Gas-liquid flow hydrogenation of nitroarenes: Efficient access to a pharmaceutically relevant pyrrolobenzo[1,4]diazepine scaffold

Article abstract of DOI:10.1016/j.tet.2018.09.025

Using a Tube-in-Tube device based on the amorphous Teflon AF-2400 fluoropolymer, a series of nitroarenes was hydrogenated to afford the corresponding aniline compounds. The system was then applied to the construction of a pyrrolobenzo[1,4]diazapene scaffold through a tandem hydrogenation-condensation-hydrogenation sequence.

Full text of DOI:10.1016/j.tet.2018.09.025

Accepted Manuscript
Gas-liquid flow hydrogenation of nitroarenes: Efficient access to a pharmaceutically
relevant pyrrolobenzo[1,4]diazepine scaffold
Eleni Dimitriou, Richard H. Jones, Robin G. Pritchard, Gavin J. Miller, Matthew
O'Brien
PII:
S0040-4020(18)31094-9
10.1016/j.tet.2018.09.025
TET 29797
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 10 April 2018
Revised Date: 31 August 2018
Accepted Date: 11 September 2018
Please cite this article as: Dimitriou E, Jones RH, Pritchard RG, Miller GJ, O'Brien M, Gas-liquid flow
hydrogenation of nitroarenes: Efficient access to a pharmaceutically relevant pyrrolobenzo[1,4]diazepine
scaffold, Tetrahedron (2018), doi: https://doi.org/10.1016/j.tet.2018.09.025.
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Gas-liquid flow hydrogenation of
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pharmaceutically relevant
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1
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Tetrahedron
journal homepage: www.elsevier.com
Gas-liquid flow hydrogenation of nitroarenes: efficient access to a pharmaceutically
relevant pyrrolobenzo[1,4]diazepine scaffold
Eleni Dimitrioua, Richard H. Jonesa, Robin G. Pritchardb, Gavin J. Millera and Matthew O’Briena*
aLennard-Jones Laboratories, School of Chemical and Physical Sciences, Keele University, Keele, Borough of Newcastle-under-Lyme, Staffordshire, ST5 5BG,
United Kingdom.
bThe School of Chemistry, The University of Manchester, Oxford Road, Manchester, M13 9PL, United Kingdom.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Using a Tube-in-Tube device based on the amorphous Teflon AF-2400 fluoropolymer, a series
of nitroarenes was hydrogenated to afford the corresponding aniline compounds. The system
was then applied to the construction of a pyrrolobenzo[1,4]diazapene scaffold through a tandem
hydrogenation-condensation-hydrogenation sequence.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
Gas-liquid flow
Hydrogenation
Pyrrolobenzodiazepine
Reduction
Cyclisation
1. Introduction
Also important is the inclusion of the structural template of 1
within the development of pyrrolo[2,1c][1,4]benzodiazepines 3
(PBDs) as DNA interactive agents.2 Since their discovery in the
1960s the field of PBD research has expanded rapidly and now
includes over thirteen different PBD architectures used across
synthetic mechanistic and medicinal chemistry and as ‘warheads’
in therapeutic antibody applications.3 The utility of 1 requires
that efficient synthetic methods to access it are available. Several
chemical syntheses of 1 have been reported in the literature4 and,
as their key tricycle-forming step, propose a tandem sequence
involving the reduction of the nitro group in pyrroloaldehyde 4,
condensation of the resultant aniline moiety with the pyrrolic
aldehyde and finally reduction of the imine to form 1 (Scheme 1).
The pyrrolobenzodiazepine scaffold 1 (10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine, Figure 1) is a medicinally
important heterocycle consisting of a benzo[1,4]diazepine unit
fused to a pyrrole. This structure is commonly encountered as a
constituent part of important synthetic drug scaffolds, for
example, in the development of non-peptidic oxytocin and
vasopressin small molecule agonists and antagonists, typified by
Lixivaptan 2 (Figure 1).1
N
N
N
N
H
O
H
Reductive cyclisation
O
imine formation and reduction
1
N
O
N
O
Cl
R2
N
H
1
N
N
H
O
R1
H
NO2
2
N
4
N
N
F
N
3
NH2
Figure 1. The pyrrolobenzodiazepine scaffold 1, Lixivaptan 2 and
the PDB scaffold 3.
———
Scheme 1. Access to 1 (via nitro reduction, imine formation and
reduction) from pyrroloaldehyde 4.
Corresponding authors. Tel.: +44 1782 734442;
e-mail: m.obrien@keele.ac.uk, g.j.miller@keele.ac.uk

2
Tetrahedron
A key consideration when using gases in continuous flow is the
ACCEPTED MANUSCRIPT
nature of the contact between the gas and liquid phases. In
These two transformations are usually completed as a one-
systems where biphasic flow streams are generated, governing
the morphology of the flow regime is not always
straightforward.10 A number of different approaches to gas-liquid
contacting in flow have been developed, many of which provide
enhanced mass transfer of gas between the two phases, often by
maximising the interfacial surface area.11 For hydrogenation
reactions, the commercially available H-Cube system has also
seen growing popularity among synthetic chemists.12
We have previously demonstrated that flow reactors based on
gas-permeable membranes, such as Teflon AF-2400,13 which
combines very high levels of gas permeability with excellent
chemical resistance properties, facilitate the reliable and scale-
invariant generation of homogeneous flow streams of reactive
gasses in solution.14 These devices avoid many of the
complications associated with heterogeneous biphasic flow
regimes which result from 'mechanical mixing' of gas and liquid
flow streams. The relationship between gas concentration and
operational variables, such as residence time, gas pressure, and
tubing dimension, is straightforward and can be reliably
modelled using standard mathematical analyses.15 When high
pressures of gas are required to achieve sufficient solution
concentrations, the 'tube-in-tube' configuration (Figure 2) is an
efficient arrangement which keeps the volume of pressurised gas
to a minimum. A simple and inexpensive 'tube-in-tube' device
can easily be constructed using just two standard T-piece
junctions (e.g. Swagelok), as shown in Figure 3.
step, domino process where nitro reduction, cyclisation and imine
reduction are globally effected under hydrogenation conditions.
From a process standpoint, the use of gaseous reagents is in
many ways advantageous. Several equivalents of gas can be used
to drive reactions to completion and the excess material can
easily be removed post reaction simply by opening the container.
However, the use of gasses is often accompanied by significant
safety issues. As gas concentrations in solution are proportional
to pressure in the head space (according to Henry's law5), high
pressures are often required to achieve sufficient concentrations
for reactions to take place. This generally requires the use of
specialised high-pressure reactors. As the potential energy stored
due to pressurisation (which would be converted to kinetic
energy in the event of a mechanical failure) is proportional to the
volume of the vessel, this becomes more serious during scale up.
Hydrogen is also one of the most flammable of gasses and this
leads to additional fire and explosion hazards.6 Furthermore, as
interfacial surface-area scales with the square of dimension,
whilst volume scales with its cube, surface-area to volume ratios
decrease as the size of the vessel increases (assuming the same
shape is maintained). This leads to a scale variant rate of gas
transfer, from the head space into the solution, which often
becomes rate limiting.
In recent years, continuous flow chemistry has emerged as an
alternative to traditional batch based synthetic protocols.7 Due to
the fact that only a small amount of material is being processed at
any one time, through relatively small reaction zones, this can
often mitigate some of the safety issues associated with the scale-
up of batch reactions, particularly for those transformations that
involve the formation of hazardous intermediates, or that use
high temperatures or pressures.8 In addition, as interfacial surface
contact is often enhanced and well-defined, this can often
facilitate more efficient and controllable interfacial mass and
energy transfer.9
Figure 3. Photograph of the Tube-in-Tube device used in this
work. The plastic ruler the Swagelok T-pieces are cable-tied to is
used only for attachment and to provide a scale. The left-hand T-
piece was connected to the hydrogen cylinder via a standard 2-
stage poppet regulator. The right-hand T-piece was connected to
a stopcock that was normally closed during operation, so that the
jacket of gas remained 'static' (the only flow of gas being through
the AF-2400 tubing into the liquid flow stream).
Figure 2. Cartoon schematic of Tube-in-Tube device. A)
Configuration with liquid flow within inner AF-2400 tubing, and
gas flow in outer jacket (as used in this work). B) Alternative
configuration with gas in inner AF-2400 tubing and liquid flow
in outer jacket.
Whilst commercial gas-liquid flow devices tend to be well
engineered, and can perform admirably in a wide range of
hydrogenation applications, their proprietary nature generally
precludes full disclosure of their internal design and workings
(including materials). This encourages a ‘black box’ approach
which may inhibit further modification and/or development of
the systems by the user. The simple and fully disclosed nature of
these Teflon AF-2400 based devices is perhaps one of the
reasons (in addition to their low cost) for their rapidly growing
popularity.
As part of a program investigating the use of gas-liquid flow
technologies as a replacement for traditional batch hydrogenation
and hydrogenolysis processes, we were interested in their
application to the synthesis of 1.

3
We, and others, have successfully demonstrated the use of
EtOH flow stream at 0.5 mL min-1. The outlet solution was
ACCEPTED MANUSCRIPT
Teflon AF-2400 based reactors with a number of reactive gasses
including ozone,16 oxygen,17 ammonia,18 methylamine,19 carbon
dioxide,15b, 20 carbon monoxide,19, 21 ethylene,22 diazomethane23,
formaldehyde,24 and fluoroform.25 Importantly, in the context of
the current work, they have been used with hydrogen gas,22c, 26 on
its own or as a mixture with carbon monoxide (syngas).22b, 27
collected for 120 minutes and the product was isolated by
removing the solvent under reduced pressure to afford a mixture
of the desired aniline 6a and the starting material 5a in a ratio of
approximately 3:1. When the concentration of starting material
was lowered to 0.076 M (42 mg in 3.6 mL EtOH), under the
same conditions, the conversion was complete and the desired
product 6a was isolated in a very high yield of 95 %. Likewise,
when the hydrogenation of tert-butyl nitrophenylpropanoate 5b
was attempted at a concentration of 0.152 M, the product was
isolated alongside unreacted starting material (6b:5b = 2:1) but
when the reaction was carried out at 0.076 M, complete
conversion to 6b was observed. Using a concentration of 0.076
M, a series of nitroarene compounds 5a-i was cleanly converted
to the corresponding anilines 6a-i which were isolated in very
high yields. (Scheme 2). 1H and 13C NMR alongside MS analysis
confirmed the desired nitro to aniline conversions had occurred
and that nitroso products were not formed. Having thus
established that we could perform simple nitro reduction using
our gas-liquid flow hydrogenation setup, we next attempted the
proposed nitro-reduction/cyclisation/imine-reduction domino
process to access 1 from 4.
2. Results and Discussion
2.1. Reduction of Simple Nitroarenes.
Pd/ C
sand
Tube-in-Tube
10 cm
+ celite
celite
H2
R-NO2
Pd/C
13 bar
BPR
R-NH2
EtOH
H2 (16 bar), Pd-C,
EtOH (0.076 M)
R
R
Figure 4. Schematic of the flow setup.
Prior to attempting a synthesis of 1 using gas-liquid flow
hydrogenation, we first wanted to establish that the system was
capable of effecting the hydrogenation of simple nitroarene
compounds 5a-i in continuous flow28 using the general setup
shown in Figure 4. The starting material was loaded into a flow
stream of solvent using an injection loop. The flow stream
becomes enriched with hydrogen gas by passing through a
relatively short 10 cm Tube-in-Tube device (this single Tube-in-
Tube device was used for all the work described in this paper).
We have previously found that saturation is rapid using hydrogen
gas with Tube-in-Tube reactors. Upon exiting the Tube-in-Tube
stage, the flow stream passes through a glass omnifit cartridge
containing Pd-C (5%). We found that back-pressure due to
compression/blocking of the catalyst powder could be avoided by
mixing it with celite (1:1 wt:wt) and packing it into the cartridge
with plugs of celite and sand at each end (see Figure 4). Using
the powdered supported catalyst by itself led to a significant and
variable build up of back-pressure. During a brief initial
screening (of solvent, flow rates etc), we used a small cartridge
(11.1 mm OD, 6.6 mm ID) containing 370 mg of 5% palladium
on carbon (which was used repeatedly). It was found that 15 mg
of nitroanisole 5a, (injected as a 0.027 M EtOH solution in a 3.6
mL loop) could be cleanly converted to the corresponding aniline
6a with quantitative conversion and in high yield using ethanol as
solvent with a flow rate of 0.5 ml min-1 and a hydrogen pressure
of 16 bar. No premature outgassing (formation of hydrogen
bubbles) upstream of the 13 bar back-pressure regulator was
observed under these conditions. A noticeable drop in outgassing
downstream of the back pressure regulator was observed about
15 minutes after injection, indicating that hydrogen was being
used up. This continued until about 20 minutes after injection, at
which point the outgassing reached its original level, indicating
that the rate of hydrogen consumption had significantly
diminished. It should be pointed out that the system was allowed
to equilibrate for 30 minutes under H2 pressure prior to the
injection of the substrate solution, after which time the rate of
hydrogen outgassing downstream of the back pressure regulator
reached a steady state. The product stream was collected at the
outlet for 40 min. The reaction was then increased in scale, using
a larger cartridge (20.0 mm OD, 15.0 mm ID) containing 1.0 g of
palladium on carbon, again with a hydrogen pressure of 16 bar. A
0.152 M solution of 5a (84 mg in 3.6 mL) was injected into an
O2N
H2N
see Fig. 1
5a-i
6a-i
Me
O
OMe
Me
Me
O
OMe
Me
O
NH2
NH2
H2N
6c
6a
6b
conv: 100%
yield: 96%
conv: 100%
yield: 95%
conv: 100%
yield: 99%
O
OH
O
OH
O
OH
Me
NH2
F
H2N
F
NH2
6d
conv: 100%
yield: 98%
6f
6e
conv: 100%
yield: 95%
conv: 100%
yield: 95%
N
O
OH
Me
NH2
NH2
NH2
F
NH2
6g
conv: 100%
yield: 98%
F
6i
6h
conv: 100%
yield: 95%
conv: 100%
yield: 97%
Scheme 2. Results of continuous flow nitroarene hydrogenations.
Conversions were determined by 1H NMR. Yields refer to
isolated yields based on mass recovery. The starting material for

4
Tetrahedron
ACCEPTED MANUSCRIPT
6i was 2-fluoro-5-nitro-aniline. The same cartridge of Pd-C
O
catalyst was used for all substrates.
N
H2, Pd-C, EtOH
N
60%
N
NO2
2.2. Pyrrolobenzazepine synthesis using gas-liquid flow
hydrogenation.
H
1
4
NaBH4,
THF
75%
HO
In our initial investigations for the continuous-flow
conversion of 4 into 1, we reverted to using the smaller cartridge
of palladium catalyst (11.1 mm OD, 6.6 mm ID, 370 mg of 5%
Pd-C). Again using EtOH as a solvent, nitro-aldehyde 4 (easily
obtained from alkylation of 2-nitrobenzyl bromide with pyrrole-
2-carbaldehyde5) at a concentration of 8.7 mM (7.2 mg in 3.6
mL) was exposed to analogous flow conditions (0.5 mL min-1, 16
bar H2). The outlet was collected for 45 minutes. Analysis of the
isolated product material by 1H NMR suggested that the majority
of the starting material, approximately 65%, had not been
converted to the desired product 1, but to another compound with
quite similar spectral features. Data reported in the literature for 1
suggested that this was, in fact, the minor component, formed in
35% yield. We were thus interested in firmly establishing the
HO
N
NaH2PO2, Pd-C,
K2CO3, THF
N
NO2
8
90%
NH2
7
Scheme 4. Batch synthesis of anilino-alcohol
pyrrolobenzazepine 1; i) Pd/C, H2, EtOH, 60% ii) NaBH4, THF, 75%
iii) Pd/C, K2CO3, H2O, THF, 90%.
7
and
We compared our NMR data for 7 with the initial gas-liquid
flow results as well as with the spectra of pure 1 (selected H
region shown in Figure 5, bottom, blue line). The product of the
1
hydrogenation of 8 and the major product from the flow
hydrogenation had identical H and 13C NMR spectra as well as
1
1
identity of the two products. H NMR analysis indicated that, in
both products, two CH2X (X = heteroatom) environments were
present. This suggested that aldehyde reduction had occurred and
that the amino-alcohol structure 7 was a possibility for the major
product. Consistent with this, we found, after chromatographic
separation, that the major product also had a significantly lower
Rf value than the minor product. It occurred to us that the
formation of 7 might result from hydrogenation of the aldehyde
identical Rf values. This corroborated our conclusion that flow
hydrogenolysis conditions had converted 65% of 4 to 7 and 35%
to 1. The structures of products 1 and 7 from the batch reactions
were further confirmed by Mass Spectrometry and single-crystal
X-ray diffraction (see Figure 6).
prior to the nitro group.
N
1
H2,
Pd-C
flow
N
O
H
(Fig 4)
N
EtOH
NO2
HO
N
4
7
NH2
Scheme 3 Reductive cyclisation of pyrrolocarbaldehyde 4 to 1 and
formation of the minor reaction by-product 7.
We separately synthesised 1 and 7 from 4 in batch. To access
1 we used the same solvent and catalyst, but at atmospheric
(balloon) pressure of H2 and isolated the desired product 1 in
60% yield after chromatography. To obtain 4 we used an
alternative two-step proces. (68% overall yield, Scheme 4).
NaBH4 treatment of 4 proceeded smoothly to deliver novel nitro
alcohol 8 in 90% yield. Using mildly basic conditions and H2
generated in situ from sodium hypophosphite (NaH2PO2), Pd/C
catalysed reduction of 8 delivered 7 smoothly in 75% isolated
yield (with no evidence of any cyclisation to 1). Attempts to
access 7 using acidic nitro-reducing conditions (Fe/AcOH) were
unsuccessful, leading to extensive material degradation.
Figure 5. 400 MHz 1H NMR overlays of initial attempted synthesis
of 1 using gas-liquid flow hydrogenolysis (bottom, blue line) and
using traditional batch conditions1a,b, 4 (top). The spectra of 7 made in
batch via hydrogenation of nitro-alcohol 8 is overlaid on the bottom
spectrum as a green line.

5
C) the desired compound 1 was obtained in a yield of 95%, and
in the absence of the ring-opened by-product 7.
ACCEPTED MANUSCRIPT
For larger scale runs, the injection loop became unsuitable and
the substrate solution was introduced directly through the pump
inlet (Figure 7). When the scale was increased to 500 mg (at the
same concentration: 21.7 mM, 500 mg in 100 mL EtOH) then we
found that significant amounts of unreacted starting material 4
were obtained, alongside the product 1 and other components
(not including 7), Table 1, entry 1. This reduction in conversion
at a higher scale might be explained by the palladium acting as a
‘reservoir’ of hydrogen. During the equilibration prior to the start
of the run, it may take up and store a quantity of hydrogen and,
after equilibration is reached, outgassing of hydrogen is then
observed downstream of the back pressure regulator. During the
run, once the starting material is introduced, this stored hydrogen
may (for a while) allow higher conversion than would be possible
solely from the hydrogen present in solution. Clearly, any stored
hydrogen will be consumed and, during longer runs (i.e. larger
scale reactions) may become completely depleted, leading to
lower conversions.
Figure 6. X-ray structures of 1 (top) and 7 (bottom, thermal
ellipoids shown at 50%).
It was found that, if the crude 35:65 mixture of 1 and 7
obtained in flow was re-injected into the continuous flow system,
then the product that emerged from this second pass (which was
isolated with quantitative mass recovery) contained
predominantly 7 (now in a 1:12 ratio of 1:7). This suggested the
possibility that 1 might be an intermediate in the formation of 7.
To test this hypothesis, we separately passed purified samples of
1 and 7 through the flow system again and found that they were
recovered, unaltered, in essentially quantitative yield, which
negates the suggestion that 7 is formed from 1. As the 36:65 ratio
mixture of 1 and 7 that was recycled was crude, we cannot rule
out the possibility that it contained residual palladium that may
have catalysed changes in the time between the two runs
(including exposure to NMR solvents etc.). The fact that the
relative proportions of 1 and 7 seem to be sensitive to the
concentration of 4 at a given hydrogen pressure and flow rate
(more 7 being formed at a lower substrate concentration)
Tube-in-Tube
10 cm
H2
O
N
N
Pd/C
BPR
N
H
NO2
1g
1 (+ 7)
4 (500 mg in EtOH)
suggests that the aldehyde in
1
might be undergoing
Figure 7. For the larger (500 mg) scale experiments, the starting
material 4 was added directly through the pump inlet.
hydrogenative reduction to the alcohol when the hydrogen
concentration is higher. If aldehyde hydrogenation occurs either
before the nitro group is reduced, or before the formation of the
imine intermediate (which is perhaps more likely as reduction of
the nitro group might also be expected to proceed more rapidly at
higher hydrogen concentration), this would explain the formation
of 7. Whilst transition-metal catalysed hydrogenations of pyrrolic
aldehydes are known,29 literature precedent suggests that the nitro
group should be reduced more quickly under these conditions.30
Using a lower concentration of subsrate (14.5 mM, 500 mg in
150 mL) and a higher pressure of hydrogen (25 bar, with the
back pressure regulator adjusted to 20 bar), the loss of starting
material was complete but now the product 1 was accompanied
by a significant amount of amino alcohol 7 (1:7 = 1:0.87, Table
1, entry 2). Lowering the pressure to 20 bar (at this reduced
concentration) reduced the quantity of 7 obtained (1:7 = 1:0.40,
Table 1, entry 3). Pleasingly, by using this 20 bar pressure with
the original concentration (21.7 mM), we were able to obtain a
product which contained minimal quantities of 7 (1:7 = 1:0.05)
and, after column chromatography, the isolated product 1 was
obtained in an 81% yield (356 mg).
Consistent with this, when 4 was injected under the same
conditions, but with the addition of 20 equivalents of pyridine
(which is a known poison/modifier of palladium catalytic
activity31) then 1 was obtained in a 2.7:1 ratio with 7. Also, when
36 mg of nitro-alcohol 8 (in 18 mL EtOH) was subjected to the
flow hydrogenation conditions (using the larger 1g Pd-C
cartridge, H2 at 16 bar, 0.5 mL min-1), the amino-alcohol 7 was
the sole product, isolated in 97% yield, strongly suggesting that 7
is not a precursor to 1
H2
(bar)
S.M.
consumed?
Entry
Conc.(mM)
1:7
Yld (1)
1
2
3
4
16
25
20
20
21.7
14.5
14.5
21.7
N
Y
Y
Y
-
-
Having fully established the identity of the two products from
the flow hydrogenation reaction, we were keen to optimise
conditions to favour production of the desired material 1. Whilst
the addition of pyridine was observed to have a positive influence
in this regard, we noticed that its effect on the smaller catalyst
cartridge was not quickly reversed and flushing with copious
fresh solvent was required to 'regenerate' the original catalytic
activity. Wanting to avoid complications arising from cumulative
(and perhaps variable) poisoning effects over time, we
investigated whether the same outcome could be obtained by
varying simple parameters such as concentration. Pleasingly,
when 4 was injected in a higher concentration of 0.0217 M (90
mg in 18 mL EtOH), with a flow rate of 0.5 mL min-1 and an H2
pressure of 16 bar, using the larger catalyst cartridge (1.0 g of Pd-
1:0.87
1:0.40
1:0.05
-
-
81%
Table 1. Results for the 500 mg scale hydrogenations of 1. Yld
refers to the isolated yield of 1 after column chromatography on
silica gel.
3. Conclusion
In conclusion, we have developed a simple and effective
continuous-flow heterogeneous hydrogenation protocol for

6
Tetrahedron
ACCEPTED MANUSCRIPT
nitroarenes based around an inexpensive Teflon AF-2400 tube-
Flow apparatus: A Knauer Azura P-4.1S HPLC pumping unit
in-tube reactor. This was used to effect the formation of a series
of substituted anilines in high yields and high purities. With
nitro-aldehyde 4, the flow conditions could be tuned to
was used to pump the solvent through the system. Aside from the
Tube-in-Tube device, the general liquid flow line consisted of
FEP tubing (1/16’’ x 1.0 mm ID, VICI-jour) and the tubing
interconnects were of the flat seated Omnifit/Diba type (1/4-28-
UNF thread). The backpressure regulator was an Upchurch/IDEX
type (Kinesis UK) and was manually adjusted to provide the
desired back pressure of 13 bar (gauge), as measured using the
pressure meter of the Knauer Azura pump. The injection loop
was constructed using four Omnifit/Diba 3-way valves (two
valves to open/close the loop itself for filling, two valves to
connect/disconnect the loop to the flow stream). The hydrogen
pressure in the Tube-in-Tube device was regulated at the cylinder
outlet using a Gas-Arc Techmaster GA600 multi-stage regulator.
As shown in Figure 3, the side-port of one of the Swagelok T-
pieces of the Tube-in-Tube device was connected to the regulator
outlet, and the side-port of the other T-piece was connected to a
Swagelok stopcock (which was closed during normal operation
and only used for maintenance/start-up/shutdown etc). With this
arrangement, the hydrogen gas could only exit the Tube-in-Tube
device during normal operation by passing into the solvent flow
stream.
preferentially
obtain
either
the
desired
pyrrolobenzo[1,4]diazapene compound 1 or the amino-alcohol
by-product 7. Despite the fact that 7 was not the desired
compound in this particular case, this nevertheless demonstrates
that the flow conditions used can provide controlled access to
alternative products. There appears to be a relationship between
the relative amounts/concentrations of the starting material/H2
and the product selectivity. We are currently performing
investigations aimed at establishing the mechanistic manifold by
which 1 and 7 are formed, including a comparison between flow
and batch modes across a range of pressures (it should be pointed
out that the batch hydrogenation in this work was only carried
out at atmospheric pressure). We are also investigating whether
the palladium is acting as a hydrogen reservoir (and the effect
this has on the reactivity), as well as the extent of any palladium
leaching, and will report our findings in due course.
4. Experimental Section
1H NMR spectra were recorded on a Bruker Avance 300
(300.1 MHz) instrument or a Bruker Avance 400 (399.9 MHz)
instrument using deuterochloroform (or other indicated solvent)
as reference. The chemical shift data for each signal are given as
δ in units of parts per million (ppm) relative to tetramethylsilane
(TMS) where δ (TMS) = 0.00 ppm. The multiplicity of each
signal is indicated by: s (singlet); brs (broad singlet); d (doublet);
t (triplet); dd (doublet of doublets); ddd (doublet of doublet of
doublets); dddd (doublet of doublet of doublet of doublets); ddt
(doublet of doublet of triplets); sp (septet) or m (multiplet). The
number of protons (n) for a given resonance is indicated by nH.
Coupling constants (J) are quoted in Hz and are recorded to the
nearest 0.1 Hz. 13C NMR spectra were recorded on a Bruker
Avance 300 (75.5 MHz) instrument using the PENDANT
sequence and internal deuterium lock. The chemical shift data for
each signal are given as δ in units of ppm relative to TMS where
δ (TMS) = 0.00 ppm. Where appropriate, coupling constants (J)
are quoted in Hz and are recorded to the nearest 0.1 Hz. Melting
points were determined using Gallenkamp MF-370 or
Electrothermal 9100 melting point apparatuses and are
uncorrected. Analytical thin layer chromatography (TLC) was
carried out on pre-coated 0.25 mm ICN Biomedicals GmbH 60
F254 silica gel plates. Visualisation was by absorption of UV
light, or thermal development after dipping in 5 % H2SO4 in
MeOH. Manual Column chromatography was carried out on
silica gel (Apollo Scientific Ltd 40- 63 micron) under a positive
pressure of compressed air. Automatic Column Flash
chromatography was carried out on silica gel (Reveleris® X2
system) under a positive pressure of compressed N2. Dry CH2Cl2
and DMF was acquired from an Innovative Technology solvent
purification system. Anhydrous MeOH was dried over 4 Å
molecular sieves. Chemicals were purchased from Acros UK,
Aldrich UK, Avocado UK, Fisher UK or Fluka UK. All solvents
and reagents were purified and dried where necessary, by
standard techniques. Where appropriate and if not stated
otherwise, all non-aqueous reactions were performed under an
inert atmosphere of nitrogen, using a vacuum manifold with
nitrogen passed through 4 Å molecular sieves and self-indicating
silica gel. In vacuo refers to the use of a rotary evaporator
attached to a diaphragm pump. Brine refers to a saturated
aqueous solution of sodium chloride. Hexane refers to n-hexane
and petroleum ether to the fraction boiling between 40-60 °C.
The heterocyclic ring numbering for NMR assignments of 7 and
8 is shown in the supplementary material.
4.1 Pyrrolobenzodiazepine 1
Batch:
To
a
stirred
solution
of
1-[(2-
nitrophenyl)methyl]pyrrole-2-carbaldehyde 4 (300 mg, 1.30
mmol, 1.0 equiv.) in EtOH (4 mL), was added 5% Pd-C (5.5 mg,
0.002 equiv.) and the reaction mixture left stirring overnight
under a H2 atmosphere (balloon). Upon completion, as indicated
by TLC (1/2, ethyl acetate/hexane), the mixture was filtered
through Celite™ and the solution concentrated in vacuo. The
crude product was purified by Reveleris® automated silica gel
flash column chromatography (liquid injection onto column),
eluting with ethyl acetate/hexane (0/100, 40/60, 60/40 and
100/0), furnishing 1 (160 mg, 0.79 mmol, 60%) as a brown solid.
Rf 0.61 (1/2, ethyl acetate/hexane);
Flow (500 mg run): The system (see Figure 6), incorporating
the 1g Pd-C cartridge (20.0 mm OD, 15.0 mm ID), was primed
by pumping through ethanol at a rate of 0.5 mL min-1. No
injection loop was used. A 20 bar back pressure regulator was
used. To avoid an overpressure of the system in the event of
blockage, the upper pressure cut-off limit on the Knauer pump
was set to 25 bar. The tube-in-tube device was subjected to 20
bar of hydrogen pressure using a 2-stage regulator on the
cylinder. Priming continued for 30 minutes before starting the
run (out-gassing of hydrogen downstream of the back-pressure
regulator could be observed after about 20 minutes). The starting
nitro-aldehyde 4 (500 mg, 2.17 mmol) was dissolved in EtOH
(100 mL solution). To introduce the starting material solution,
the pump was momentarily stopped and the inlet was switched
from the EtOH reservoir to the starting material solution. The
pump was then immediately restarted. The level of the inlet
solution was monitored and at the moment when it had all been
taken in (but before any air could be drawn in to the pump inlet
line), the pump was momentarily stopped and the inlet line
switched back to the EtOH reservoir. The pump was then
immediately restarted. The output from the system was collected
for 450 minutes. Solvent was removed under reduced pressure
(using a rotary evaporator followed by a 2-stage rotary vane
pump) to afford an off-white solid (450 mg crude). The material
was purified using column chromatography on silica gel (Merck
9385 grade) eluting with a gradient from petroleum ether to ethyl
acetate, to afford 1 as a white solid (356 mg, 81%);

7
1H NMR (300 MHz; CDCl3) δ 7.08-7.00 (m, 2H, H4, H2),
6.71 (t, J = 2.1 Hz, 1H, H5), 6.65 (td, J = 7.4, 1.1 Hz, 1H, H3),
6.52 (dd, J = 8.0, 1.0 Hz, 1H, H1), 6.08-6.05 (m, 2H, H6, H7),
1H NMR (400 MHz, CD3CN) δ 7.20 (s, 1H), 7.03 (d, J = 8.0
ACCEPTED MANUSCRIPT
Hz, 1H), 6.76 (d, J = 7.7 Hz, 1H), 4.26 (br.s, 2H,), 2.42 (s, 3H);
13C NMR (101 MHz, CD3CN) δ 169.2, 146.4, 132.8, 130.7,
128.5, 118.8, 116.7, 20.3; HRMS (ESI-TOF, m/z): calculated
for C8H10NO2 ([M+ H]+): 152.0706, found: 152.0701. The data
are consistent with values reported in the literature.35
5.21 (s, 2H, CH2N), 4.49 (s, 2H, CH2O), 3.71 (brs, 1H, NH); 13
C
NMR (75 MHz; CDCl3) δ 146.5, 131.0, 129.9, 128.8, 120.6,
120.0, 117.79, 117.65, 106.2, 105.6, 51.6, 40.7; MS ESI+ m/z
185 ([M+Na]+, 100 %); HRMS ESI+ m/z Found: 185.1071 for
C12H13N2 [(M+H)+] requires 185.1073; Data matched those
previously reported1b; CCDC No: 1584964.
4.7. 3-Amino-4-fluoro-benzoic acid 6f
40.3 mg from 50.6 mg 5f (95%).
1H NMR (400 MHz, CD3CN) δ 7.48 (d, J = 8.8 Hz, 1H), 7.37 –
7.28 (m, 1H), 7.07 (t, J = 9.8 Hz, 1H); 13C NMR (101 MHz,
CD3CN) δ 167.3, 155.9, 153.5, 136.5, 127.4, 120.1, 118.3, 115.7;
HRMS (ESI-TOF, m/z): calculated for C7H7FNO2 ([M+ H]+):
156.0455, found: 156.0449. The data are consistent with values
reported in the literature.36
General Procedure for Flow hydrogenation of Nitro Arenes
(Scheme 2):
Before each run, the system (see Figure 4) was allowed to
equilibrate by pumping solvent through for 30 minutes with the
Tube-in-Tube device at 16 bar of hydrogen. An omnifit cartridge
(20.0 mm OD, 15.0 mm ID) containing 1g of Pd-C catalyst was
used. To avoid an overpressure of the system in the event of
blockage, the upper pressure cut-off limit on the Knauer pump
was set to 25 bar. With the injection loop disconnected from the
flow line, the loop was opened and filled manually (using a
syringe) with 3.6 mL of a 0.076 M solution of starting material in
ethanol (excess starting material solution exiting the loop was
recovered for reuse). The injection loop was then closed off and
switched into the flow stream. The outlet from the system
(downstream of the back-pressure regulator) was collected for
120 min. The solvent was removed under reduced pressure (using
a rotary evaporator followed by a 2-stage rotary vane pump) to
afford the product.
4.8. 4-Amino-2-methyl-benzoic acid 6g
40.5 mg from 49.5 mg 5g (98%).
1H NMR (400 MHz, CD3CN) δ 7.79 (d, J = 8.3 Hz, 1H), 6.50 (d,
J = 6.8 Hz, 2H); 13C NMR (101 MHz, CD3CN) δ 169.3, 152.7,
143.8, 134.1, 117.1, 116.9, 111.5, 22.2; HRMS (ESI-TOF, m/z):
calculated for C8H10NO2 ([M+ H]+): 152.0706, found: 152.0700.
4.9. 3-Amino-4-fluoro-benzonitrile 6h
36.1 mg from 45.4 mg 5h (97%).
1H NMR (400 MHz, CDCl3) δ 7.09 – 6.98 (m, 3H), 3.98 (br.s,
2H); 13C NMR (101 MHz, CDCl3) δ154.9, 152.5, 135.9, 122.9,
119.7, 118.5, 116.3, 108.6.
4.2. 4-amino methoxybenzene 6a
32.0 mg from 41.9 mg 5a (95%).
4.10 2,4-Diamino-1-fluorobenzene 6i
32.8 mg from 42.7 mg 5i (95%).
1H NMR (400 MHz, CDCl3) δ 6.78 (d, J = 8.3 Hz, 2H), 6.69 (d,
J = 8.3 Hz, 2H), 3.78 (s, 3H), 3.39 (br.s, 2H); 13C NMR (101
MHz, CDCl3) δ 152.9, 139.9, 116.4, 114.9, 55.8. The data are
consistent with values reported in the literature.32
1H NMR (400 MHz; CDCl3) δ 6.80 (t, J = 9.7 Hz, 1H), 6.14 (dd,
J = 7.6, 2.1 Hz, 1H), 6.03 (d, J = 8.5 Hz, 1H), 3.64 (s, 2H), 3.51
(s, 2H); 13C NMR (101 MHz; CDCl3) δ 115.7, 115.5, 105.1,
105.0, 103.7, 103.7; HRMS (ESI-TOF, m/z): calculated for
C6H8FN2 ([M+ H]+ ): 127.0666, found: 127.0667. The data are
consistent with values reported in the literature.37
4.3. 1 tert-Butyl 3-(4-aminophenyl)propionate 6b
59.9 mg from 68.8 mg 5b (99%).
1H NMR (400 MHz, CDCl3) δ 6.98 (d, J = 7.7 Hz, 2H), 6.61 (d, J
= 7.6 Hz, 2H), 3.57 (br.s, 2H), 2.79 (t, J = 7.8 Hz, 2H), 2.47 (t, J
= 7.8 Hz, 2H), 1.42 (s, 9H); 13C NMR (101 MHz, CDCl3) δ
172.5, 144.5, 130.9, 129.1, 115.2, 80.2, 37.5, 30.4, 28.1; HRMS
(ESI-TOF, m/z): calculated for C18H20NO2 ([M+ H]+): 222.1489,
found: 222.1484. The data are consistent with values reported in
the literature.33
4.11. 1-[(2-aminophenyl)methyl]pyrrole-2-carbinol 7
Batch: a slurry consisting of 8 (200 mg, 0.86 mmol, 1 equiv.),
K2CO3 (80 mg, 0.60 mmol, 0.7 equiv.), 5% Pd-C (4 mg, 0.002
equiv.) in H2O (1.0 mL) and THF (1.5 mL) was heated to 60 °C.
To this vigorously stirred mixture was added dropwise a solution
of NaH2PO2 (350 mg, 3.27 mmol, 3.8 equiv.) in H2O (1 mL). The
reaction was refluxed for 3 h, cooled to room temperature, and
toluene (5 mL) was added. The mixture was then filtered through
Celite™, the layers separated, and the aqueous extracted with
toluene (2 x 10 mL). The combined organic layers were washed
with H2O (10 mL), dried (MgSO4), filtered and concentrated in
vacuo. The crude product was crystallised from hexane/diethyl
ether (1/1) to yield 7 (90 mg, 0.49 mmol, 65%) as a brown
powder;
4.4. Methyl-3-methyl-4-nitro benzoate 6c
43.4 mg from 53.4 mg 5c (96%).
1H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 7.7 Hz, 1H), 7.05
(app.t, J = 7.8 Hz, 1H), 6.82 (d, J = 7.9 Hz, 1H), 3.88 (s, 3H),
3.73 (br.s, 2H), 2.34 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
169.1, 145.5, 131.6, 126.1, 122.9, 120.4, 118.2, 51.9, 13.8;
HRMS (ESI-TOF, m/z): calculated for C9H11NO2 ([M+ H]+):
166.0863, found: 166.0857. The data are consistent with values
reported in the literature.34
Flow: The system (see Figure 4), incorporating the 1g Pd-C
cartridge (20.0 mm OD, 15.0 mm ID), was primed by pumping
through ethanol at a rate of 0.5 mL min-1. To avoid an
overpressure of the system in the event of blockage, the upper
pressure cut-off limit on the Knauer pump was set to 25 bar. The
tube-in-tube device was subjected to 16 bar of hydrogen pressure
using a 2-stage regulator on the cylinder. Priming continued for
30 minutes before starting the run (out-gassing of hydrogen
downstream of the back-pressure regulator could be observed
after about 20 minutes). The starting nitro-alcohol 8 (36.0 mg,
0.155 mmol) was dissolved in EtOH (18 mL solution). This
solution was loaded into an 18 mL injection loop using a syringe.
The injection loop was switched into the flow stream and the
4.5. 4-Amino-3-fluoro-benzoic acid 6d
41.6 mg from 50.6 mg 5d (98%).
1H NMR (400 MHz, CD3CN) δ 7.63 (d, J = 8.3 Hz, 1H), 7.59 (s,
1H), 6.84 (t, J = 8.4 Hz, 1H); 13C NMR (101 MHz, CD3CN) δ
167.1, 151.7, 149.4, 141.5, 127.7, 116.9, 115.6; HRMS (ESI-
TOF, m/z): calculated for C6H7FNO2 ([M+ H]+): 156.0455,
found: 156.0453.
4.6. 5-Amino-2-methyl-benzoic acid 6e
39.3 mg from 49.6 mg 5e (95%).

8
Tetrahedron
ACCEPTED MANUSCRIPT
output from the system was collected for 180 min. Solvent was
3
Masterson, L. A.; Spanswick, V. J.; Hartley, J. A.; Begent, R.
H.; Howard, P. W.; Thurston, D. E. Bioorg. Med. Chem. Lett.
2006, 16, 252.
(a) Artico, M. D., G.; Filacchioni, G.; Giuliano, R. Farmaco
Sci. 1969, 24, 276; (b) Wright, W. B.; Greenblatt, E. N.; Day,
I. P.; Quinones, N. Q.; Hardy, R. A. J. Med. Chem. 1980, 23,
462; (c) Craighead, M.; Palin, R.; Murray, N.; Lindsay, D.;
A2, W., 2012; (d) Failli, A. A.; Steffan, R. J.
WO/2000/046225 A.2000.
removed under reduced pressure (using a rotary evaporator
followed by a 2-stage rotary vane upmp) to afford an off-white
solid (27.8 mg, 97%);
4
o
1
Rf 0.17 (1/2, ethyl acetate/hexane); mp 113-115 C; H NMR
(400 MHz; CDCl3) δ 7.18 (t, J = 7.7 Hz, 1H, H2), 7.01 (d, J = 7.3
Hz, 1H, H4), 6.80 (t, J = 7.1 Hz, 1H, H3), 6.71 (d, J = 8.0 Hz, 1H,
H1), 6.64 (t, J = 2.2 Hz, 1H, H5), 6.20 (dd, J = 3.3, 1.7 Hz, 1H,
H6), 6.13 (t, J = 3.1 Hz, 1H, H7), 5.10 (s, 2H, CH2N), 4.66 (s, 2H,
CH2O); 13C NMR (100 MHz; CDCl3) δ 144.9, 131.6, 129.8,
129.2, 122.4, 121.5, 118.7, 116.3, 109.5, 107.6, 56.6, 47.9; MS
ESI+ m/z 225 ([M+Na]+, 100%); HRMS ESI+ m/z Found:
225.1013 for C12H14N2ONa [(M+Na)+] requires 225.0998; CCDC
No: 1816148.
5
6
Henry, W. Philosophical Transactions of the Royal Society
of London 1803, 93, 29.
(a) Eigenberger, G.; Wegerle, U. ACS Symp. Ser. 1982, 196,
133; (b) MacDiarmid, J. A.; North, G. J. T. Plant/Operations
Progress 1989, 8, 96; (c) Dryer, F.; Chaos, M.; Zhao, Z.;
Stein, J.; Alpert, J.; Homer, C. Combust. Sci. Technol. 2007,
179, 663; (d) Lee, B. J.; Jeung, I.-S. Int. J. Hydrogen Energy
2009, 34, 8763.
4.12. 1-[(2-nitrophenyl)methyl]pyrrole-2-carbinol 8
To a stirred solution of 1-[(2-nitrophenyl)methyl]pyrrole-2-
carbaldehyde1 (200 mg, 0.87 mmol, 1 equiv.) in dry THF (8 mL)
at 0 °C was added NaBH4 (60 mg, 1.6 mmol, 1.9 equiv.) and
stirring was continued for 48 h at room temperature. The reaction
mixture was acidified with 1 M HCl to pH 5 and the solvent
removed in vacuo. The crude oil was reconstituted between H2O
(25 mL) and CH2Cl2 (25 mL) and the aqueous phase extracted
with CH2Cl2 (2 x 25 mL). The combined organic phases were
washed with saturated aqueous sodium chloride (20 mL), dried
(MgSO4), filtered and concentrated in vacuo. Purification by
Reveleris® automated silica gel flash column chromatography
(liquid injection onto column), eluting with ethyl acetate/hexane
(0/100, 40/60, 60/40 and 100/0) afforded 8 (180 mg, 0.77 mmol,
93%) as a brown solid. Rf = 0.38 (1/2, ethyl acetate/hexane); m.p.
7
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Ley, S. V. Chemical Record 2012, 12, 378; (i) Ley, S. V.;
Fitzpatrick, D. E.; Ingham, R. J.; Myers, R. M. Angewandte
Chemie-International Edition 2015, 54, 3449; (j) Plutschack,
M. B.; Pieber, B.; Gilmore, K.; Seeberger, P. H. Chem. Rev.
2017, 117, 11796; (k) Pieber, B.; Gilmore, K.; Seeberger, P.
H. J. Flow Chem. 2017, 7, 129; (l) Gemoets, H. P. L.; Su, Y.
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K. F. Green Chem. 2013, 15, 1456.
98-100 oC; H NMR (300 MHz; CDCl3) δ 8.15 (dd, J = 8.1, 1.4
1
Hz, 1H, H1), 7.53 (td, J = 7.6, 1.4 Hz, 1H, H3), 7.47-7.41 (m, 1H,
H2), 6.70 (dd, J = 2.7, 1.8 Hz, 1H, H5), 6.46 (dd, J = 7.7, 1.2 Hz,
1H, H4), 6.23-6.18 (m, 2H, H6, H7), 5.61 (s, 2H, CH2N), 4.44 (s,
2H, CH2OH), 1.84 (br.s., 1H, OH); 13C NMR (75 MHz; CDCl3)
δ 146.7, 135.5, 134.4, 132.1, 128.2, 128.0, 125.0, 123.5, 109.9,
108.2, 56.5, 48.3; MS ESI- m/z 231 ([M-H]-, 100%); HRMS
ESI- m/z Found: 231.0776 for C12H11N2O3 [(M-H)-], requires
231.0775.
Acknowledgements
8
(a) Razzaq, T.; Kappe, C. O. Chemistry-an Asian Journal
2010, 5, 1274; (b) Muller, S. T. R.; Wirth, T. Chemsuschem
2015, 8, 245; (c) Delville, M. M. E.; van Hest, J. C. M.;
Rutjes, F. Beilstein J. Org. Chem. 2013, 9, 1813; (d)
Movsisyan, M.; Delbeke, E. I. P.; Berton, J.; Battilocchio, C.;
Ley, S. V.; Stevens, C. V. Chem. Soc. Rev. 2016, 45, 4892;
(e) Singh, R.; Lee, H. J.; Singh, A. K.; Kim, D. P. Korean J.
Chem. Eng. 2016, 33, 2253.
(a) Knowles, J. P.; Elliott, L. D.; Booker-Milburn, K. I.
Beilstein J. Org. Chem. 2012, 8, 2025; (b) Hook, B. D. A.;
Dohle, W.; Hirst, P. R.; Pickworth, M.; Berry, M. B.;
Booker-Milburn, K. I. J. Org. Chem. 2005, 70, 7558; (c)
Castell, O. K.; Allender, C. J.; Barrow, D. A. Lab Chip 2009,
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Keele University are thanked for a studentship to E.D. We also
thank the EPSRC UK National Mass Spectrometry Facility
(NMSF) at Swansea University and Dr Ilia Koev of Biogeneral
Inc., San Diego, California, for donating the Teflon AF-2400
tubing used in this work.
Supplementary Material
Supplementary data associated with this article can be found,
in the online version, at:
9
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