactor unit (PFA tubing, 0.8 mm i.d., 10 mL) in which the
rearrangement to 2a took place at elevated temperature.
[c]
1a
39
10
3
2a
48
27
95
CBr4
41
24
7
1
2
3
10
10
20
25
25
50
50
100
50
[a] The solution for stream 1 was degassed by Ar sparging for 15 min; 0.8 mL
for stream 1 and 0.5 mL solution for stream 2 were injected for each run; T1 =
0 °C, T2 = 40 °C. [b] Determined by HPLC at 254 nm using p-terphenyl as
internal standard. [c] Unconverted CBr4 in the reaction mixture.
Using the two-step system and setting the temperatures at
0 °C for the photochemical reactor and 40 °C for the Beckmann
rearrangement reactor unit, excellent results were achieved
(Table 3). Adjusting the residence times to 20 min and 50 min for
the photochemical and thermal transformations, respectively, a
95% HPLC assay yield of 2a was obtained (Table 3, entry 3).
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With the optimal conditions in hand (Table 3 entry 3), a
series of ketoximes was transformed to the corresponding amides
using the two-step continuous flow Beckmann rearrangement
(Table 4).
14 (l)
60
27 (23)
5% 1l; 1l (major/minor
= 81 : 19)
[a] The solution for stream 1 was degassed by Ar sparging for 15 min; 4 mL
solution for stream 1 and 3 mL (1.2 mmol) for stream 2 were injected for each
run; T1 = 0 °C. [b] Determined by HPLC peak area integration at 254 nm; the
values in parenthesis are isolated yields.
Table 4. Substrate scope for the continuous flow Beckmann rearrangement
using a photochemically V-H reagent (Figure 3). [a]
The temperature for the second reactor unit (T2, Beckmann
rearrangement) was adjusted in some cases to improve the yield
of the target compound. All products were isolated by column
chromatography after evaporating the crude reaction mixture
collected from the reactor output under reduced pressure (see
Experimental Section for details). Unsubstituted acetophenone
oxime (1a) and benzophenone oxime (1b) were converted cleanly
to amides (2a and 2b) at 40 °C (Table 4, entries 1-2). Substituted
acetophenone oximes required 50 °C or higher temperatures,
depending on the nature and position of the substituents. Thus,
acetanilides decorated with electron donating groups in the
aromatic ring (Table 4, entries 3-8) were obtained with good to
excellent yields at 50 °C. Substrates bearing electron withdrawing
groups generally required higher temperatures (60 °C) for the
rearrangement, gproviding only low to moderate yields (Table 4,
entries 9-14). In addition to a slower Beckmann rearrangement,
the electron poor oximes as well as the resulting amides were
more prone to hydrolysis, a side-product observed for these
reactions. The rearrangement of p-chloroacetophenone oxime
(1j) was especially slow, and a significant amount of the ketone
resulting from hydrolysis of the oxime was obtained (Table 4,
entry 10). Elevating the temperature resulted in higher conversion
of the starting material, but also increased the degree of
hydrolysis of the product (Table 4, entries 11 and 12). Ortho-
substituted acetophenone oximes (1e, 1h and 1l) provided lower
yields compared to their meta and para isomers, since the
formation of a highly solvated intermediate is disfavored by the
steric hindrance. Although these oximes (1e, 1h and 1l) were
isolated as mixture of E- and Z-isomers[14] (NMR spectra are
collected in the Supporting Information), which in principle might
lead to a mixture of the N-methyl and N-phenyl amide products, a
single product (N-phenyl) was obtained in all cases. This is most
likely due to E – Z isomerization under the reaction condition.[30]
Entry
Amide (2)
T2
[°C]
Yield[b]
[%]
remarks
1 (a)
40
40
50
95 (76)
96 (77)
94 (77)
2 (b)
3 (c)
4 (d)
5 (e)
50
50
91 (70)
72 (62)
1e (major/minor = 89 :
11)
6 (f)
7 (g)
8 (h)
50
50
50
93 (75)
95 (76)
62 (54)
1h (major/minor = 76 :
24)
9 (i)
60
50
60 (57)
51 (45)
Table 5. Substrate scope for the continuous flow aldoxime dehydration using
a photochemically generated V-H reagent (Figure 3). [a]
10 (j)
36% (32%) 1j;
13% (12%) ketone
11 (j)
12 (j)
13 (k)
65
80
60
37
63% aniline
74% aniline
7% (9%) 1k;
26
Entry
Nitrile (13)
T2
[°C]
Yield[b]
[%]
remarks
45 (50)
1 (a)
80
84 (66)
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10.1002/ejoc.201900231
European Journal of Organic Chemistry
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quenched by CBr4, releasing Br─ and a ꞏCBr3 radical. The
electrophilic ꞏCBr3 radical then adds to a DMF molecule, and the
resulting complex is oxidized to the iminium cation 14 by Ru(III),
regenerating the catalyst. Intermediate 14 decomposes to the V-
H reagent 5A and bromophosgene (15). As its chlorinated
counterpart phosgene, [11c] 15 is able to react with a second DMF
molecule, generating an additional equivalent of V-H reagent,
accounting for the reaction stoichiometry confirmed
experimentally (cf. Scheme 4). The hydroxy group in oxime 1 is
activated by 5A, undergoing substituent migration and hydrolysis
to afford the amide product 2 (non-self-propagative Beckmann
rearrangement). In the case of aldoximes 12, nitriles 13 are
formed after elimination of DMF and a proton (Scheme 7b).
Bromophosgene 15 is an electrophile, and therefore can
directly activate the oxime OH group without forming intermediate
5A. An attempt to trap 15 was made by adding 2-aminophenol
(16) as scavenger to the reaction mixture (See Supporting
Information for details). However, only benzoxazole (17) was
detected in the reaction mixture instead of benzoxazolone (18),
indicating the presence of a formylating agent, namely 5A, and
not the carbonylating agent 15. Due to the instability and the
reactivity of 15, it is likely to be formed and consumed very rapidly;
but the formation of CO (detected by CO sensor at the outlet)
(Table 1, entry 3-4) can be explained by the transient presence of
15, since it is the only species that decomposes to CO under the
reaction condition.[31] Isoxazolone (8a) could be formed by
oxidation of 3a with the ꞏCBr3 radical, as shown in detail in
Scheme 6.
2 (b)
80
80
10
90%
recovered
substrate
substrate
3 (c)
< 1
99%
recovered
[a] The solution for stream 1 was degassed by Ar sparging for 15 min; 4 mL
solution for stream 1 and 3 mL (1.2 mmol) for stream 2 were injected for each
run; T1 = 0 °C. [b] Determined by HPLC peak area integration at 254 nm; the
values in parenthesis are isolated yields.
Using the continuous flow setup and the optimal conditions,
several aldoximes were also processed (Table 5). In this case,
dehydration of the substrate takes place, resulting in the
corresponding nitrile. These reactions required higher
temperatures for the second reactor unit (80 °C), and only
performed well when electron-rich aldoximes were utilized as
substrates (Table 5, entry 1). The oximes of benzaldehyde (Table
6, entry 2) and 4-chlorobenzaldehyde (Table 6, entry 3) exhibited
low reactivity.
Proposed Reaction Mechanism
Based on previously suggested reaction mechanisms[17-18] and
evidence obtained during the reaction optimization in this work,
including the detection of several important by-products, a
plausible pathway for the visible light-promoted Beckmann
rearrangement was postulated (Scheme 7a). The catalyst
(Ru(II)) is excited to a reductive triplet state
Ru(bpy)32+* (Ru(II)*) upon blue light irradiation, and thereafter
2+
Ru(bpy)3
Scheme 7. Postulated mechanism for the (a) Beckmann rearrangement and (b) aldoxime dehydration promoted by the photochemically generated V-H reagent.
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10.1002/ejoc.201900231
European Journal of Organic Chemistry
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the collection, a drop of reaction mixture was sampled and diluted with
acetonitrile in a standard 2 mL HPLC vial for HPLC analysis. After the
collection, the reaction mixture was concentrated to ca. 3 mL in vacuo,
dissolved in 25 mL pf CHCl3, washed with 3 × 25 mL distillated water, dried
over anhydrous Na2SO4 and concentrated in vacuo. The residue was
purified by flash chromatography on silica gel (40 – 63 µm) using
petroleum ether (PE, 40 – 60 °C) and a 1:1 mixture of dichloromethane
and ethyl acetate (DCM/EA) as eluent (Gradient: 0 – 15% DCM/EA over
10 CV, maintained at 15 % DCM/EA over 15 CV, 15 – 80% DCM/EA over
20 CV) to afford products 2.
Conclusions
In summary, we have developed a continuous flow procedure for
the light-induced Beckmann rearrangement. A Vilsmeier-Haack
reagent, generated by means of photoredox catalysis, acts as
electrophile to promote the rearrangement. Execution of the two-
step reaction in one pot proved troublesome due to the different
reaction conditions, in particular temperature, optimal for the light-
induced and thermal processes. These limitations have been
overcome by disentangling the photochemical and thermal
phenomena in an integrated, two-step sequential continuous flow
process. Thus, the electrophilic species is initially generated in a
flow photoreactor at low temperature, and then mixed with the
substrate and reacted in a second flow reactor at elevated
temperature. Using this approach a diverse set of oximes have
been transformed into the corresponding amides under mild
conditions without the need of hazardous reagents typically
required for this transformation. Moderate to excellent product
yields have been obtained after purification by column
chromatography. The procedure has also been applied to
aldoximes, providing the corresponding nitriles, although only
electron-rich substrates performed well. In addition, several
reaction intermediates and side-products of the reaction have
been detected, shedding light to the reaction mechanism.
Acknowledgements
The CC FLOW Project (Austrian Research Promotion Agency
FFG No. 862766) is funded through the Austrian COMET
Program by the Austrian Federal Ministry of Transport, Innovation
and Technology (BMVIT), the Austrian Federal Ministry of
Science, Research and Economy (BMWFW), and by the State of
Styria (Styrian Funding Agency SFG).
Keywords: Beckmann rearrangement • Vilsmeier-Haack
reagent • Photoredox Catalysis • Chemical Generator • Flow
Chemistry
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Entry for the Table of Contents
Layout 1:
FULL PAPER
A two-step sequential process
involving a photochemical and a
thermal reaction have been carried
out in a continuous flow reactor.
Separation of the two
transformations has enabled their
independent operation at different
optimal temperatures improving their
individual performance and
Yuesu Chen, David Cantillo, C. Oliver
Kappe*
Page No. – Page No.
Visible Light-Promoted Beckmann
Rearrangements: Separating
Sequential Photochemical and
Thermal Phenomena in a
Continuous Flow Reactor
maximizing the overall yield.
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