Scalable Wolff-Kishner Reductions in Extreme Process Windows Using a Silicon Carbide Flow Reactor

Article abstract of DOI:10.1021/acs.oprd.9b00336

A safe and scalable continuous flow strategy for Wolff-Kishner reductions that employs methanol as the solvent has been developed. The use of low-cost hydrazine as the reducing agent in combination with a caustic base provides an atom-efficient, environmentally friendly method for the deoxygenation of aldehydes and ketones to alkanes. Because of the required harsh and corrosive reaction conditions (200 °C, 50 bar), reactor materials such as stainless steel, glass, or any type of polymer have compatibility problems, rendering this process problematic on a production scale. The use of corrosion-resistant silicon carbide (SiC) as the reactor material opens up the possibility of performing Wolff-Kishner reductions on scale with a considerably improved safety profile. Methanol as the solvent significantly simplifies the workup procedure compared with the generally employed high-boiling solvents such as diethylene glycol. The continuous flow protocol was applied to a number of substrates and provided the desired products in good to high yields with space-time yields of up to 152 g L^-1 h^-1. In addition, a pharmaceutically valuable active pharmaceutical ingredient precursor was synthesized by employing this higherature/pressure Wolff-Kishner protocol.

Full text of DOI:10.1021/acs.oprd.9b00336

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Full Paper
Scalable Wolff-Kishner Reductions in Extreme Process
Windows Using a Silicon Carbide Flow Reactor
Desiree Znidar, Anne O'Kearney-McMullan, Rachel H Munday, Charlotte Wiles,
Peter Poechlauer, Christoph Schmoelzer, Doris Dallinger, and C. Oliver Kappe
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00336 • Publication Date (Web): 07 Oct 2019
Downloaded from pubs.acs.org on October 8, 2019
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Scalable Wolff-Kishner Reductions in Extreme Process Windows
Using a Silicon Carbide Flow Reactor
Desiree Znidar, †,‡ Anne O´Kearney-McMullan,§ Rachel Munday,§ Charlotte
Wiles,# Peter Poechlauer,┴ Christoph Schmoelzer, ┴ Doris Dallinger*†,‡ and C.
Oliver Kappe*,†,‡
† Center for Continuous Flow Synthesis and Processing (CCFLOW), Research Center
Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria
‡ Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz,
Austria
§ AstraZeneca, Silk Road Business Park, Macclesfield SK10 2NA, United Kingdom
# Chemtrix BV, Galvaniweg 8A, 6101 XH Echt, The Netherlands
┴ Patheon Austria GmbH & Co KG, Sankt-Peter-Straße 25, 4020 Linz, Austria
____________________
* Corresponding authors. E-mail: do.dallinger@uni-graz.at, oliver.kappe@uni-graz.at
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TABLE OF CONTENTS ENTRY
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ABSTRACT
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A safe and scalable continuous flow strategy for Wolff-Kishner reductions that employs
methanol as the solvent has been developed. The use of low-cost hydrazine as the reducing
agent in combination with a caustic base provides an atom efficient, environmentally friendly
method for the deoxygenation of aldehydes and ketones to alkanes. Due to the required harsh
and corrosive reaction conditions (200 °C, 50 bar), reactor materials such as stainless steel,
glass or any type of polymer have compatibility problems, rendering this process problematic
on production scale. The use of corrosion-resistant silicon carbide (SiC) as the reactor material
opens up the possibility of performing Wolff-Kishner reductions on scale with a considerably
improved safety profile. Methanol as the solvent significantly simplifies the work-up procedure
compared to the generally employed high-boiling solvents such as diethylene glycol. The
continuous flow protocol was applied to a number of substrates and provided the desired
products in good to high yields with space-time-yields of up to 152 g L-1 h-1. In addition, a
pharmaceutically valuable API (active pharmaceutical ingredient) precursor was synthesized
by employing this high-temperature/pressure Wolff-Kishner protocol.
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Keywords: reduction of carbonyls; hydrazine; process intensification; continuous flow; silicon
carbide
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INTRODUCTION
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Hydrazine has been used as a hydrogenation agent in synthetic organic chemistry for more than
a century.1 In particular, employing hydrazine in the presence of a strong base for the conversion
of the carbonyl functionality in aldehydes and ketones into a methylene moiety has attracted
considerable interest and is commonly referred to as the Wolff-Kishner reduction.2-6 The
original protocols require the preformation and isolation of the corresponding hydrazones
which are then added to a hot solution of the base.2,3 Since then, several modifications have
been developed, with the Huang-Minlon modification nowadays being the most frequently used
procedure.7 Compared to the original Wolff-Kishner protocol, the use of hydrazine hydrate ‒
instead of highly explosive anhydrous hydrazine ‒ in the presence of KOH or NaOH in a high
boiling solvent such as diethylene glycol renders the process much safer. In addition, the
isolation of the (sometimes) unstable hydrazone intermediate prior to the actual reduction step
can often be avoided. The Huang-Minlon procedure takes place over three steps (Scheme 1)
and usually requires extended reaction times of several hours. First, the hydrazone is formed
with a large excess of hydrazine hydrate under reflux conditions. To shift the equilibrium
towards the hydrazone intermediate, the temperature is increased in order to remove the
generated water and residual hydrazine hydrate. During the hydrazone formation process, azine
by-product formation via reaction of the hydrazone with the carbonyl compound is often an
issue (Scheme 1).4,5 The third stage involves an irreversible thermal reduction with KOH (>180
°C) including rapid nitrogen liberation.
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R'
R
N
R
N
azine
R'
O
N2H4
R
R'
N2H4
-H2O
H2N
R
O
N
KOH
-N2
R
R'
R
R'
R'
hydrazone
thermal reduction
(high T)
reflux
distillation
3
1
2
.
(removal of H2O + N2H4 H2O)
Scheme 1. Huang-Minlon modification of the Wolff-Kishner reduction.
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Compared to other deoxygenation methods ‒ such as the Clemmensen reduction, use of metal
hydrides with a Lewis acid or metal-catalyzed hydrogenations ‒ the Wolff-Kishner reduction
is probably the most appealing, owing to the low cost and atom efficiency of hydrazine as a
reducing reagent.4 The only chemical waste products formed are environmentally benign water
and nitrogen. However, from an industrial manufacturing point of view this protocol raises
serious concerns regarding safety and reactor material compatibility. Hydrazine hydrate is a
highly toxic, potential carcinogenic and corrosive liquid with a relatively low boiling point (120
°C) considering the required reaction temperature of around 180–200 °C. In particular, the
accumulation of this volatile reaction component in the headspace of a batch reactor can result
in violent explosions.8 Employing continuous flow technology can overcome this limitation by
eliminating gaseous headspace and by reducing the exposure risk for the operator.9,10 Other
benefits, in addition to increased safety are, better process control and product quality, along
with the greater ability to seamlessly translate from lab- to industrial-scale, which significantly
reduces the discovery-to-manufacturing time frame. These advantages are the main drivers for
the pharmaceutical industry to implement continuous processes in active pharmaceutical
ingredient (API) manufacturing.11-16
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Furthermore, continuous reactors provide a wide temperature window, high pressure
resistance, and together with the exceptional mass- and heat-transfer capacity they are perfect
tools for employing intensified conditions (“Novel Process Windows”) on scale.17–20
Temperatures far beyond the atmospheric boiling point of a solvent can be safely attained, and
consequently the reaction rate can often be accelerated. High-temperature/high-pressure (high-
T/p) processes require robust reactor materials and are usually conducted in stainless steel coils
or other special alloys. However, as hydrazine is known to decompose in the presence of metals,
stainless steel should be avoided as reactor material, especially at high temperatures.8 In the
case of the Wolff-Kishner reaction, the use of glass is also not ideal, as the high concentration
of base can cause etching of the glass at elevated temperature.21
In recent years, sintered silicon carbide (SiC) has been increasingly used in organic
synthesis as an alternative to glass or stainless steel as the reactor material.21–24 The chemically
inert and corrosion resistant advanced ceramic material can be utilized at extremely high
temperature due to its high thermal conductivity and very low thermal expansion coefficient
(4.1x10-6K-1).25 Microwave vials made of SiC allow the use of highly corrosive reagents under
high-T/p conditions using microwave heating without degradation of the material.21,22 Flow
reactors made of SiC are already used in the pharmaceutical industry to handle e.g., fluorine
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gas in a safe and scalable manner.23 Notably, Jensen and co-workers developed a custom-made
SiC microreactor (470 L internal volume) for the implementation of Wolff-Kishner reductions
under continuous flow conditions.24 Significantly shortened reaction times and a decreased
hydrazine loading could be achieved by employing an intensified continuous flow approach.
Carbitol (diethylene glycol monoethyl ether) as high boiling solvent (bp. 245 °C) was employed
in their study, thus requiring chromatography to obtain the pure reduced products. Due to the
small internal volume of the reactor, throughputs of only 0.85–9.3 mmol/h could be achieved
with this protocol.
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Herein, we describe a safe and scalable Wolff-Kishner protocol under continuous flow
conditions using a commercially available modular lab-scale SiC reactor, which provides
seamless scale-up capabilities to a manufacturing process.26 To our knowledge, large-scale
Wolff-Kishner reductions have very little literature precedent to date,27-29 presumably due to
the hazards encountered in batch as described above. Therefore, a scalable and safe continuous
flow process is of considerable interest to the pharmaceutical and related chemical industries.
The high-pressure stability of sintered SiC enabled the use of MeOH as a low boiling solvent
in a high-temperature/pressure regime. This solvent switch not only allowed a higher
concentrated substrate feed to be processed and in turn a higher productivity, but also a simple
extractive product isolation procedure due to a higher purity profile.
RESULTS AND DISCUSSION
Optimization in Batch. Before performing Wolff-Kishner reductions in flow, a detailed
optimization study was done in a single-mode microwave batch reactor using sealed 10 mL SiC
reaction vials.21 Optimized conditions could then be translated to a scalable high-T/p continuous
flow process following the “microwave-to-flow paradigm”.30 In 2009, our group reported the
use of SiC as microwave reaction vessel material for the safe use of corrosive reagents in a
high-T/p regime.22 SiC is a strong microwave absorber and rapidly transfers the produced
thermal energy via conduction phenomena to the reaction mixture, which allows uniform
heating to rather high temperatures (up to 300 °C), thereby mimicking autoclave conditions.31
The reduction of α-tetralone (1) to 1,2,3,4-tetrahydronaphthalene (4) was chosen as the
model transformation for a thorough study of the Wolff-Kishner reduction (Scheme 2). Fully
homogeneous reaction mixtures, short reaction times (≤ 30 min) and a high product purity were
the major requirements for the microwave protocol to be translated into a continuous flow
process. To visually inspect the homogeneity of the reaction mixture, preliminary screening
experiments were performed in sealed Pyrex microwave vials.
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.
OH
1.5 equiv N2H4 H2O
H2N
N
O
3 equiv KOH or NaOH
N
N
8
9
2 mL solvent
4
5
170-190 °C, 30 min
1
2
3
side-product
-tetralone
hydrazone
azine
desired product
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Scheme 2. Wolff-Kishner reduction of α-tetralone in a microwave batch reactor.
We initially performed a solvent screen in order to identify reaction conditions amenable to
flow processing. Typically, a 0.6 M solution of α-tetralone in the respective solvent, 3 equiv of
KOH and 1.5 equiv of N2H4•H2O were heated at 170 °C for 30 min in a single-mode microwave
reactor employing a fiber optic sensor for internal temperature control.31 Hydrazone 2 and azine
3 intermediates, product 4 as well as alcohol 5 as a side product were detected via HPLC
analysis (Scheme 2). This screening revealed that hydroxylic solvents showed the highest
reactivity toward the reduction of model substrate 1 (see Table S1, Supporting Information).
These results were in good agreement with the mechanism proposed by Szmant, which indicates
that the hydroxyl group of the solvent plays an important role in the reduction mechanism.32 As
expected, all typical Wolff-Kishner solvents such as ethylene glycol, diethylene glycol and
carbitol provided homogenous reaction mixtures. Carbitol showed the highest conversion to the
desired product 4 (67%), however the high boiling point of the solvent (245 °C) and low product
purity (17% unidentified impurities) diminished its suitability for our purposes. Among the low-
boiling solvents, MeOH proved to be the best; it provided homogenous reaction mixtures and
highest conversion to 4 (53%) and an optimum purity profile (only 2% alcohol 5). We therefore
considered MeOH as the solvent of choice for the prospective flow process. Further
optimizations were conducted using this solvent with respect to temperature and reaction time,
type of base, reagent stoichiometry and concentration for the reduction of α-tetralone (1). As
expected, the high reaction temperature (170 °C) in conjunction with a strong base resulted in
significant etching of the glass vessels after single use.21 For this reason, all further experiments
where performed in SiC microwave vials.
Increasing the temperature to 190 °C resulted in a significantly higher conversion
reaching 86% after 40 min (Figure 1). Owing to the large amount of N2 gas evolved during the
reaction and the high vapor pressure of MeOH, the pressure limit of the microwave reactor
(30 bar) was reached at this temperature. NaOH provided a slightly increased substrate
conversion compared to KOH and NaOMe (see Table S2, Supporting Information). Further
investigation on the reagent stoichiometry showed that 1.5 equiv of N2H4•H2O and 3.0 equiv of
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NaOH presented the optimum with respect to conversion and reagent economy (see Table S3,
Supporting Information).
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Figure 1. Process intensification for the reduction of α-tetralone (1) in microwave batch.
Conditions: 1.6 mmol α-tetralone (1), 3 equiv KOH, 1.5 equiv N2H4•H2O, 2 mL MeOH, 10 mL
SiC vessel. (a) Temperature screening, keeping the reaction time constant at 30 min; (b)
Reaction time screening, keeping the temperature constant at 190 °C.
A significant improvement of the conversion to the desired product 4 could be achieved by an
increase in concentration (Table 1): 87% (0.6 M) vs 97% (1.0 M). The concentration could be
raised to 1.4 M, however, a further increase was again restricted by the operational pressure
limit of the microwave reactor (see Figure S1, Supporting Information). Best results could be
achieved by microwave irradiation of 0.8–1.0 M solutions of substrate 1 in MeOH with 1.5
equiv of N2H4•H2O and 3 equiv of NaOH for 30 min at 190 °C. Under these optimized
conditions the reduction of α-tetralone (1) proceeded to completion and tetrahydronaphthalene
4 could be isolated in 79% yield (containing 2% of alcohol as side-product) after the addition
of water and extraction with cyclohexane.
Table 1. Microwave-Batch Optimization of Substrate Concentrationa
entry
conc
pressure
product 4
[%]c
substrate 1 intermediates 2+3 alcohol 5
[mol/L] [bar]b
[%]c
[%]c
[%]c
1
2
3
0.6
1.0
1.4
26.7
24.6
31.6
87
<1
10
3
97
95
<1
<1
<1
2
3
3
a Conditions: α-tetralone (1), 3.0 equiv NaOH, 1.5 equiv N2H4•H2O, 2 mL MeOH, 30 min at 190 °C,
FO temperature measurement, 10 mL SiC vessel.
b Maximum pressure measured in the sealed microwave vessel
c Determined by HPLC peak area integration at 215 nm
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Observed Side Reactions. In an attempt to improve the purity profile of the reaction, we further
investigated the formation of side products and insoluble intermediates. Hydrazone 2 is known
to react with the substrate 1 to give azine 3,5 however, this process is reversible at high
temperatures in the presence of hydrazine (see Figure 1). Nevertheless, formation of azine 3
was identified as problematic since it precipitates at room temperature and could potentially
cause clogging in the flow system. Less problematic with respect to continuous flow processing
is the base-mediated formation of secondary alcohol 5 as side product. The reduction of the
carbonyl to the corresponding alcohol seems to be competitive to the hydrazone formation.
Although the possibility cannot be ruled out that alcohol is generated in the presence of
hydrazine (reduction in the presence of O2 via diimide),33 experiments have shown that its
formation is mainly driven by the base. Considerable amounts of alcohol 5 were formed by
heating substrate 1 in the presence of 3 equiv of NaOH in different solvents without the addition
of hydrazine hydrate (Table 2). Furthermore, the amount of alcohol 5 formed during the reaction
is strongly dependent on the solvent. A clear trend with respect to hydride donating capacity of
the alcoholic solvent could be observed: iPrOH > EtOH > MeOH (Table 2). A plausible
mechanism for the formation of the secondary alcohol involves intramolecular hydride transfer
similar to a Meerwein-Ponndorf-Verley type mechanism.34–36 It has to be noted, that alcohol
formation could be suppressed by preformation of the hydrazone and subsequent addition of
base. However, this was generally not necessary when MeOH was used since only 2% of
alcohol 5 was formed in the one-pot Wolff-Kishner reduction.
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Table 2. Influence of Solvent on Alcohol Formation.a
OH
O
3 equiv NaOH
solvent
MW, 190 °C, 30 min
1
5
entry solvent substrate 1 alcohol 5 unidentified impurities
[%]b
[%]b
[%]b
1
2
3
4
MeOH
EtOH
49
-
-
51
56
4
44
53
20
i-PrOH
carbitol
43
26
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a Conditions: 1.2 M α-tetralone (1), 10 mL SiC vessel
b Determined by HPLC peak area integration at 215 nm
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Continuous Flow Reduction. Next, we turned our attention to the translation of the optimized
batch microwave protocol toward a continuous flow process. In order to prove the necessity of
SiC as reactor material, a control experiment was performed using a stainless steel reactor coil
(Uniqsis, FlowSyn).37 As expected, immediate gas formation owing to the decomposition of
hydrazine to nitrogen and water or ammonia was observed at the reactor outlet when pumping
a solution of N2H4•H2O in MeOH at 150 °C through the reactor.8 Consequently, all further
experiments were performed employing a commercially available modular plate-based SiC
flow reactor platform (Chemtrix, Protrix).26
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To evaluate the performance of the continuous flow set-up, initial experiments were
conducted using carbitol as the solvent. This allowed the performance of our system to be
directly compared to the published microreactor procedure by Jensen,24 and the high boiling
point of carbitol (245 °C) allowed the use of a relatively low back pressure (15–20 bar), which,
for safety reasons, was preferred for an initial validation of the system. The starting conditions
were based on those reported by Jensen and co-workers.24 The feed solution, containing α-
tetralone (0.8 M), 3.0 equiv KOH, 1.5 equiv N2H4•H2O and carbitol, was pumped into the
reactor from a sample loop by a high-pressure syringe pump (HiTec Zang, Syrdos) with a flow
rate of 0.5 mL/min to achieve a calculated residence time of 14 min (Figure 2). The mixture
went through a 6.91 mL reaction zone consisting of two SiC plate modules at 200 °C.
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O
5
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+
.
N2H4 H2O, KOH/NaOH
solvent
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190-200 °C
< 45°C
BPR
SL
(4 mL)
6.91 mL
3.61 mL
solvent
N2 + H2O
Figure 2. Schematic overview of the continuous flow set-up for initial optimization studies of
the Wolff-Kishner reduction using a modular SiC reactor. For further details, see the Supporting
Information, Figures S2-S3.
Before the processed mixture left the system through an adjustable back pressure regulator
(BPR, set to 15–20 bar) it was cooled down to 40–50 °C in an additional SiC module (3.61 mL)
serving as cooling zone. It should be noted, that the actual residence time was lower than the
calculated one due to the expulsion of N2 gas during the reaction. Therefore, residence times
had to be experimentally determined.38 Initial experiments were performed using a 1 mL sample
loop (SL) and the system pressure was maintained by using an adjustable BPR (Swagelok, 0–
70 bar). Surprisingly, the reaction outcome was neither comparable to the reported one24 nor to
the microwave batch experiment (Table 3, entry 1 vs. 2). This could be attributed to dispersion
issues caused by the small sample loop inserted in the feedline. By simply changing the 1 mL
SL to a 4 mL SL, the reaction performance could be significantly improved from 49% to 74%
(Table 3, entries 2, 3). However, neither the larger sample loop nor a longer residence time
could drive the reaction to completion. We assumed that the large inner volume of the BPR (ca
4 mL) in combination with the low flow rates might be the reason for the lower conversion and
unstable product distribution (Table 3, entries 2–5, see also Figure S4, Supporting Information).
The reaction mixture is accumulated inside the BPR, and due to the large amount of N2 gas, it
is pushed out uncontrollably, which in turn resulted in a pressure drop. Furthermore, the large
inner volume led to diffusion inside the BPR. Indeed, by employing a different adjustable BPR
(Chemtrix, 0–60 bar) with an inner volume of only 0.16 mL, the hold-up problem could be
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overcome, and the reaction was driven to full conversion to give 91% of 4 and 9% of 5 (Table
3, entry 6). This result corresponds well to the 78% isolated yield reported by Jensen and co-
workers.24
7
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9
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Table 3. Continuous Flow Optimization Study using Carbitol as the Solvent.
.
OH
H2N
1.5 equiv N2H4 H2O
O
N
3 equiv KOH
N
N
Carbitol
15-20 bar
0.8 M
4
1
2
3
5
VSL
tres
flow rate
T
product 1+2+3
alcohol
5 [%]b
other
[%]b
entry
[mL] [min]a [mL/min] [°C]
4 [%]b
[%]b
Batch
MW
1
-
15
200
86
-
10
4
2c
3c,d
4c
1
4
4
4
4
4
4
-
12
9
0.5
200
200
200
200
200
200
210
200
49
74
88
87
91
76
91
91
37
17
5
14
9
-
-
-
-
-
-
-
-
0.5
12
18
12
9
0.38
0.25
0.38
0.5
7
5c
5
8
6e
<1
17
<1
<1
9
7d,e
8e
7
8
0.5
9
9e,f
11
0.38
9
a Estimated by observing the total residence time in the reactor (visual inspection)
b Determined by HPLC peak area integration at 215 nm
c Swagelok BPR
d Conditions according to Ref 23
e Chemtrix BPR
f Steady state conditions: ~ 15 mL feed, direct injection through pump (Syrris, Asia), 15 bar
Having a reliable continuous flow set-up, we aimed to increase the throughput of the reaction
by increasing the flow rate to 0.5 mL/min. Again, the shorter residence time diminished the
reaction performance and only a 76% conversion to the product could be achieved (Table 3,
entry 7). Only an increase in temperature to 210 °C at the same flow rate led to full conversion
(Table 3, entry 8). However, since 200 °C is the recommended temperature limit for this specific
configuration of the Protrix SiC reactor (see Experimental Section) we decided to refrain from
employing temperatures >200 °C in all subsequent experiments. Increasing the productivity by
enhancing the substrate concentration also remained unsuccessful due to limited solubility of
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KOH in carbitol. A steady-state continuous flow experiment was conducted under conditions
that provided the best results (Table 3, entry 9). Therefore, the feed solution was directly
pumped through the reactor system and pure tetrahydronaphthalene 4 was isolated after column
chromatography in 66% yield (806 mg) which corresponds to a throughput of 1.6 g/h.
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Employing Methanol as the Solvent. Switching from carbitol (bp 245 °C) to MeOH (bp 65 °C)
at reaction temperatures around 200 °C for a Wolff-Kishner reduction obviously requires a
significantly higher back-pressure owing to the high vapor pressure of MeOH (38 bar at 200
°C). To ensure safe operation of the highly corrosive mixtures at these extreme temperatures
and pressures a customized high-T/p version of the Protrix SiC reactor was provided by the
manufacturer (see Experimental Section for details). After a careful validation of this reactor
system under intensified conditions, we were confident in operating up to 50 bar and 200 °C.
Our initial conditions for the Wolff-Kishner reduction studies were based on the previously
optimized batch protocol (see Table 1, entry 2). The same set-up as described in Figure 2 was
employed, and the feed solution containing α-tetralone (1), 1.5 equiv of N2H4•H2O and
3 equiv of NaOH in MeOH was pumped into the reactor from a 4 mL sample loop by a high-
pressure syringe pump (HiTec Zang, Syrdos) with a flow rate of 0.2 mL/min. We commenced
our investigation by evaluating the minimum required back pressure to provide a controlled
outlet stream. At 190 °C a back pressure of 40 bar (Table 4, entry 2) was sufficient to provide
a stable flow. However, the resulting residence time of 25 min at 190 °C turned out to be too
short to provide full conversion. A reaction temperature of 200 °C and a system pressure of
50 bar was required to achieve full conversion and a stable flow (Table 4, entry 4).
Table 4. Fine-Tuning of Conditions using Methanol as the Solvent.
.
1.5 equiv N2H4 H2O
3 equiv NaOH
H2N
O
OH
N
N
N
MeOH
SL: 4 mL
4
5
1
3
2
entry
conc
tres
pressure flow rate
T
product 1+2+3
alcohol
5 [%]a
[mol/L] [min]a
[bar]
[mL/min] [°C]
4 [%]a
[%]a
Batch
190
1
2
1.0
1.0
25
25
30
91
7
2
2
MW
40
0.2
190
87
11
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1.0
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45
50
0.2
0.2
200
200
95
96
2
3
4
<1
7
8
9
a Estimated by observing the total residence time in the reactor (visual inspection)
b Determined by HPLC peak area integration at 215 nm
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Since the productivity could not be further improved by increasing the flow rate, a higher
substrate concentration was pursued. It was assumed that a larger amount of N2 gas formed
from the higher concentrated reaction mixtures could potentially lead to unstable residence time
distributions. Those reactions, therefore, were performed under steady state conditions by
directly pumping the reaction mixture into the system, omitting the sample loop. By the
increased run-time a more stable system was achieved. As expected, the residence time
decreased noticeably by increasing the concentration of the feed, while the high conversion was
maintained up to a substrate concentration of 1.6 M (Table 5). Unfortunately, due to the large
amount of generated N2 gas, we did not achieve a controlled outlet stream for a 1.6 M solution
at 50 bar. At a 1.3 M substrate concentration, though, a reliable and safe collection of product
at the outlet was still guaranteed (Figure 3) and tetrahydronaphthalene 4 could be isolated in
81% yield (Table 5, entry 2). Even though the reaction time compared to the solvent carbitol
was longer (22 vs 11 min), MeOH provided a slightly higher productivity (1.7 vs 1.6 g/h), a
much better purity profile and most importantly a significantly simplified work-up procedure
(extraction vs chromatography). Compared to the previously reported work,24 the productivity
could be increased by a factor of 10.
Table 5. Steady State Experiments in Methanol.a
entry
conc
tres
product 1+2+3 alcohol yield purity productivity
[mol/L] [min]b 4 [%]c
[%]c
<1
2
5 [%]c [%]d
[%]c
[g/h]
1
2
3
1.0
1.3
1.6
25
22
21
96
95
95
4
3
4
80
81
81
96
1.3
95
1.7
1
95
2.1
a Conditions: α-tetralone (1), 1.5 equiv N2H4•H2O, 3 equiv NaOH, 12 mL MeOH, 200 °C, 50 bar,
0.2 mL/min
b Estimated by observing the total residence time in the reactor (visual inspection)
c Determined by HPLC peak area integration at 215 nm
d Isolated yield
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0
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10 11 12 13
Fraction No
Figure 3. Product distribution of the steady state experiment at a 1.3 M concentration of -
tetralone (1). Fractions were collected at 7 min intervals.
Substrate Scope. To investigate the applicability of the continuous Wolff-Kishner reduction in
MeOH, a set of aldehydes and ketones was pre-screened under batch microwave conditions
with respect to homogeneity and substrate/product stability. Most of the selected ketones
underwent full conversion to the corresponding alkane under the conditions used for model
substrate 1 in batch and could thus be easily translated to the optimized flow conditions (Table
6, entries 1–5). Aldehydes, on the other hand, reacted relatively fast at room temperature with
hydrazine in the presence of base which resulted in precipitation of the respective hydrazone.
Therefore, the flow set-up had to be modified for a two-feed approach (Figure 4). Due to the
modularity of the SiC reactor, the needs of various reaction conditions/types can be easily
addressed by employing different mixing- and residence time units (see Experimental Section
and the Supporting Information for more details). For the reduction of the aldehydes, the same
SiC modules as for the single feed system could be used, but an additional reaction channel was
utilized. A 2 M solution of substrate with 1.5 equiv of N2H4•H2O in MeOH was introduced via
a 4 mL sample loop (Feed 1), and in a 0.54 mL residence time unit the hydrazone intermediate
was pre-formed (2.7 min residence time). Then, the feed containing the 6 M NaOH (3 equiv)
in MeOH was introduced into the reactor plate. The combined mixture then passed through the
6.91 mL reaction zone with a nominal total flow rate of 0.4 mL/min. Before the processed
mixture left the system through the BPR it was cooled down to 40–50°C in an additional cooling
zone. In this way, also aldehydes could be reduced successfully under continuous conditions
using MeOH as the solvent.
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4
O
1.5 equiv
N2H4 H2O
+
.
5
6
7
R
2 M
H
200 °C
< 45°C
BPR
8
9
FEED 1
R
H
4 mL SL
0.2 mL/min
MeOH
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50 bar
0.2 mL/min
NaOH in MeOH
(6 M)
FEED 2
Figure 4. Continuous flow set-up for the reduction of aldehydes employing a two-feed system.
A small set of different ketones and aldehydes were successfully reduced and isolated by simple
extraction in good yields and sufficient purities (Table 6). In the case of benzophenone (9) only
80% purity could be achieved due to formation of 20% alcohol as side product (Table 6, entry
5). Reduction of halogenated ketones was also attempted. However, dehalogenation and several
other side reactions, resulting in insufficient purities, were experienced in the MW optimization
studies (see Table S4, Supporting Information). It should be noted that the focus of the substrate
scope was on simple, generic structures of ketones and aldehydes similar to AstraZeneca´s API
substructure (vide infra). Therefore, no further optimizations toward those substrates to improve
the process nor a further extension of the substrate scope with respect to functional groups was
pursued.
Table 6. Substrate Scope for the Continuous Wolff-Kishner Reduction.
product
[%]b
yield
[%]c
purity
[%]b
entry
substrate
O
1
96
86
80
81
96
93
1
O
MeO
2
6
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O
5
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N
3
92
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9
O
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4
5
97
80
70
75
>99
80
NH
8
O
9
O
6
7
>99
>99
82
87
>99
>99
H
O
10
MeO
H
OMe
11
a Conditions: entries 1–5: 1.0 M substrate, 1.5 equiv N2H4•H2O, 3 equiv NaOH, MeOH, 200 °C, 50 bar,
0.2 mL/min, 8 mL sample loop; entries: 6–7: Feed 1: 2.0 M substrate, 1.5 equiv N2H4•H2O, MeOH, 0.2
mL/min, 4 mL sample loop; Feed 2: 6.0 M NaOH in MeOH, 0.2 mL/min; 200 °C, 50 bar
b Determined by HPLC peak area integration
c Isolated yield
Synthesis of a Precursor of AZD4573. Pyrazole 13 is a key intermediate in the preparation of
AZD4573, which has been demonstrated to be a potent CDK9 inhibitor. AZD4573, developed
by AstraZeneca, is currently in Phase 1 clinical trials as an investigational treatment for
hematological malignancies.39 The disclosed batch procedure for the preparation of pyrazole
13 is treatment of ketone 12 with 5 equiv of N2H4•H2O in diethylene glycol at 180 °C for 1 h
followed by the thermal reduction with 3.5 equiv of KOH at 150 °C for 2 h providing 40%
product yield.40 A one-pot approach was tested in preliminary microwave batch experiments,
however, a significant amount of 22% of alcohol as side product was detected by HPLC.
Therefore, the two feed approach developed for aldehydes (see Figure 4) was employed for the
continuous synthesis. We were able to significantly decrease the overall reaction time to less
than 20 min and reduce the hydrazine loading to 1.5 equivalents. The desired key intermediate
13 could be obtained in 80% yield and >99% purity after extraction with water and diethyl
ether.
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N N
5
6
7
8
H2N
N
O
Cl
.
N2H4 H2O
O
NaOH
H
N
9
N
N
N
N
N
N
N
N
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MeOH
H
12
O
13
AZD4573
80% yield
Scheme 3. Reduction of a key intermediate for AZD4573.
Long run. The reduction of α-tetralone (1) was used as a model reaction to demonstrate the
productivity of the reactor over an 8 h working day. First, investigations on the stability of the
feed solution in MeOH were performed. Studies at different temperatures have shown that
reaction mixtures in MeOH stayed homogenous over a period of 30 h at room temperature,
however, slow formation of hydrazone 2 and azine 3 was detected (see Figure S8, Supporting
Information). By decreasing the storage temperature to 4 °C the formation of 2 could be
minimized and generation of 3 prevented. For the actual experiment, therefore, the feed
solutions were freshly prepared every 1.5 h and stored between 0–10 °C to keep the hydrazone
below 5% in the feed.
For this proof-of-concept study, the reaction conditions of the optimization study (see
Table 5, entry 2) were applied. A solution containing 1.3 M α-tetralone in MeOH, 3 equiv of
NaOH and 1.5 equiv of N2H4•H2O was pumped through the reactor with a flow rate of
0.2 mL/min that provided an estimated residence time of approximately 22 min. After reaching
steady state, >95% product in the presence of less than 5% alcohol 5 was observed by HPLC
in all 9 analytical samples that were taken every hour over the 8 h runtime. In total, the reaction
performed to an identical standard compared to the steady state experiment (see Table 5, entry
2). The amount of residual hydrazine in the product stream was determined by taking an aliquot
that was mixed with benzaldehyde as derivatization reagent. According to calibrated UPLC
analysis, 0.43 equiv of residual N2H4 were detected in the product mixture indicating that 1.07
equiv of N2H4 were consumed during the reaction and highlighted no decomposition when
using sintered SiC as a reactor material (for further details, see the Supporting Information).
Since the outlet stream is cooled to ca. 45 °C, which is far below the boiling point (120 °C) and
flash point (74 °C) of hydrazine hydrate, standard precautions were sufficient, and unconsumed
hydrazine was depleted with hydrogen peroxide.28,41 Alternatively, commercial bleach (5%)
could also be employed to rapidly quench hydrazine. 28,41
In total, 96 mL of reaction mixture was processed, resulting in 12.9 g (81% yield) of
1,2,3,4-tetrahydronaphthalene (4) after extraction. This corresponds to a productivity of 1.6 g/h
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(12.2 mmol/h) and a space-time yield of 152 g L-1 h-1. A significant advantage of the Protrix
reactor is that processes developed on lab-scale can be directly transferred to a production scale
reactor (Plantrix), maintaining corrosion resistance and thermal control.42 The performance of
the reactor should remain unchanged by keeping heat and mass transfer parameters constant
(“smart dimensioning”).43 While not explored in this study, the use of such a large-scale reactor
with an internal volume of 2.35 L would allow the production of 13.7 kg material per day, and
thus fully exploit the potential of this atom economic reduction process.
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CONCLUSION. In summary, we have developed a safe and scalable methodology for the
Wolff-Kishner reduction. Key to the success was the use of a continuous flow reactor made of
SiC, which enabled the use of hydrazine hydrate and caustic bases at very high temperatures
and pressures. Hydrazine hydrate is extremely dangerous to handle at high temperature on a
production scale, since it is volatile, toxic and highly explosive as a gas. The laboratory-scale
continuous flow process presented herein eliminates the risk of violent explosion in the
headspace of a batch reactor and, thus, offers the promise to scale-up the process in a safe
manner. Furthermore, elimination of headspace increases the concentration of the volatile
hydrazine in the liquid phase, and, in contrast to batch, a large excess of hydrazine can be
avoided.24 The use of MeOH as the solvent can be expected to be an additional factor in cost
and time savings, in particular with respect to work-up. Due to the higher purity profile and the
straightforward removal of MeOH by simple evaporation, isolation of the alkanes could be
simplified via an extractive work-up procedure, which opens the possibility of a fully integrated
Wolff-Kishner reduction, utilizing in-line extraction strategies. A single feed protocol, which
can be applied for substrates that are not prone to fast hydrazone formation was established. In
addition, a two feed process allowing pre-formation of hydrazone before the addition of base
was developed. The methodology also proved to be suitable for the synthesis of an API
intermediate from AstraZenca. Finally, a long run of the reduction of -tetralone as model
substrate was performed. This strategy enabled the production of 13 g material over 8 h,
demonstrating a stable system over that time period. In order to manufacture sufficient
quantities for industrial applications scaling-up the reactor volume for implementing higher
flow rates is a common method.43
EXPERIMENTAL SECTION
General Remarks. All chemicals, solvents, catalysts and ligands were purchased from
commercial suppliers and were used without any further purification. If not stated otherwise,
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reagents were weighed and handled in air at room temperature. 1H NMR spectra were recorded
on a Bruker 300 MHz instrument. 13C NMR spectra were recorded on the same instrument at
75 MHz. Chemical shifts (δ) are expressed in ppm downfield from TMS as internal standard.
The letters s, d, t, q, and m are used to indicate singlet, doublet, triplet, quadruplet, and multiplet.
Analytical HPLC (Shimadzu LC20) analysis was carried out on a C18 reversed-phase (RP)
analytical column (150 x 4.6 mm, particle size 5 μm) at 37 °C using a mobile phase A
(water/acetonitrile 90:10 (v/v) + 0.1 % TFA) and B (MeCN + 0.1 % TFA) at a flow rate of 1.5
mL min−1. The following gradient was applied: linear increase from solution 30 % B to 100 %
B in 10 min. GC-MS spectra were recorded using a Thermo Focus GC coupled with a Thermo
DSQ II (EI, 70 eV). A HP5-MS column (30 m × 0.250 mm × 0.025 μm) was used and helium
was the carrier gas (1 mL min−1 constant flow). The injector temperature was set to 280 °C.
After 1 min at 50 °C, the temperature was increased in 25 °C min−1 steps up to 300 °C and kept
at 300 °C for 4 min. UPLC-DAD (Shimadzu Nexera X2) analysis was carried out on a
Phenomenex Luna Omega C18 column (50 mm × 2.1 mm; 1.6 µm particle size; pore size 100
Å) at 45 °C using mobile phase A (water/acetonitrile 90:10 (v/v) + 0.1 % TFA) and B (MeCN
+ 0.1 % TFA) at a flow rate of 0.7 mL min–1. The following gradient was applied: linear increase
from solution 30 % B to 100 % B in 2.5 min. UPLC-DAD calibration curves were measured
for benzaldehyde for quantitative determination of residual hydrazine. Microwave irradiation
experiments were carried out in a Monowave 400 single-mode microwave reactor (Anton Paar)
using 10–30 mL borosilicate Pyrex vials and 10 mL SiC vials. The reaction temperature was
monitored either by an internal fiber optic sensor (SiC) or by an external infrared sensor (Pyrex)
measuring the surface temperature of the reaction vial. Reaction times refer to hold times at the
temperature indicated, not to total irradiation times. The stirring speed was set to 800 rpm.
Column chromatography was carried out using an automated flash chromatography system
(Biotage, Isolera) using cyclohexane/ethyl acetate mixtures as eluent.
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Protrix SiC Reactor. Protrix is a silicon carbide (SiC) flow reactor that is used for process
development and small-scale production. The Protrix holder contains 3MTM SiC modules that
can be flexibly configured (in terms of number and type) to deliver the required number of
reagent inputs, reaction volume and temperature zones (Figure S5, Supporting Information).
Each SiC module is fabricated from 3MTM SiC grade C and contains the process channel and
an integrated heat exchange layer to give optimal thermal control. The SiC layers are diffusion
bonded to give a gas-tight, metal-free flow path with high chemical compatibility (Figure S6,
Supporting Information). The flow path proceeds in series between the modules and the heat
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exchange layers are arranged in parallel; the SiC modules are connected in the holder using
FFKM O-rings. For the high-T/p experimentation described herein, the system was modified
from the standard system and used a GF PEEK interconnector plate to create two temperature
zones in the flow path. The standard FFKM O-rings were replaced with Chemraz Type 605.
The Protrix flow reactor comprised of two temperature zones (Figure S7, Supporting
Information), the first for the reaction and the second for safe cooling of the reaction mixture
prior to collection at the outlet: T1 = MRPX+MRPA (volume = 6.9 mL) and T2 = MRPA (3.6
mL).
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Reagent flow was controlled via high-pressure SyrDos (HiTec Zang) syringe pumps and
the feedlines were constructed from PFA, containing pressure relief assemblies (set to 5 bar
above the BPR setpoint). An adjustable BPR was positioned at the outlet of the flow reactor to
allow a range of pressures (0–60 bar) to be evaluated. For optimization experiments a sample
loop (4 to 8 mL) was employed. Wetted materials used in the flow path were PFA, ETFE,
PCTFE, FFKM (Chemraz 605), PTFE, 3MTM SiC.
Thermal control of the reaction step was achieved using a thermostat (CC304B, Huber)
with a re-circulating thermal fluid (P20.275.50) and the reaction mixture was cooled to 40 °C
in the second thermal zone using re-circulating DI H2O. Reaction products were collected in a
vial prior to analysis and/or subsequent work-up. As shown in Figure S3 (Supporting
Information), the apparatus was operated within a fume hood and behind a safety blast shield
at all times.
CAUTION: Hydrazine hydrate should be treated with extreme caution. It is potentially
explosive in its pure and undiluted form. In addition, it is toxic by inhalation or contact with
skin or eyes. Therefore, contact in any form should be avoided. Hydrazine is likely to be present
under these high temperature conditions, and particular care should be taken to avoid contact
with any vapors or liquids. All reactions should be carried out in an efficient fumehood, the
reactor should be placed in a spill tray and a safety blast shield should be used. Laboratory
personnel working with N2H4•H2O must familiarize themselves with the potential hazards and
prevention measures. Prior to performance of any high temperature and high-pressure flow
reaction, the apparatus must be checked with an inert solvent to ensure correct functionality of
all valves and safety infrastructure.
Optimized Microwave Procedure for the Reduction of α-Tetralone (1). To a 10 mL SiC
microwave process vial equipped with a magnetic stirring bar were added α-tetralone (266 µL,
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2.0 mmol), NaOH (240 mg, 6.0 mmol, 3 equiv), N2H4•H2O (146 µL, 3.0 mmol, 1.5 equiv) and
2 mL of MeOH. The vial was sealed with a snap cap and heated for 30 min at 190 °C. A fiber
optic sensor was used for internal temperature control. After the reaction time elapsed, the
mixture was cooled to 55 °C, and an aliquot was taken for HPLC analysis.
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General Flow Procedure for the Reduction of α-Tetralone (1) in Carbitol. After KOH
(538 mg, 9.6 mmol, 3.0 equiv) was dissolved in 3 mL carbitol in an ultrasound bath, α-tetralone
(426 µL, 3.2 mmol) and hydrazine hydrate (234 µL, 4.8 mmol, 1.5 equiv) were added and the
total volume was brought to 4 mL by dropwise addition of carbitol. The flow reactor was
equilibrated with carbitol at 200 °C and the BPR was adjusted to 15 bar. The feed was
introduced into the reactor via a sample loop (PFA, 0.8 mm i.d., 1.59 mm o.d.; internal volume:
4 mL) and pumped through at 0.38 mL/min using a Syrris Asia syringe pump. Fractions were
collected from the reactor output and an aliquot was taken for HPLC analysis.
Steady State Reaction and Isolation Procedure for Carbitol (Table 3, entry 9).
After KOH (1.9 g, 36.0 mmol, 3.0 equiv) was dissolved in 10 mL carbitol in an ultrasound bath,
α-tetralone (1.6 mL, 12.0 mmol) and N2H4•H2O (874 µL, 18.0 mmol, 1.5 equiv) were added.
The flow reactor was equilibrated with carbitol at 200 °C and the BPR was adjusted to 15 bar.
The feed was pumped through at 0.38 mL/min using a Syrris Asia syringe pump. Fractions
were collected from the reactor output and an aliquot was taken for HPLC analysis. 30 mL of
water were added to the combined fractions and the mixture was extracted with 3 x 30 mL
cyclohexane. Hydrogen peroxide was added to the aqueous phase in order to quench residual
hydrazine. The combined organic phase was dried over Na2SO4. After evaporation of the
solvent, the crude product was loaded onto a Biotage silica sample with cyclohexane and purified
by flash chromatography using a 10 g SNAP cartridge and cyclohexane/ethyl acetate as eluent. The
desired fractions were combined, and the solvent was evaporated under reduced pressure to provide
806 mg (66 %) of pure product 4 as a slightly yellow oil.
General Flow Procedure for the Reduction of α-Tetralone (1) in MeOH. NaOH (480 mg,
12 mmol, 3 equiv) was dissolved in 3 mL MeOH, α-tetralone (532 µL, 4 mmol) and N2H4•H2O
(292 µL, 6 mmol, 1.5 equiv) were added and the total volume was brought to 4 mL by dropwise
addition of MeOH. The flow reactor was equilibrated with MeOH at 200 °C and the BPR was
adjusted to 50 bar. The feed was introduced into the reactor via a sample loop (PFA, 0.8 mm
i.d., 1.59 mm o.d.; internal volume: 4 mL) and pumped through at 0.2 mL/min using a HiTec
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Zang SyrDos (90 bar) syringe pump. Fractions were collected from the reactor output and an
aliquot was taken for HPLC analysis.
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Steady State Reaction and Isolation Procedure for Methanol (Table 5, entry 2).
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NaOH (1.9 g, 46.8 mmol, 3.0 equiv) was dissolved in 12 mL MeOH, α-tetralone (2.1 mL,
15.6 mmol) and N2H4•H2O (1.1 mL, 23.4 mmol, 1.5 equiv) were added. The flow reactor was
equilibrated with MeOH at 200 °C and the BPR was adjusted to 50 bar. The feed was pumped
through at 0.2 mL/min using a HiTec Zang SyrDos (90 bar) syringe pump. Fractions were
collected from the reactor output and an aliquot was taken for HPLC analysis. 60 mL of water
were added to the combined fractions and the mixture was extracted with 3 x 50 mL
cyclohexane. Hydrogen peroxide was added to the aqueous phase in order to quench residual
hydrazine. The combined organic phase was dried over Na2SO4 and the solvent was evaporated
under reduced pressure to provide 1.7 g (81 %) of pure product 4 as a slightly yellow oil.
General Flow Procedure for the Substrate Scope.
1-Feed Approach. NaOH (840 mg, 21 mmol, 3 equiv) was dissolved in 7 mL MeOH then
substrate (7 mmol) and N2H4•H2O (511 µL, 10.5 mmol, 1.5 equiv) were added. The flow
reactor was equilibrated with MeOH at 200 °C and the BPR was adjusted to 50 bar. The feed
was introduced into the reactor via a sample loop (PFA, 0.8 mm i.d., 1.59 mm o.d.; internal
volume: 8 mL) and pumped through at 0.2 mL/min using a HiTec Zang SyrDos (90 bar) syringe
pump. The effluent was collected from the reactor output and an aliquot was taken for HPLC
analysis. 30 mL of water were added to the combined fractions and the mixture was extracted
with 3 x 30 mL cyclohexane or diethyl ether. Hydrogen peroxide was added to the aqueous
phase in order to quench residual hydrazine. The combined organic phases were dried over
Na2SO4. Evaporation of the solvent under reduced pressure provided the product.
2-Feed Approach. The flow reactor was equilibrated with MeOH at 200 °C and the BPR was
adjusted to 50 bar. A solution of substrate (8 mmol) and N2H4•H2O (584 µL, 12 mmol,
1.5 equiv) in 4 mL MeOH (2.0 M) was injected via a sample loop (PFA, 0.8 mm i.d., 1.59 mm
o.d.; internal volume: 4 mL). After a 0.54 mL residence time unit, feed 1 was combined with
the second liquid feed containing 6.0 M NaOH in MeOH (3 equiv). Both feed solutions were
pumped at 0.2 mL/min each using HiTec Zang SyrDos (90 bar) syringe pumps. The effluent
was collected from the reactor output and an aliquot was taken for HPLC analysis. 30 mL of
water were added to the combined fractions and the mixture was extracted with 3 x 30 mL
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cyclohexane or diethyl ether. Hydrogen peroxide was added to the aqueous phase in order to
quench residual hydrazine. The combined organic phases were dried over Na2SO4. Evaporation
of the solvent under reduced pressure provided the product.
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Long Run. The flow reactor was equilibrated with MeOH at 200 °C and the BPR was adjusted
to 50 bar. A solution containing 1.3 M α-tetralone 1 in MeOH, 3 equiv NaOH and 1.5 equiv
N2H4•H2O was pumped through at 0.2 mL/min using a HiTec Zang SyrDos (90 bar) syringe
pump. The feed solutions were freshly prepared every ~1.5 h and kept between 0–10 °C. After
44 min steady state was reached and fractions were collected from the reactor output across an
8 h runtime and aliquots were taken for HPLC analysis. 350 mL of water were added to the
combined fractions and the mixture was extracted with 3 x 250 mL cyclohexane. Hydrogen
peroxide was added to the aqueous phase in order to quench residual hydrazine. The combined
organic phase was dried over Na2SO4 and the solvent was evaporated under reduced pressure to
provide 12.9 g (81 %) of pure product 4 as a slightly yellow oil.
Long-run 1,2,3,4-Tetrahydronaphthalene (4): (12.9 g, 81%); 1H NMR (300 MHz, CDCl3) δ
7.13 – 7.03 (m, 3H), 2.85 – 2.70 (m, 3H), 1.81 (dt, J = 6.6, 3.5 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 137.5, 129.5, 125.8, 29.76, 23.6.
6-Methoxytetralin (Table 6, entry 2): (924 mg, 81%); 1H NMR (300 MHz, CDCl3) δ 7.00 (t,
J = 5.9 Hz, 1H), 6.73 – 6.59 (m, 2H), 3.78 (s, 3H), 2.71 (dd, J = 22.5, 15.5 Hz, 4H), 1.84 – 1.72
13
(m, 4H); C NMR (75 MHz, CDCl3) δ 157.5, 138.3, 130.1, 129.4, 113.8, 111.9, 55.4, 29.9,
28.7, 23.6, 23.3.
3-Benzylpyridine (Table 6, entry 3): (1.06 g, 90%); 1H NMR (300 MHz, CDCl3) δ 8.38 (dd,
J = 15.0, 4.2 Hz, 1H), 7.42 – 7.03 (m, 4H), 3.88 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 150.2,
147.7, 139.9, 136.5, 129.0, 128.8, 126.6, 123.5, 39.2;
1
2-Ethylpyrrole (Table 6, entry 4): (461 mg, 70%); H NMR (300 MHz, CDCl3) δ 7.92 (s,
1H), 6.69 (dd, J = 4.1, 2.6 Hz, 1H), 6.16 (dd, J = 5.8, 2.8 Hz, 1H), 5.95 (s, 1H), 2.66 (q, J = 7.6
13
Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H); C NMR (75 MHz, CDCl3) δ 134.3, 116.2, 108.4, 104.3,
20.9, 13.7.
Diphenylmethane (Table 6, entry 5): (878 mg, 75%); 1H NMR (300 MHz, CDCl3) δ 7.46 –
7.13 (m, 10H), 4.04 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 141.2, 129.1, 128.6, 126.2, 42.1.
Toluene (Table 6, entry 6): (604 mg, 82%, extracted with diethyl ether) 1H NMR (300 MHz,
CDCl3) δ 7.36 – 7.17 (m, 5H), 2.41 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 138.0, 129.2, 128.4,
125.4, 21.6.
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2,5-Dimethoxytoluene (Table 6, entry 7): (834 mg, 87%); 1H NMR (300 MHz, CDCl3) δ 6.87
13
– 6.65 (m, 3H), 3.78 (d, J = 8.2 Hz, 6H), 2.23 (s, 3H); C NMR (75 MHz, CDCl3) δ 153.9,
152.6, 128.4, 117.6, 111.4, 111.2, 56.4, 56.2, 17.0.
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5,5-Dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (13): (631 mg, 80%); H NMR (300
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MHz, CDCl3) δ 7.48 (d, J = 1.5 Hz, 1H), 5.93 (d, J = 0.6 Hz, 1H), 3.87 (s, 2H), 2.67 (s, 2H),
1.27 (s, 6H).13C NMR (75 MHz, CDCl3) δ 144.93, 143.0, 99.3, 61.0, 43.4, 38.8, 28.3.
ACKNOWLEDGEMENT
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). We would
also like to thank Peter Smith, Jerome Dubiez, Steve Norris and Andrew Ikin (AstraZeneca) for
their contribution to this project.
Supporting Information Available. Additional experimental information, supplementary
figures and 1H and 13C NMR spectra. This material is available free of charge via the Internet
at http://pubs.acs.
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