High-temperature Diels-Alder reactions: Transfer from batch to continuous mode

Article abstract of DOI:10.1021/op200320w

The transfer of a Diels-Alder reaction of (cyclohexa-1,5-dien-1-yloxy) trimethylsilane 1 with α-acetoxyacrylonitrile 2 and acrylonitrile 8, respectively, from batch to continuous mode is presented, using standard and widely available laboratory equipment. A standard microwave-based system was used as probe for the transfer to flow reactors. Temperature and residence time have been optimized in small coiled-tube reactors and confirmed with two production runs in a flow reactor. The inherent increase in safety caused by the small volumes at high temperatures and the achieved productivity (approximately 100 g/h using acrylonitrile) are offering advantages over the batch mode which suffers from thermokinetic limitations for scale-up.

Full text of DOI:10.1021/op200320w

Article
pubs.acs.org/OPRD
High-Temperature Diels−Alder Reactions: Transfer from Batch to
Continuous Mode
Stefan Abele,§,* Stefan Hock,∥ Gunther Schmidt,§ Jacques-Alexis Funel,§ and Roger Marti⊥,∥
̈
§Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland
∥ZHAW Zurich University of Applied Sciences, Institute of Chemistry and Biological Chemistry, Campus Reidbach, Einsiedlerstrasse
31, CH-8820 Wadenswil, Switzerland
̈
S
* Supporting Information
ABSTRACT: The transfer of a Diels−Alder reaction of (cyclohexa-1,5-dien-1-yloxy)trimethylsilane 1 with α-acetoxyacrylonitrile
2 and acrylonitrile 8, respectively, from batch to continuous mode is presented, using standard and widely available laboratory
equipment. A standard microwave-based system was used as probe for the transfer to flow reactors. Temperature and residence
time have been optimized in small coiled-tube reactors and confirmed with two production runs in a flow reactor. The inherent
increase in safety caused by the small volumes at high temperatures and the achieved productivity (approximately 100 g/h using
acrylonitrile) are offering advantages over the batch mode which suffers from thermokinetic limitations for scale-up.
affording, after distillation, the cyclo-adduct 3 in 66% yield on
INTRODUCTION
■
kilogram scale (Scheme 1).1 Safety studies of this reaction
The scale-up of [4 + 2] Diels−Alder cycloadditions is a
challenge in view of the inherent instability of the diene and/or
dienophile, especially for highly reactive reagents.1 Competing
side reactions such as rapid, uncontrolled polymerization with
explosive violence are a safety issue2 which must be addressed
early on when any scale-up is considered. In the course of our
research towards a scalable access to a key building block for an
active pharmaceutical ingredient (API) at Actelion,1,3 such
safety risks associated with the Diels−Alder reaction of
α-acetoxyacrylonitrile 2 or α-chloroacrylonitrile as dienophiles
and (cyclohexa-1,5-dien-1-yloxy)trimethylsilane as diene 1 have
been thoroughly assessed with reaction calorimetry (RC-1) and
isothermal DSC experiments.4 This culminated in the design
and development of an efficient and safe process securing the
timely delivery of 450 kg of intermediate emerging from the
Diels−Alder reaction with α-chloroacrylonitrile in batch mode.1
However, the use of α-acetoxyacrylonitrile (2) was restricted to
a few kilograms on the basis of these safety studies.4 We thus
turned to an alternative dienophile, acrylonitrile 8, which offered,
in addition, the possibility of running the Diels−Alder reaction
in a solvent.1
To cope with the restrictions imposed by the exothermic full
batch mode with both α-acetoxyacrylonitrile and acrylonitrile,
we reckoned that this cycloaddition process would be
well-suited for a continuous mode. This should, in addition,
provide a contingency technology for the timely supply of inter-
mediates. From the outset, we set ourselves the challenge to
employ conventional lab equipment that could be used for a
straightforward, low-cost, and easy-to-implement flow reactor
setup.5
Scheme 1. Diels−Alder reaction of diene 1 with
α-acetoxyacrylonitrile 2 in batch mode; only the main
regioisomer is shown, consisting of a mixture of both
diastereoisomers (endo/exo)
indicated a maximum temperature of the synthesis reaction
(MTSR) of 250 °C, at which temperature decomposition
would set in immediately with an increase in temperature
to 429 °C.4 Clearly, this reaction was not scalable to larger
volumes.
To get an insight for the kinetics of this reaction, an equi-
molar mixture of diene 1 and dienophile 2 was stirred in a glass
bottle at 140 °C for 24 h. Figure 1 shows the conversion of
diene 1 as a function of time.6 The NMR assay of the reaction
mixture was determined to be 67% w/w; however, no by-
1
products were detected by H NMR. This led to the assump-
tion that a considerable part of the reagents (especially the
diene 1) had polymerized during the reaction (polymers being
difficult to detect by NMR or GC). This polymer formation
might cause problems when transferring this reaction into a
microreactor system by blocking its fine structures.
A first test in continuous mode was done in a coaxial heat
exchanger module from Ehrfeld.7 The reactants were premixed
before being fed to the microreactor and a simple manual
HIGH TEMPERATURE DIELS−ALDER REACTION
WITH α-ACETOXYACRYLONTIRILE
First, the Diels−Alder reaction of diene 1 with α-acetoxyacry-
lonitrile 2 was tested. This reaction was usually carried out in
full batch mode (neat) at a temperature of 140−150 °C over 16 h,
■
Special Issue: Continuous Processing2012
Received: November 8, 2011
Published: December 27, 2011
© 2011 American Chemical Society
1114
dx.doi.org/10.1021/op200320w | Org. ProcessRes. Dev. 2012, 16, 1114−1120

Organic Process Research & Development
Article
Figure 1. Conversion6 of diene 1 as a function of time in the Diels−
Alder reaction of 1 and 2 in neat batch mode at 140 °C.
pressure valve from Swagelok was used to increase the pressure
in the system.8 The temperature limit for this system was 195 °C
which proved to be too low to get short residence times; only
about 20% conversion was observed at 2-min residence time. In
order to heat to higher temperature, the reactor setup was then
modified to a simple coiled steel tube that was put into a liquid
metal bath9 as shown in Figure 2.
Figure 3. Reactant conversion6 of diene 1 in the Diels−Alder reaction
of 1 and 2 after 1 min at different temperatures in the flow mode.
Figure 4. Byproducts formed in the Diels−Alder reaction of 1 and 2 at
high temperatures without exclusion of oxygen.
2-cyclohexenenone (5) and phenol (6), were formed in in-
creasing amounts when the reaction mixture was passed through
the flow reactor at higher temperatures. The influence of the
stainless steel tubing on decomposition reaction at this high
temperature10 was not studiedwe did not observe any change
in the impurity profile over time, using our equipment. A typical
1H NMR spectrum of a crude product is shown in Figure 5,
with assignment of the impurities 4, 5, and 6.
Next, we tested whether it was possible to optimize the
productivity with minimal byproduct formation. Therefore, several
residence times were screened at 250 °C, a temperature at which
byproduct formation seemed reasonably low as observed by
NMR of the crude material. Starting with an equimolar mixture
of 1 and 2, the reaction mixture contained some unreacted
diene 1 after 2.5 min, whereas 1 had completely disappeared
after 5 and 10 min. The ratio of dienophile 2 and product 3 was
stable after 5 min, but the amount of byproduct (especially
enone 5) increased at longer residence times (Figure 6). This is
in agreement with the finding that the impurities 5 and 6 are
formed at higher reaction temperature.
In order to reduce the amounts of byproduct 5 and 6, which
were assumed to be derived from an acid-catalyzed removal of
the TMS-protection group from diene 1, the reaction mixture
was saturated with a non-nucleophilic base (Na2CO3). This led
to the formation of gas bubbles at the outlet as well as to the
formation of a new series of aromatic byproducts (reaction
temperature 250 °C, residence time 5 min). One of these could
be identified as 4-cyanophenol (7). Scheme 2 shows a possible
mechanism for the formation of this new byproduct that would
be associated with the formation of ethylene gas (Alder−Rickert
reaction).11 The other source of a gas could be CO2 from the
decomposition of Na2CO3.
Figure 2. Simple flow reactor setup using a Rose metal bath as heating
source and a Swagelok pressure valve (see the Experimental Section
for the detailed parameters of the flow reactors).
The metal bath allowed for reaction temperatures of up to
300 °C. With this new setup a temperature/conversion screening
was done (Figure 3).
Higher temperatures led to higher conversion; however, more
undesired byproducts were concomitantly formed, as judged by
1H NMR analysis of the crude reaction mixture. The diene 1
proved to be unstable and formed several byproducts. The most
prominent ones were identified and assigned by two-dimensional
(2D) NMR spectra (COSY and HSCQ) (Figure 4).
It was found that the hydroxylated enone 4 was formed via a
Rubottom reaction when keeping the crude reaction mixture at
rt under an atmosphere of air for several hours. The impurities,
When diluting the reaction mixture with an equal amount of
toluene, a significant decrease of the reaction rate was observed,
and the same byproducts were formed. To accelerate the neat
1115
dx.doi.org/10.1021/op200320w | Org. ProcessRes. Dev. 2012, 16, 1114−1120

Organic Process Research & Development
Article
Figure 5. Byproducts formed from a mixture of diene 1 and α-acetoxyacrylonitrile 2 after keeping the mixture at 175 °C for 2 min and then at rt for
1
100 h. H NMR in CDCl3.
Table 1. Byproducts formed in the Diels−Alder reaction of 1
a
and 2 (1.5 equiv 1) at 250 °C
a
Values are relative to the amounts of product 3 formed at the same
1
time according to H NMR (mol %).
Figure 6. Amounts of byproduct formed in the Diels−Alder reaction
of equimolar amounts of 1 and 2 at 250 °C. Molar ratios of 2 (■), 5
The best compromise between long residence times at low
(▲) and 6 (⧫) are presented relative to the amounts of product 3
1
temperatures on the one hand and byproduct formation at
higher temperatures on the other hand was finally the reaction
of 1.5 equiv of diene 1 with dienophile 2 at 250 °C and a
residence time of 10 min. In a production experiment, the small
flow reactor (Experimental Section) was operated under these
conditions for 1.75 h after conditioning, i.e. running the reactor
steadily with the process parameters. During that time no
clogging of the reactor was observed, and the pressure in the
reactor was constant at 5 bar. The crude product’s content was
44% w/w (1H NMR assay, see Experimental Section), which
corresponds to an assay-corrected yield of 57% (Table 2). The
1H NMR of the crude product indicated the typical impurities
described above. The risks associated with this Diels−Alder
reaction have been mitigated by the transfer from batch to con-
tinuous mode. However, the dienophile 2 was not commer-
cially available because its custom synthesis required handling
formed at the same time, according to H NMR (mol %).
Scheme 2. Possible mechanism for the formation of
4-cyanophenol 7 via an Alder−Rickert reaction in the
presence of Na2CO3
Diels−Alder reaction, 1.5 equiv of the diene 1 were used next.12
The results for two different residence times at 250 °C in the flow
reactor are shown in Table 1. Accordingly, the dienophile 2
reacted faster while less of cyclohexenone 5 was formed.
1116
dx.doi.org/10.1021/op200320w | Org. ProcessRes. Dev. 2012, 16, 1114−1120

Organic Process Research & Development
Article
product 9 were determined (Figure 7). The impurities 4, 5, and
6 were not observed mainly due to the lower temperature as
Table 2. Overview of the parameters for the Diels−Alder
reactions of diene 1 with dienophiles 2 and 8
dienophile α-acetoxyacrylonitrile
a
b
2
acrylonitrile 8
1:3
ratio of 1:dienophile
reaction temp
1.5:1
250 °C
600 s
57%
215 °C
60 s
residence time
assay-corrected yield
isolated yield
65%
d
−
11 g/h
33%
c
c
d
productivity
96 g/h /48 g/h
a
Data from the ‘small flow reactor’ (0.03 mL, 0.3 mL/min, 5 bar),
b
used in this work. Data from the ‘large flow reactor’ (4.5 mL, flow
c
rate 4.5 mL/min, 50 bar), used in this work. Based on assay-corrected
d
yield (by 1H NMR) of crude reaction mixture. Based on isolated yield
after distillation.
Figure 7. Screening of the temperature of the Diels−Alder reaction of
diene 1 and acrylonitrile 8 at a ratio of 1:1 for 2 h. Molar ratios of 1
(▲) and 8 (■) are presented relative to the amounts of product 9
of cyanides, and it was not stable enough for large-scale
manufacturing.1,4
1
formed at the same time, according to H NMR (mol %).
HIGH TEMPERATURE DIELS−ALDER REACTION
■
WITH ACRYLONITRILE
compared to those of reactions with dienophile 1 (250 °C).
The amount of both starting materials left in the crude reaction
mixture decreased with increasing reaction temperature. It was
also observed (not shown) that a temperature of at least ∼175 °C
is required to attain a reasonable reaction rate for the Diels−
Alder reaction. As the amount of unreacted acrylonitrile was
always significantly lower than that for diene 1, we assumed
that polymerization of acrylonitrile took place as a side reaction.
We therefore decided to use an excess of acrylonitrile which
should simultaneously accelerate the Diels−Alder reaction.
By applying the van’t Hoff rule as approximationan increase
of the reaction temperature by 10 °C results in a doubling of
the reaction ratewe raised the reaction temperature by 30 °C
to 205 °C, which should reduce the residence time of 2 h by a
factor of 8 to ∼10 min. In the following, a residence time
screening was done in the flow reactor at 205 °C using 1.2
equiv of acrylonitrile (Figure 8). The diene 1 was consumed
Acrylonitrile (8) is much cheaper and less toxic13 than α-
acetoxyacrylonitrile 2. Therefore, an excess of this dienophile
was deemed acceptable and should have a positive effect on the
kinetics of the bimolecular reaction to the desired Diels−Alder
product 9. Again, the batch reaction served as starting point
(Scheme 3). Diene 1 and 3 equiv of acrylonitrile 8 were heated
Scheme 3. Neat Diels−Alder reaction of diene 1 with
acrylonitrile 8 as dienophile in batch mode
in an oil bath set at 90 °C for 20 h. The yield of cycloadduct 9
was 62% after correction for the NMR assay of the crude
reaction mixture. Nitrile 9 was formed as an endo/exo mixture
of regioisomers with the depicted 2,5-isomer as main product.
The distillation was thwarted by polymerization of acrylonitrile.
Later,1 we found 2,2,6,6-tetramethyl-piperidine-1-oxyl
(TEMPO) as a suitable polymerization inhibitor for the system
of 1 and acrylonitrile 8. The addition of catalytic amounts of
TEMPO prevented the polymer formation during the Diels−
Alder reaction with excess acrylonitrile in neat batch conditions
and enabled isolation of 9 by distillation (Experimental Section,
62% corrected yield). Likewise, an equimolar mixture of diene 1
and acrylonitrile was reacted in xylenes at 135 °C jacket tem-
perature for 16 h. The nitrile 9 was isolated in 65% yield after
distillation.14 Still, the exothermic neat full-batch mode of this
reaction triggered the development of a flow reactor technology.
In preliminary batch experiments polymerization of acrylo-
nitrile was observed. To avoid any problem in continuous pro-
cessing by blocking the channels of microreactors, the reaction
was therefore screened first in a microwave reactor at different
temperatures.15 A microwave reactor is perfectly suited for higher
temperature under pressure. A 1:1 mixture of diene 1 and acry-
lonitrile 8 was heated for 2 h at different temperatures. The
Figure 8. Screening of the residence time of the Diels−Alder reaction
of diene 1 and acrylonitrile 8 at a ratio of 1:1.2 at 205 °C. Molar ratios
of 1 (▲) and 8 (■) are presented relative to the amount of product 9
1
formed at the same time, according to H NMR (mol %).
within 5 min, whereas some acrylonitrile 8 was still detected in
the crude reaction mixture.
With 2 equiv of acrylonitrile and a reaction temperature
of 205 °C, the diene was already consumed after 1.25 min.
A residence time of ∼1 min secured a reasonable productivity
for continuous processing. No precipitation was observed in the
1
reaction mixture was analyzed by H NMR, and the molar
amounts of starting materials 1 and 8 left relative to that of
1117
dx.doi.org/10.1021/op200320w | Org. ProcessRes. Dev. 2012, 16, 1114−1120

Organic Process Research & Development
Article
reaction mixture during or after the reaction. An increase of the
amount of acrylonitrile to 3 equiv and of the temperature to
215 °C allowed for an acceptable residence time of ∼1 min
(Figure 9). The yield of Diels−Alder product 9 was 81%,
8 have been transferred from batch to continuous mode.
Microwave heating was successfully used for the screening of
the temperature and optimal residence time. A key feature is
the use of a simple steel tube and a Swagelok pressure valve for
this flow reactor system. Although it was possible to reach a
practical reaction time of 10 min for the Diels−Alder reaction
of α-acetoxyacrylonitrile 2 with 1.5 equiv of diene 1 by in-
creasing the temperature to 250 °C, this led to the formation of
several new byproducts and polymerization. The reaction of
diene 1 with acrylonitrile 8 has been transferred into a con-
tinuous process at 215 °C with a residence time of ∼1 min by
using a large excess of this dienophile (3 equiv). The crude
yield was comparable to the one obtained in the batch reaction.
The formation of polymeric byproduct from acrylonitrile
during distillation of the Diels−Alder product 9 was omitted
by the addition of an inhibitor (TEMPO) to the reaction mixture.17
A short-path distillation for continuous product isolation would
be the preferred option on larger scales.
Figure 9. Residence time screening of the Diels−Alder reaction of
diene 1 and acrylonitrile 8 at a ratio of 1:3 at 215 °C. Molar ratios of 1
(■) are presented relative to the amounts of product 9 formed at the
EXPERIMENTAL SECTION
■
General. All chemicals were reagent grade and used as sup-
plied, unless stated otherwise. Analytical thin layer chromatog-
raphy (TLC): precoated Merck silica gel 60 F254 plates
(0.25 mm). Column chromatography (FC): Fluka silica gel 60
1
same time, according to H NMR (mol %).
corrected for the NMR assay of the crude reaction mixture
(56% w/w).
1
(230−400 mesh). H (300 MHz) and 13C NMR (75 MHz)
These final conditions (i.e., 3 equiv acrylonitrile, 215 °C,
1 min) were then confirmed in two production runs. First, the
0.3 mL flow reactor (‘small flow reactor’) was operated for
35 min at 215 °C with a residence time of 60 s. The assay-
corrected yield was 56%. In a second experiment, a larger steel
tube with an inner diameter of ∼2 mm and a volume of 4.5 mL
was used (‘large flow reactor’, Table 2). During 45 min, 164 g
of reaction mixture was collected and purified by vacuum dis-
tillation. The purity of the reaction mixture was acceptable for
downstream chemistry (44% w/w by NMR assay, 65% assay-
corrected yield).16
spectra were recorded on a Bruker AVANCE 300. Chemical
shifts (δ) are reported in ppm relative to Me4Si (0.00 ppm).
NMR assay: the content (% w/w) of all crude products and
reaction mixtures was assessed by NMR assay with dihydro-
quinone dimethylether as internal standard. In case of bicycle 3,
integrals of the signals of the bridgehead hydrogen C(1)H
(two dt at 3.3−3.2 ppm) were compared to the integral of the
methyl singlet of dihydroquinone dimethylether (3.56 ppm). In
case of bicycle 9 the olefin signals (two dd at 5.2−5.0 ppm)
were used as the reference signal. In all cases, the time between
scans (relaxation delay, D1) was set to 20 s. Microwave equipment:
reactions under microwave irradiation were carried out in a
closed vessel in a Biotage Initiator device. Flow reactor setup:
(a) Small flow reactor: coiled stainless steel tube (0.3 mL,
680-mm length, 0.75-mm I.D.). (b) Large flow reactor: coiled
stainless steel tube (4.5 mL, 1200-mm length, 2.2-mm I.D.).
For heating, the reactors were immersed in a metal bath (Rose’s
alloy: 50% Bi, 25% Pb, 25% Sn). The feed was pumped using
a Merck Hitachi L-6200A HPLC pump with a pressure control
(a Swagelok SS needle valve).
With these flow parameters at hand, the requirements for a
productivity of 100 kg Diels−Alder products 3 or 9 in 24 h
were estimated for a flow reactor with internal diameter of
4 mm (Table 3). While the reaction with α-acetoxyacrylonitrile
a
Table 3. Estimated mass and flow reactor requirements for
a production of 100 kg 3 or 9 in 24 h, extrapolated with flow
parameters of the two production runs in Table 2
α-acetoxyacrylonitrile 2 acrylonitrile 8
Synthesis of rac-2-Cyano-5-(trimethylsilyloxy)bicyclo-
[2.2.2]oct-5-en-2-yl acetate (3). Reference Batch Experi-
ment. A mixture of diene 1 (9.21 g, 54.8 mmol, 1 equiv) and
α-acetoxyacrylonitrile (2) (6.09 g, 54.8 mmol, 1 equiv) was stirred
at 140 °C for 24 h. The amount of product was determined by
1H NMR assay at regular intervals. After 24 h, 99% of the die-
nophile 2 has reacted and crude 3 was obtained as thick, brown
oil. Yield: 15.3 g (100% uncorrected yield). NMR-assay: 67%
w/w. This corresponds to an assay-corrected yield of 67%.
Production Run, Small Flow Reactor. The feedprepared
by mixing diene 1 (5.04 g, 5.60 mL, 30 mmol, 1.5 equiv)
and α-acetoxyacrylonitrile (2) (2.22 g, 2.09 mL, 20 mmol,
1 equiv)was pumped with a flow of 0.03 mL/min (this
corresponds to a residence time of 10 min) through the small
flow reactor at 250 °C and a pressure of 5 bar. The reactor was
run under these conditions for 15 min before the reaction
mixture was collected during 1.75 h to afford crude 3 as brown
72 kg
218 kg
230 kg
390 mL
31 m
diene 1
164 kg
1665 mL
132 m
flow reactor volume
flow reactor length
flow reactor internal diameter
flow rate
4 mm
4 mm
10.0 L/h
23.4 L/h
a
Based on assay-corrected yield (by 1H NMR) of crude reaction
mixture.
2 would require a coil with 132-m length, a 31-m tube with a
flow rate of ∼23 L/h would be sufficient for the production of
100 kg of 9 from acrylonitrile 8 and diene 1.
CONCLUSIONS
■
High-temperature Diels−Alder reactions of (cyclohexa-1,5-dien-1-
yloxy)trimethylsilane 1 and α-acetoxyacrylonitrile 2 or acrylonitrile
1118
dx.doi.org/10.1021/op200320w | Org. ProcessRes. Dev. 2012, 16, 1114−1120

Organic Process Research & Development
Article
oil. Yield: 3.1 g (104% recovery, 8.2 mmol 2). NMR assay: 44%
w/w. This corresponds to an assay-corrected yield of 57%.
Analytical data of byproduct.18 6-Hydroxy-2-cyclohexenone
(4). 1H NMR (CDCl3):19 δ 6.98 (br, dt, J = 10.1, 4.1 Hz, 1H);
5.98 (dt, J = 10.1, 2.0 Hz, 1H); 4.14 (dd, J = 13.7, 5.6 Hz, 1H);
2.7−1.8 (m, 4H). These values are in accordance with literature
values.20
afforded 9 as colorless oil. Yield: 36.4 g (33%). Due to
polymerization (viscous liquid) some product was left trapped
in the distillation flask. NMR data correspond to those of 9.1
ASSOCIATED CONTENT
■
S
* Supporting Information
1
GC−MS method, representatives copies of H NMR of com-
2-Cyclohexenone (5). 1H NMR (CDCl3): 7.0 (m, 1H); 6.07
(dt, J = 10.0, ∼2.0 Hz, 1H); 2.7−1.8 (m, 6H). These values are
in accordance with literature values.21
pounds 3 and 9. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
Phenol (6). H NMR (CDCl3): δ 7.18 (m, 2H), 6.87−6.78
AUTHOR INFORMATION
Corresponding Author
*E-mail: stefan.abele@actelion.com. Telephone: +41 61 565 67 59.
■
(m, 3H).
Synthesis of rac-5-(Trimethylsilyloxy)bicyclo[2.2.2]-
oct-5-ene-2-carbonitrile (9). Batch Reaction (without
TEMPO, in Xylenes). TMS−diene 1 (50 g, 0.297 mol, 1 equiv)
and acrylonitrile (8) (19.5 mL, 0.297 mol, 1 equiv) were dissolved
in xylenes (100 mL) and heated to 135 °C (oil bath) at normal
pressure for 16 h. The solvent was removed under reduced
pressure. Distillation under high vacuum (∼0.1 mbar) and a
head temperature of 95 °C afforded 9 as a colorless liquid.
Yield: 43 g (65% uncorrected).
Batch Reaction (Neat, with Tempo). TMS−diene 1 (50 g,
0.297 mol, 1 equiv), TEMPO (0.5 g, 0.003 mol, 0.01 equiv)
and acrylonitrile (8) (58.7 mL, 0.891 mol, 3 equiv) were heated
to 90 °C (external temperature) for 24 h. Distillation under
high vacuum (∼0.1 mbar) and a head temperature of 90 °C
afforded 9 as a colorless liquid. Yield: 55 g (84% uncorrected).
NMR assay: 74% w/w. This corresponds to an assay-corrected
yield of 62%.
Present Address
⊥Ecole d’Ingen
́
ieurs et d’Architectes de Fribourg, Institut de la
Chimie, Bd de Perolles 80, CH-1705 Fribourg, Switzerland.
́
REFERENCES
■
(1) Funel, J.-A.; Schmidt, G.; Abele, S. Org. Process Res. Dev. 2011, 15,
1420−1427, and references cited therein.
(2) (a) Langvardt, P. W. Acrylonitrile. In Ullmann’s Encyclopedia of
Industrial Chemistry; Wiley: New York published online: June 15,
2000; DOI: 10.1002/14356007.a01_177, pp 1−9 (accessed Dec 18,
2010). (b) Kirch, L. S.; Kargol, J. A.; Magee, J. W.; Stuper, W. S. Plant
Oper. Progr. 1988, 7, 270−274.
(3) Hilpert, K.; Hubler, F.; Renneberg, D. PCT Int. Appl. WO/2008/
132679, 2008.
(4) (a) In collaboration with Swiss Safety Institute, Basel, Switzerland;
RC1 and DSC experiments were performed, see: Abele, S.; Stoessel, F.
et al. Safety Assessment of Diels−Alder Reactions with Highly Reactive
Reagents. Org. Process Res. Dev. 2012. Manuscript in preparation.
(b) Abele, S. Design of a Scalable Diels−Alder Reaction with Highly
Reactive Reagents. Scientific Update, Hazardous Chemistry for Stream-
lined Large Scale Synthesis Conference;Cologne, Germany , June 23−24,
2011.
Batch Reaction (Neat, without Tempo). TMS−diene 1 (50 g,
0.297 mol, 1 equiv) and acrylonitrile (8) (58.7 mL, 0.891 mol,
3 equiv) were heated to 90 °C (external temperature) for 20 h.
The mixture was cooled to 20 °C to obtain 9 as a yellow,
1
viscous oil. Yield: 97 g (62% corrected by assay by H NMR
(5) Continuous Diels−Alder reactions: (a) Jahnisch, K.; Hessel, V.;
̈
(CDCl3): 42% w/w). Distillation at 88−95 °C head temper-
ature, 130 °C bath temperature, and ∼0.1 mbar afforded puri-
fied 9 as a colorless liquid. Yield: 30 g (46% uncorrected).
NMR assay: 85% w/w. This corresponds to an assay-corrected
yield of 39%.
Lowe, H.; Baerns, M. Angew. Chem., Int. Ed. 2004, 43, 406−446.
̈
(b) Snyder, D. A.; Noti, C.; Seeberger, P. H.; Schael, F.; Bieber, T.;
Rimmel, G.; Ehrfeld, W. Helv. Chim. Acta 2005, 88, 1−9.
(c) McMullen, J. P.; Jensen, K. F. Org. Process Res. Dev. 2011, 15,
398−407. (d) Damm, M.; Glasnov, T. N.; Kappe, C. O. Org. Process
Res. Dev. 2010, 14, 215−224. (e) Rasheed, M.; Wirth, T. Chim. Oggi
2011, 29, 54−56. (f) Monbaliu, J.-C. M. R.; Cukalovic, A.; Marchand-
Brynaert, J.; Stevens, C. V. Tetrahedron Lett. 2010, 51, 5830−5833.
(6) Determined by comparing the olefin signals of the diene 1 at 5.7
ppm with the bridgehead signals of the Diels−Alder product 3 at 3.25
ppm; conversion is defined as the percentage of the integral of 3 to the
sum of the integrals of 1 and 3.
Production Run, Small Flow Reactor. The feedprepared
by mixing diene 1 (8.4 g, 9.33 mL, 50 mmol, 1 equiv) and
acrylonitrile (8) (7.96 g, 9.83 mL, 150 mmol, 3 equiv)was
pumped with a flow of 0.3 mL/min (this corresponds a
residence time of 60 s) through the small flow reactor at 215 °C
and a pressure of 50 bar. The reactor was run under these
conditions for 10 min before the reaction mixture was
collected for 35 min to afford crude 9 (8.926 g, 100% recovery,
27.3 mmol 1). The excess acrylonitrile was evaporated under
reduced pressure (40 °C, 20 mbar) affording 9 as a brown turbid
oil. Yield: 6.046 g (100% uncorrected). Only traces of impurities
(7) The www.ehrfeld.com web site (accessed 12 May 2011).
(8) Microreactor setup: Ehrfeld coaxial heat excha nger (0.62 mL)
heated with a Julabo ME-6 thermostate, Merck Hitachi L-6200A
HPLC pump system, Swagelok needle valve
(9) (a) Rose’s alloy: 50% Bi, 25% Pb, and 25% Sn with a melting
point of 98 °C. (b) Electrical heating is the preferred option for
heating for larger production systems.
(10) Shore, G.; Organ, M. G. Chem. Commun. 2008, 7, 838−840.
(11) Alder, K.; Stein, G.; Pries, P.; Winckler, J. Ber. Dtsch. Chem. Ges.
1929, 62B, 2337−2372.
(12) An excess of the diene 1 was used, since the dienophile 2 is
more toxic and less readily available.
(13) Acrylonitrile is a bulk chemical, is readily available on large scale,
and has fewer toxicity issues as compared to 2 as no cyanides in the
waste stream have to be treated in the downstream chemistry.1
(14) Forsyth et al. used 2.5 equiv acrylonitrile in toluene at 140 °C
for 24 h, 92% undistilled crude yield, see: Forsyth, D. A.; Botkin, J. H.;
Puckace, J. S.; Servis, K. L.; Domenick, R. L. J. Am. Chem. Soc. 1987,
109, 7270−7276.
1
were detected in the H and 13C NMR spectra. NMR assay:
56% w/w. This corresponds to an assay-corrected yield of 56%.
Production Run, Large Flow Reactor. The feed, prepared
by mixing diene 1 (117.7 g, 130.8 mL, 0.7 mol, 1 equiv) and
acrylonitrile (8) (111.4 g, 137.5 mL, 2.1 mol, 3 equiv), was
pumped with a flow of 4.5 mL/min (this corresponds to a
residence time of 60 s) through the large flow reactor at 215 °C
and a pressure of 50 bar. The reactor was operated under these
conditions for 2 min before the reaction mixture was collected
for 45 min to afford crude 9 (164 g, 95% recovery, 0.5 mol 1).
NMR assay of crude reaction mixture: 44% w/w. This cor-
responds to an assay-corrected yield of 65%. Vacuum distilla-
tion (bath temperature: 150 °C, head temperature 90 °C, 0.1 mbar)
1119
dx.doi.org/10.1021/op200320w | Org. ProcessRes. Dev. 2012, 16, 1114−1120

Organic Process Research & Development
Article
(15) Applied for the Diels−Alder reaction of acrylonitrile and 2,3-
dimethylbutadiene, see ref 5d.
(16) Only 33% of the product 9 was isolated after distillation. This
was due to polymerized acrylonitrile in the crude reaction mixture,
which led to difficulties during the distillation process, see ref 17.
(17) Successfully demonstrated in batch mode where contact times
are longer as compared to continuous mode (Experimental Section).
1
(18) Based on H NMR spectra of a mixture of compounds 2, 4, 5,
and 6. Some of the signals could therefore only be roughly assigned.
(19) The signal of the OH group was hidden under the signals of
other compounds and could not be assigned.
(20) Rubottom, G. M.; Gruber, J. M. J. Org. Chem. 1978, 43, 1599−
1602.
̈
(21) Ponaras, A. A.; Zaim, O.; Pazo, Y.; Ohannesian, L. J. Org. Chem.
1988, 53, 1110−1112.
1120
dx.doi.org/10.1021/op200320w | Org. ProcessRes. Dev. 2012, 16, 1114−1120