Intensification of Free-Radical Racemization for a Non-activated Amine in a Continuous Flow Reactor

Article abstract of DOI:10.1055/s-0040-1707339

The free-radical racemization of non-activated amines is a powerful tool for process design in the pharmaceutical industry, allowing the recycling of undesired enantiomers after chiral separation. This paper describes the development of the free-radical racemization of a key API intermediate in a continuous flow reactor. Upon development, a significant reduction of the solvent usage and radical initiator was made possible thanks to the conversion into a continuous flow mode. This intensification positively impacted both the environmental footprint and the safety of the reaction as well as maintaining satisfactory productivity.

Full text of DOI:10.1055/s-0040-1707339

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–H
special topic
A
en
F. C. Toussaint et al.
Special Topic
Synthesis
Intensification of Free-Radical Racemization for a Non-activated
Amine in a Continuous Flow Reactor
Frédéric C. Toussaint*
Thierry Defrance*
Serge Decouvreur
Nicolas Carly
Alain Merschaert
UCB Pharma S.A., Avenue de l’Industrie 1, 1420 Braine-l’Alleud,
Belgium
frederic.toussaint@ucb.com
thierry.defrance@ucb.com
Published as part of the Special Topic Synthesis in Industry
Received: 04.05.2020
Accepted after revision: 26.05.2020
Published online: 07.07.2020
Although numerous APIs and pharmaceutical intermedi-
ates have chiral centers based at carbon atoms which can
easily be deprotonated, numerous non-activated chiral spe-
cies cannot undergo racemization by acid/base-mediated
exchange.
For instance, APIs containing non-activated amines at
the -position of chiral centers cannot be easily racemized
by deprotonation. A strategy for the racemization of such
compounds, firstly proposed by Escoubet et al.5 (Scheme 1),
consists of a free-radical hydrogen atom transfer (HAT) cat-
alyzed by thiyl radical (polarity reversal catalysis).6
DOI: 10.1055/s-0040-1707339; Art ID: ss-2020-c0232-st
Abstract The free-radical racemization of non-activated amines is a
powerful tool for process design in the pharmaceutical industry, allow-
ing the recycling of undesired enantiomers after chiral separation. This
paper describes the development of the free-radical racemization of a
key API intermediate in a continuous flow reactor. Upon development, a
significant reduction of the solvent usage and radical initiator was made
possible thanks to the conversion into a continuous flow mode. This in-
tensification positively impacted both the environmental footprint and
the safety of the reaction as well as maintaining satisfactory productivi-
ty.
NH2
NH2
nC8H17SH (1.2 mol equiv)
AIBN (0.2 mol equiv)
Key words racemization, radical reaction, hydrogen atom transfer,
Ph
Ph
flow chemistry, intensification, drugs
benzene (11 volumes), reflux, 2 h
(S)-1 (ee 94%)
rac-1 (ee 2%)
Scheme 1 Thiyl radical mediated racemization of amine (Escoubet et al.5)
The control of chirality during the molecular construc-
tion of active pharmaceutical ingredients (APIs) is a major
field of research and development in the pharmaceutical
sector.1 Chirality can be controlled by using compounds de-
rived from ‘the natural pool’ of chiral molecules (e.g., amino
acids,2 sugars,3 enzymes4), by inversion of chiral centers, or
by chiral separation (e.g., preferential diastereoisomer crys-
tallization, chiral chromatography).
If applied in later stages of the synthesis of a complex
API, the chiral separation of enantiomers may dramatically
impact the cost of the overall process, since half of the total
product is the separated undesired enantiomer. Therefore, a
recycling of this undesired enantiomer should be envisaged
to ensure both a minimal financial cost of the final API and
a minimal environmental impact of the industrial produc-
tion process.
In this reaction, the reduction of enantiomeric excess
(ee) is achieved by forward and backward transfers of the
hydrogen atom between the chiral carbon bearing the
amine group at the -position and a thiyl radical acting as
electrophilic polarity reversal catalyst.
Discovered in 1952 by Barrett and Waters 7 on decarbo-
nylation reactions, this property of thiyl radicals in polarity
reversal catalysis has been thoroughly exemplified in nu-
merous other applications,8 such as deoxygenations,9 epi-
merizations of alcohols,10 acetal rearrangements,11 dehalo-
genations,12 cyclizations,13 and deuterium incorporations
on amines14 and aldehydes,15 and by halogen–deuterium
exchanges.16
The recycling of an undesired enantiomer consists of its
racemization: the so-produced racemic mixture can be en-
tered in a new cycle of chiral separation and racemization.
Several examples of racemization have already con-
firmed the efficiency of this methodology17 and could even
be coupled with a resolution of an enantiomer mixture.18
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
F. C. Toussaint et al.
Special Topic
Synthesis
At UCB Pharma, it has long been our goal to design effi-
cient chemical processes for our pharmaceutical products.
In the production of a key API intermediate, (S)-N-propyl-5-
methoxy-2-aminotetralin [(S)-2], isolation of the desired
enantiomer was performed by preferential diastereoisomer
crystallization (Scheme 2). The main drawback of this unit
operation was the sacrifice of the undesired enantiomer
(R)-2: the process yield of the chiral purification was there-
fore limited to a maximum of 50%.
The aromatization product 3 was detected up to 1.0%
area in the reaction mixture after the racemization reaction
(Scheme 4). Based on the proposed mechanism for the for-
mation of benzylic radicals and impurity 3, the amount of
thiyl radicals available in the reaction mixture, and thus the
amount of AIBN loaded in the reaction, is expected to di-
rectly impact the level of that impurity.
A
+20.2 kJ/mol
–8.1 kJ/mol
O
•
O
O
S•
( )6
•
Chiral acid
•
N
API
•
H
EtOAc
+
N
N
–OOCR*
H
H2
(S)-2 salt (ee >99%)
–20.2 kJ/mol
+8.1 kJ/mol
rac-2
O
B
O
O
O
abs
+ RS•
+ RS•
NH2+
(R)-2 salt (ee 60–80%)
–OOCR*
– RSH
– RSH
N
N
N
•
H
H
H
Scheme 2 Preferential crystallization of (S)-2 salt with chiral acid and
rejection of (R)-2 salt in the mother liquors
rac-2
O
+ 2 RS•
Based on the work of Escoubet et al.,5 the recycling of
the undesired enantiomer (R)-2 was evaluated. The design
of an industrial process for the racemization of (R)-2 would
have to satisfy three key conditions: (1) an enantiomer ex-
cess of the isolated product ≤4%, (2) an isolated yield of the
product ≥95% (mol), and (3) a purity of the isolated product
≥99% area.
– 2 RSH
N
H
3
Scheme 4 (A) Competitive hydrogen atom transfers19 on 2; (B) pro-
posed mechanism20 for the formation of impurity 3
As a proof of concept, an experiment was performed on
the readily available, optically pure (S)-2 enantiomer
(Scheme 3), before testing the recycled enriched (R)-2
mother liquors. The reaction was performed with octane-
thiol as thiol catalyst and 2,2′-azobis(isobutyronitrile)
(AIBN) as radical initiator, in toluene (5 mL/g, 5 volumes) at
reflux, and successfully delivered the racemic product in
good yield and purity.
As a first wave of optimization, six solvents and two thi-
ol catalysts [octanethiol (OctSH) and dodecanethiol
(DodSH)] were tested on the material from recycled en-
riched (R)-2 mother liquors (Table 1). All solvents except
isobutyl acetate (Table 1, entries 9–12) and the two thiol
catalysts gave comparable results in terms of enantiomeric
excess reduction and purity of the isolated product. In the
case of isobutyl acetate, the reaction produced a significant
amount of impurity 3.
Based on the competitive hydrogen atom transfers pre-
viously presented (Scheme 4), it could be hypothesized that
isobutyl acetate could also participate in such exchanges
with its tertiary carbon (Scheme 5). Although a mechanism
for a preferential production of impurity 3 was not yet pro-
posed, the high molar equivalence excess of isobutyl acetate
(8.3 mol equiv vs the amine) and the nucleophilic nature of
the isobutyl acetate radical might explain this significant
production of impurity 3.
O
O
nC8H17SH (1.2 mol equiv)
AIBN (0.1 mol equiv)
toluene (5 volumes), reflux, <1 h
N
N
H
H
rac-2 (ee 0%)
(S)-2 (ee >99%)
90% (isolated as HCl salt)
95% area purity (HPLC)
Scheme 3 Proof-of-concept racemization of optically pure (S)-2
This first proof of concept revealed the viability of our
approach, but also revealed some challenges that would be
encountered during the development work. Substrate 2 ap-
peared prone to several hydrogen atom exchanges compet-
ing with each other, which might lead to the production of
impurities.
From this first set of experiments, ethyl acetate was
chosen as solvent for practical reasons as it was already
used in the previous step of chiral separation. The recycled
enriched (R)-2 mother liquors could be directly used in the
racemization process without an additional step of solvent
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

C
F. C. Toussaint et al.
Special Topic
Synthesis
Table 1 Screening of Solvents and Thiol Catalysts in the Racemization Reaction of Enriched (R)-2 Material and Isolation Reaction in the Batch Reactor
O
O
O
thiol (1.2 mol equiv)
AIBN (0.1 mol equiv)
HClaq 37%
solvent (5 volumes), reflux, 1–2 h
reflux to 20 °C
N +
H2
Cl–
N
H
N
H
(R)-2
Step 1
rac-2
Step 2
rac-2•HCl
Entry
Solvent
toluene
Thiol catalyst
OctSH
Step(s)
ee (HPLC) (%)
Purity (HPLC) (% area)
Impurity 3 (HPLC) (% area) Residual thiol (HPLC) (% area)
1a
2a
1
0.6
–
94.07
96.85
91.47
96.85
93.39
97.71
92.32
98.26
86.65
97.84
87.66
98.03
93.80
99.00
92.55
99.09
92.10
98.40
93.25
98.53
94.65
98.46
95.66
98.77
0.77
1.85
0.72
1.65
1.17
0.93
0.75
0.62
7.76
1.34
7.35
1.17
0.39
0.37
0.57
0.30
0.81
0.73
0.40
0.25
0.37
0.76
0.32
0.59
3.38
0.00
3.19
0.00
2.60
0.00
2.8
1 + 2
1
3b
0.4
–
DodSH
OctSH
DodSH
OctSH
DodSH
OctSH
DodSH
OctSH
DodSH
OctSH
DodSH
4b
1 + 2
1
5a
0.7
–
6a
1 + 2
1
o-xylene
iBuOAc
THF
7b
0.1
–
8b
1 + 2
1
0.00
3.01
0.00
2.94
0.00
3.44
0.00
2.80
0.00
3.13
0.00
2.95
0.00
2.69
0.00
2.64
0.00
9a
0.8
–
10a
11b
12b
13a
14a
15b
16b
17a
18a
19b
20b
21a
22a
23b
24b
1 + 2
1
0.0
–
1 + 2
1
0.1
–
1 + 2
1
0.0
–
1 + 2
1
0.2
–
1 + 2
1
2-MeTHF
EtOAc
0.0
–
1 + 2
1
0.5
–
1 + 2
1
0.0
–
1 + 2
a Starting material: enriched (R)-2 (ee 65%, purity 94.72% area).
b Starting material: enriched (R)-2 (ee 83%, purity 94.99% area).
swap. Finally, dodecanethiol was preferred as catalyst as its
limited stench made it more convenient to handle at indus-
trial scale (Table 1, entries 23 and 24).
O
•
–8.1 kJ/mol
+20.2 kJ/mol
•
Once the categorical parameters were determined, opti-
mization of the continuous parameters of the racemization
were investigated. The optimal molar equivalences of AIBN
and dodecanethiol were determined, as well as the dilution
in ethyl acetate (Table 2). It appeared that the loading of
AIBN cannot be lowered without dramatically decreasing
the racemization rate: none of the experiments performed
with less than 0.10 molar equivalents of AIBN gave a satis-
factory reduction of the enantiomeric excess. Among three
experiments (Table 2, entries 6–8) resulting in good conver-
sions, only the conditions with an excess of dodecanethiol
•
N
H
•
S•
( )6
–20.2 kJ/mol
–38.0 kJ/mol
+8.1 kJ/mol
+38.0 kJ/mol
•
OAc
Scheme 5 Competitive hydrogen atom transfers19 between amines,
benzylic carbons, and isobutyl acetate
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

D
F. C. Toussaint et al.
Special Topic
Synthesis
Table 2 Optimization of Racemization Parameters in the Batch Reactor
O
O
nC12H25SH
AIBN
EtOAc, reflux
N
N
H
H
(R)-2
rac-2
Entrya
AIBN (mol equiv) DodSH (mol equiv) EtOAc (volumes) Reaction time (min) ee (HPLC) (%)
Purity (HPLC) (% area) Impurity 3 (HPLC) (% area)
1
2
3
4
5
6
7
8
9
0.5
0.5
1.5
1.5
1.0
0.5
0.5
1.5
1.5
5
15
5
360
360
360
360
360
60
35
49
13
30
24
1
95.63
95.36
93.12
95.15
92.41
94.69
90.00
95.92
90.83
0.38
0.46
0.57
0.41
0.44
1.11
1.97
0.53
0.76
0.02
0.06
0.10
15
10
5
15
5
180
30
1
0
15
360
11
a Starting material: enriched (R)-2 (ee 65%, purity 94.72% area).
(Table 2, entry 8) gave a low level of impurity 3 and a higher
purity of the product. These conditions (Table 2, entry 8)
were selected for the rest of the study.
ture and the residence time were easily investigated for
each composition.
The best result of the optimization (Table 3, entry 14)
was selected to refine the determination of an adequate res-
idence time in the continuous flow reactor (Table 4). In or-
der to achieve a satisfactory decrease of enantiomeric ex-
cess, a residence time of 3 minutes appeared to be suffi-
cient.
A demonstration of the final racemization process in the
continuous flow reactor and the isolation reaction was per-
formed (final procedure given in the experimental section).
The enantiomeric excess, the purity, and the level of impu-
rity 3 were measured for each step of the process (Table 5).
A mass balance analysis of the product rac-2 (Table 6)
was also conducted. The molar yield of the overall racem-
ization and isolation is 96.0% and the mass balance of the
process is 97.5%.
Racemization in the continuous flow reactor proved to
deliver a reliable recycling process of the undesired enan-
tiomer (R)-2 with a reduction of enantiomeric excess to 3%,
an isolated yield of 96.0%, and a product purity of 99.5% ar-
ea. Productivity in the continuous flow reactor, defined as
the quantity of product rac-2 exiting a continuous flow re-
actor of 1 L·h–1, is 2.88 kg·L–1·h–1. The racemization was also
tested in a larger version of the flow reactor ‘Sandwich’ (30
mL) (Figure 1) and did not show any significant difference
in terms of yield or purity of isolated product: it demon-
strated the easy scale-up of such a process. With these ex-
cellent results, the intensification of the process was at-
tempted to maximize the productivity of the racemization
reaction. Our efforts were directed towards a decrease of
the residence time via both an increase of the temperature
The control of the radical initiation had to be thoroughly
understood in order to design a safe and reliable addition of
AIBN to the reaction mixture while allowing an efficient
initiation of the racemization. Continuous flow reactor
(CFR) technology would address these challenges by ensur-
ing a safe and fast heating of the reaction mixture contain-
ing the AIBN initiator and a better control of both tempera-
ture and pressure within the reactor. Based on our experi-
ence in continuous flow reactor technology, stainless steel
flow reactors from Ehrfeld Mikrotechnik GmbH were se-
lected for the study. A flow reactor setup was quickly de-
signed with Ehrfeld MMRS modules, including a 11.3 mL
‘Meander’-type flow reactor and two coaxial heat exchang-
ers: an even larger 30.0 mL ‘Sandwich’ continuous flow re-
actor was considered in the study (Figure 1).
This optimization study (Table 3) in the continuous flow
reactor setup confirmed that the level of impurity 3 in the
isolated product significantly increases with a higher molar
equivalence of AIBN and with a higher reaction tempera-
ture. Unsurprisingly, the enantiomeric excess significantly
decreases with a higher molar equivalence of AIBN, with a
higher reaction temperature, and with a more concentrated
reaction mixture.
The first tests in the continuous flow reactor were a rep-
licate of the optimization previously performed in the batch
reactor (Table 3). So, the molar equivalences of AIBN and
dodecanethiol as well as the dilution in ethyl acetate were
studied. Since each reaction mixture composition meant
the preparation of a stock solution, the reaction tempera-
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

E
F. C. Toussaint et al.
Special Topic
Synthesis
Table 3 Optimization of Racemization Parameters in the CFR
O
O
nC12H25SH
AIBN
EtOAc
N
H
N
H
temperature
residence time
(R)-2
rac-2
Entrya AIBN
(mol equiv)
DodSH
(mol equiv)
EtOAc
(volumes)
Temp
(°C)
Residence time
(min)
ee (HPLC)
(%)
Purity (HPLC)
(% area)
Impurity 3 (HPLC)
(% area)
1
2
80
5
25
15
5
64
48
7
99.13
98.91
98.27
97.98
98.05
99.24
98.97
98.23
97.89
98.01
99.18
99.21
98.64
97.91
97.98
98.84
98.96
98.32
97.54
97.63
98.97
98.84
96.46
95.86
95.61
99.23
98.35
95.81
94.70
94.03
98.95
98.26
95.12
94.10
93.86
0.00
0.05
0.45
0.51
0.61
0.00
0.06
0.49
0.57
0.58
0.02
0.03
0.42
0.74
0.79
0.00
0.05
0.55
0.83
0.87
0.04
0.29
1.43
1.40
1.66
0.08
0.48
1.74
1.74
2.07
0.15
0.61
2.36
2.26
2.58
80
100
120
120
80
3
5
4
10
8
5
25
5
0.5
6
65
59
27
28
23
60
44
1
7
80
25
15
5
8
15
100
120
120
80
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
25
5
0.02
80
25
15
5
5
100
120
120
80
0
25
5
0
1.5
64
55
8
80
25
15
5
15
10
5
100
120
120
80
7
25
5
6
55
14
0
80
25
15
5
0.06
1.0
0.5
1.5
100
120
120
80
1
25
5
0
44
10
2
80
25
15
5
100
120
120
80
1
25
5
1
0.10
49
5
80
25
15
5
15
100
120
120
0
0
25
0
a Starting material: enriched (R)-2 (ee 65%, purity 94.72% area).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

F
F. C. Toussaint et al.
Special Topic
Synthesis
Table 4 Study of Residence Time on the Racemization Reaction in the
CFRa
Entry Residence
time (min)
ee (HPLC)
(%)
Purity (HPLC)
(% area)
Impurity 3 (HPLC)
(% area)
1
2
3
4
5
6
0.0
1.0
2.0
3.0
4.0
5.0
66
21
8
99.32b
99.02
98.61
98.31
98.22
97.91
0.00
0.18
0.45
0.56
0.61
0.72
4
3
2
a Reaction conditions: AIBN (0.02 mol equiv), DodSH (1.5 mol equiv), EtO-
Ac (5 volumes), 120 °C.
b Mother liquors purified on charcoal before racemization.
Table 5 Demonstration of Racemization and Isolation Process in the
CFR
1. nC12H25SH (1.5 mol equiv), AIBN (0.02 mol equiv),
EtOAc (5 volumes), 120 °C, 3 min
2. EtOAc, water, reflux 80 °C
3. HCl 37%, cooling to 20 °C
4. Filtration
O
O
5. Washings (EtOAc)
N +
H2
Cl–
N
H
(R)-2
rac-2•HCl
Entry
Step
ee (HPLC) Purity (HPLC) Impurity 3 (HPLC)
(%)
(% area)
(% area)
1
2
3
4
5
6
7
feed
65
99.36a
98.17
98.42
43.08
42.25
42.48
99.57
0.00
0.69
racemization
holding 80 °C
mother liquors
washing 1
3
–
–
–
–
3
0.60
18.60
16.38
0.00
washing 2
isolated product
0.13
a Mother liquors purified on charcoal before racemization.
Table 6 Mass Balance Analysis of Equivalent rac-2·HCl Product in In-
put/Outputs of the Continuous Flow Racemization and Isolation Pro-
cesses
Entry Input/output
Mass
(g)
rac-2·HCl
(% w/w)
rac-2·HCl
(g)
mol%
1
2
3
4
5
6
feed
–
–
23.32
0.34
0.01
0.00
22.39
–
100.0
1.4
mother liquors
washing 1
washing 2
isolated product
total
201.77
0.17
0.09
0.00
>99.9
–
16.45
11.39
22.39
–
0.1
Figure 1 (A) Assembled continuous flow reactor setup with Ehrfeld
MMRS modules; (B) stainless steel ‘Meander’ flow reactor module (11.3
mL); (C/D/E) stainless steel ‘Sandwich’ flow reactor module (30.0 mL)
equipped with mixer grid in the reactor channels. Photo: Courtesy of
Ehrfeld Mikrotechnik GmbH.
0.0
96.0
97.5
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

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F. C. Toussaint et al.
Special Topic
Synthesis
and concentration (Table 7). The racemization was success-
fully performed in only 1 volume of ethyl acetate and 1
minute of residence time and at a temperature of 130 °C
(Table 7, entry 2). The intensification allowed the produc-
tivity to be increased to 20.4 kg·L–1·h–1.
Table 8 Calculations for Estimated Productivity and Production Time
in the Batch Reactor and in the CFR
Reactor
Productivity DodSH AIBN
(kg·L–1·h–1
(L) (kg)
5000a 0.029
20.4
EtOAc Production time
(L) (h)
5.0b
4.9c
(L)
)
batch
CFR
819
819
37.5
7.5
2500
500
Table 7 Intensification of the Racemization Process in the CFR
5
a A 5000 L batch reactor was selected as a medium range batch reactor for a
pharma production; 5000 L is the maximal volume of the reactor and the
maximal volume of the reaction mixture at 20 °C is estimated at 3480 L.
b Production time in the batch reactor was estimated on the basis of typical
times for addition of all reagents (3 h), heating (1 h), and reaction (1 h).
c Production time in the CFR only takes into account the production time in
flow, as preparation of the mixture can be performed during the production
time in flow.
O
O
nC12H25SH (1.5 mol equiv)
AIBN (0.02 mol equiv)
EtOAc
N
H
N
H
temperature
residence time
(R)-2
rac-2
Entrya
EtOAc
(volumes)(°C)
Temp Residence time ee (HPLC)
Impurity 3
(HPLC) (% area)
(min)
(%)
the racemization of 500 kg with a cycle time comparable to
the expected productivity of a 5000 L industrial batch reac-
tor. A reduction of ethyl acetate would also lower the waste
amount generated. Finally, a reduction of AIBN loading
would also make the storage, the handling, and the addition
of this hazardous reagent safer in an industrial environ-
ment.
In conclusion, a free-radical racemization process for a
chiral amine has been successfully demonstrated, allowing
the recycling of an undesired enantiomer after chiral sepa-
ration. With a decrease of enantiomeric excess to 4%, an iso-
lated yield of 96%, and a purity of isolated product above
99% w/w, this racemization process satisfied our three key
conditions for an implementation at industrial scale. It was
possible to drastically upscale the process by using a con-
tinuous flow reactor which significantly contributed to a
reduction of the amounts of solvent and radical initiator re-
quired. These improvements rendered the overall process
more efficient, environmentally friendly, and cost-competi-
tive to meet an industrial demand.
1
2
0.5
1.0
0.5
1.0
0.5
1.0
0.5
1.0
1.0
3.0
5.0
1.0
3.0
5.0
1.0
3.0
5.0
1.0
3.0
5.0
1.0
3.0
5.0
18
0.28
0.64
0.61
0.89
0.30
0.64
0.59
0.84
0.35
0.97
0.95
0.67
1.20
1.20
0.93
0.92
0.94
0.83
0.95
0.98
0.79
0.82
0.93
130
4
6
1
3
3
140
130
140
4
2
5
20
6
6
7
7
8
4
9
22
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
120
130
140
150
160
3
8
3
3
6
5
5
4
This example of process intensification showcases the
benefits of continuous flow reactor technology in the devel-
opment of safer, greener, and cost-effective large-scale pro-
cesses of free-radical hydrogen atom transfers whose appli-
cations can be expanded beyond the racemization of non-
activated amines.
8
8
7
10
10
6
a Starting material: enriched (R)-2 (ee 65%, purity 94.72% area).
All chemicals were purchased from Sigma-Aldrich, VWR, or Acros Or-
ganics. 1H NMR spectra (400 MHz) and 13C NMR spectra (100 MHz)
were measured in deuterated solvents with TMS as an internal stan-
dard on a Varian 400 MHz spectrometer at room temperature. HPLC
spectra were recorded on an Alliance Waters 2695 system equipped
with an Atlantis T3 3 m column (4.6 × 100 mm), with detection at
200 nm; starting solvent composition = water: 90 vol %/water + 1%
H3PO4: 10 vol %; final solvent composition = water + 1% H3PO4: 10
vol %/acetonitrile: 90 vol % in 6 min, followed by a re-equilibration pe-
riod of 1 min to the initial solvent composition. Chiral HPLC was re-
corded on an Alliance Waters 2695 system equipped with a Chiralpak
AD-H 5 m (250 × 4.6 mm) column, with detection at 229 nm. Mass
In an industrial perspective, this value of productivity
was used to calculate the requirements for the treatment of
500 kg of (R)-2 (Table 8) with the best racemization process
in the batch reactor (Table 2, entry 8) and with the intensi-
fied process in the continuous flow reactor (Table 7, entry
2).
These preliminary calculations gave some insights into
the potential benefits at industrial scale. A continuous flow
reactor with a volume of 5 L would be sufficient to ensure
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

H
F. C. Toussaint et al.
Special Topic
Synthesis
spectra were recorded on a Waters 3100 triple quadrupole spectrom-
eter.
Acknowledgment
We would like to thank Bozhidar Palashev for his thorough bib-
liographic research on free-radical racemization as well as Dr Alexan-
dre Barthelme and Dr John Pavey for their kind contribution to the
review of this paper. We also would like to thank Dr Carmine Raffa
and Anne Kaaden for their kind technical support.
Free-Radical Racemization of (R)-N-Propyl-5-methoxy-2-amino-
tetralin [(R)-2]
To a degassed solution of enriched (R)-2 (23.32 g, ee 66%, purity
99.32%) in EtOAc (69.96 mL, 3 mL/g) previously treated on charcoal
were added, in a nitrogen-flushed and dried Schott glass bottle, EtOAc
(46.67 mL, 2 mL/g), 2,2′-azobis(isobutyronitrile) (AIBN; 0.35 g, 0.02
mol equiv), and 1-dodecanethiol (32.27 g, 1.50 mol equiv). The mix-
ture was allowed to stir at room temperature to ensure the full solubi-
lization of AIBN. The mixture was then injected at a flow rate of 3.9
mL/min by a Knauer pump (ceramic pump head 50 mL, model K-501)
in an MMRS continuous flow reactor setup (Ehrfeld Mikrotechnik
GmbH) (Figure 1) equipped with a Meander reactor (11.3 mL, model
Ehrfeld 0211-2-0311-F) heated at 120 °C by heating fluid and pres-
surized at 15 barg by a back-pressure controller (model Ehrfeld 0515-
1-8011-F). Cooling of the mixture after reaction was ensured by a co-
axial heat exchanger (model Ehrfeld 0309-3-0001-F), cooled at 15 °C
by heating fluid. Monitoring of the temperature of the reaction at the
outlet of the reactor and after the cooling was ensured by two tem-
perature probes (model Ehrfeld 0501-2-1001-F). The reaction mix-
ture was collected in a Schott glass bottle at the outlet of the continu-
ous flow reactor setup (ee 3%, purity HPLC 98.2% area).
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Isolation of rac-2·HCl Salt
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To the solution collected from the continuous flow reactor were add-
ed EtOAc (116.6 mL, 5 mL/g) and water (11.66 mL, 0.5 mL/g). The mix-
ture was transferred to a batch reactor and was heated to reflux (inner
temperature ~76 °C). An aqueous solution of HCl 37% w/w (11.53 g,
1.1 mol equiv) was added to the mixture at reflux over 20 min. Pre-
cipitation of rac-2·HCl salt was observed during the addition of the
HCl solution and the suspension was stirred at reflux for 1 h. The sus-
pension was cooled to 20 °C (cooling ramp: –10 K/h) and stirred at
20 °C for 1 h. The solid was collected by filtration and washed with
EtOAc (2 × 23 mL, 2 × 1 mL/g). The isolated solid was dried under vac-
uum at 40 °C; yield: 26.11 g (96%); ee 3%; purity HPLC 99.5% area;
assay HPLC >99.9% w/w.
1H NMR (400 MHz, DMSO-d6):  = 9.10 (broad s, 2 H), 7.13 (t, J = 6.0
Hz, 1 H), 6.79 (d, J = 6.0 Hz, 1 H), 6.72 (d, J = 6.0 Hz, 1 H), 3.77 (s, 1 H),
3.17 (dd, J = 3.4, 3.0 Hz, 1 H), 2.90 (m, 4 H), 2.49 (m, 4 H), 2.29 (m,
1 H), 1.72 (m, 3 H), 0.95 (t, J = 5.6 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6):  = 156.68, 133.89, 126.78, 123.35,
121.04, 107.87, 55.24, 52.89, 45.57, 31.34, 24.77, 21.51, 19.25, 11.12.
MS (ES+): m/z (%) = 161.2 (100), 220.2 (47) [M + H]+.
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Chem. Res. 2003, 36, 255.
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© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H