A flow chemistry route to 2-phenyl-3-(1H-pyrrol-2-yl)propan-1-amines

Article abstract of DOI:10.1016/j.tetlet.2011.01.096

The Knoevenagel condensation of pyrrole-2-carboxaldehyde (1) with a range of substituted benzyl nitriles (2a-e) afforded rapid access to a family of α,β-unsaturated nitriles (3a-e) in good yields (67-78%). Flow hydrogenation (ThalesNano H-cube) at 60 °C, 50 bar H₂ pressure, 1.0 mL/min through a 10% Pd-C catalyst selectively, and quantitatively, hydrogenated the olefin double bond (4a-e). Use of a Raney Nickel catalyst at 70 °C, 70 bar H₂ pressure and flow rates of 0.5-1.0 mL/min afforded quantitative conversion into the corresponding saturated amines with the reduction of both the olefin and nitrile bonds (5a-e). The versatility of this approach was further exemplified by reaction of 5a and 5c with norcantharidin to afford acid amide norcantharidin analogues 7 and 8 as novel protein phosphatase 1 and 2A inhibitors.

Full text of DOI:10.1016/j.tetlet.2011.01.096

Tetrahedron Letters 52 (2011) 1583–1586
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A flow chemistry route to 2-phenyl-3-(1H-pyrrol-2-yl)propan-1-amines
⇑
Mark Tarleton, Adam McCluskey
Chemistry, School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW 2308, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
The Knoevenagel condensation of pyrrole-2-carboxaldehyde (1) with a range of substituted benzyl
Received 7 October 2010
Revised 22 December 2010
Accepted 21 January 2011
Available online 27 January 2011
nitriles (2a–e) afforded rapid access to a family of
a,b-unsaturated nitriles (3a–e) in good yields (67–
78%). Flow hydrogenation (ThalesNano H-cube™) at 60 °C, 50 bar H2 pressure, 1.0 mL/min through a
10% Pd-C catalyst selectively, and quantitatively, hydrogenated the olefin double bond (4a–e). Use of a
Raney Nickel catalyst at 70 °C, 70 bar H2 pressure and flow rates of 0.5–1.0 mL/min afforded quantitative
conversion into the corresponding saturated amines with the reduction of both the olefin and nitrile
bonds (5a–e). The versatility of this approach was further exemplified by reaction of 5a and 5c with nor-
cantharidin to afford acid amide norcantharidin analogues 7 and 8 as novel protein phosphatase 1 and 2A
inhibitors.
Keywords:
Knoevenagel condensation
Flow hydrogenation
Selective hydrogenation
Medicinal chemistry
Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
The current focus of our medicinal chemistry team is in the
development of protein phosphatase 1 and 2A and dynamin
GTPase inhibitors.1–3 While targets change, all medicinal chemistry
programmes require access to novel building blocks to explore
new chemical space.4 These new building blocks are initially only
required in milligram quantities. As the drug development pro-
gramme progresses, increased quantities of the drug are required.
Thus there is a pressing need to develop elegant approaches ame-
nable to the rapid production of novel building blocks, but also
production scale-up to meet the demands of whole cell, and ulti-
mately whole animal studies. In our case, this has demanded the
development of approaches capable of delivering building blocks
for libraries of 12–24 compounds and subsequent scale-up from
10 mg to 10 g.
Until recently, synthetic re-scaling required laborious re-opti-
misation of methods developed to access the small quantities of re-
agents required at the initial library synthesis stage. However, the
introduction of flow chemistry has had a significant impact on our
ability to deliver the required compound quantities both at the ini-
tial building block stage and the animal testing stages of our pro-
grammes.5–9 Recently, we had cause to require rapid access to a
range of novel amines of the type shown in Figure 1.10,11
Arom-1
NH2
N
H
generic
structure
R
Arom-2
Figure 1. Generic structure of the target bis-aromatic amines.
low generation of mg to gram quantities of each of the library
components. In the initial Knoevenagel approaches this was a rel-
atively trivial proposition, and one that has been addressed by us,
and others elsewhere.10–19 However, the hydrogenation require-
ment stalls rapid library development in a standard laboratory
environment, typically limiting this step to a batch-wise approach
with the quantity of each batch limited by the available volume of
the hydrogenating equipment. This is clearly a disadvantage not
only in regards to high throughput, but with reaction scale-up. In
efforts to accelerate both analogue development and reaction
scale-up, our team has invested heavily in flow chemistry technol-
ogy. Having access to the ThalesNano H-cube™ (H-cube) flow
hydrogenator we turned our attention to the synthesis of Type A
(4a–e) and Type B (5a–e) analogues as shown in Scheme 1.
We rationalised that access to the required amines should be
attainable by a two-step process commencing from pyrrole-2-car-
boxaldehyde (1) and a range of substituted benzyl nitriles 2a–e via
a Knoevenagel condensation.10–19 Reduction would then afford the
desired analogues. In our subsequent synthetic efforts we also im-
posed additional constraints requiring flexible approaches that al-
In
hydroxide [PhCH2NMe3(OH)] mediated Knoevenagel condensation
allowed direct access to the desired ,b-unsaturated nitriles
(Scheme 1) in good yields (67–78%).10,11,20
a typical experiment, the benzyltrimethylammonium
a
With these nitriles in hand we next turned our attention to the
flow hydrogenation using the H-cube. Flow chemistry approaches
⇑
Corresponding author. Tel.: +61 2 4921 6486; fax: +61 2 4921 5472.
E-mail address: Adam.McCluskey@newcastle.edu.au (A. McCluskey).
0040-4039/$ - see front matter Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.096

1584
M. Tarleton, A. McCluskey / Tetrahedron Letters 52 (2011) 1583–1586
CN
CN
i
N
+
N
H
H
O
R
R
1
2a-e
3a-e
ii
iii
NH2
R
5a-e
TYPE B
CN
N
N
H
H
R
4a-e
TYPE A
Scheme 1. Reagents and conditions: (i) H2O, PhCH2NMe3(OH), 50 °C, 5 h; (ii) 0.05 M 3a–e (acetone), 10% Pd-C, 50 °C, 50 bar H2, 1.0 mL/min, H-cube; (iii) 0.05 M 3a–e (1 M
NH3 in MeOH), Raney Ni, 70 °C, 70 bar H2, 0.5 mL/min, H-cube.
safety concerns normally associated with hydrogen gas and han-
Table 1
dling of catalyst materials.22
Optimisation of temperature and H2 pressure, for the reduction of 3a to 5a using a
Our first series of optimisation reactions involved passing
0.05 M solutions of (Z)-2-phenyl-3-(1H-pyrrol-2-yl)acrylonitrile
(3a) (in acetone) through each of three hydrogenation catalyst car-
tridges: 5% Pd-C; 10% Pd-C and Raney Nickel (Ra/Ni).22 To best
maximise the potential reduction in each instance our initial
examinations were conducted at 100 °C and 100 bar H2 pressure
(H-cube ‘controlled mode’), flow rate was 1.0 mL/min. No reaction
was observed with the 5% Pd-C catalyst under these conditions, but
complete reduction of the olefinic double bond was accomplished
with the 10% Pd-C catalyst (100%),23 and reduction of both the ole-
fin and the nitrile moieties was accomplished with the Raney Nick-
el (Ra/Ni) catalyst (95%). The reduced isolated yield (95% vs 100%)
with the Ra/Ni catalyst was attributed to issues with product sta-
bility and work-up. With both the catalysts we noted 100% con-
sumption of the starting material, but with the Ra/Ni catalyst,
the product was contaminated with ca. 5% of an unidentified
highly polar by-product. Filtration through a silica gel plug re-
moved this material, but afforded a slightly reduced isolated yield.
The amine produced via the Ra/Ni-catalysed reduction also rapidly
discoloured on exposure to air. In this latter case the amino ana-
logue was only obtained after the feeder solution was allowed to
re-circulate until no starting material was detected by mass spec-
trometry. While we did not explore the flow hydrogenation of the
olefinic double bond in great detail, all the evaluated analogues
Raney Ni hydrogenation catalyst at a 1.0 mL/min flow rate. Reactions were conducted
for 10 min
Entry
P (bar)
T (°C)
Conversion (%)
1
2
3
4
5
6
7
8
9
90
80
70
60
50
100
100
100
100
100
100
90
80
70
60
50
30
30
30
30
25
25
25
15
12
5
40
100
100
100
100
100
100
10
11
12
0
0
40
have facilitated rapid modification, and reaction optimisation. As
only sufficient sample was required for analysis, for example, by
HPLC or MS, incredibly short reaction times were feasible allowing
multiple runs in a single day.21 This greatly enhanced our ability to
survey a range of reaction conditions from temperature, catalyst
residence time (flow rate), stoichiometry and in this instance,
hydrogen pressure. The H-cube uses pre-packed catalyst cartridges
and in situ hydrogen generation from deionised water alleviating
Table 2
Flow hydrogenation of acrylonitrile analogues 3a–e at 60 °C and 50 bar H2 pressure at 1.0 mL/min
NH2
CN
R2
R1
acetone
R2
R1
N
N
H
Ra/Ni, H2
H
3a - e
5a - e
Entry
R1
R2
Pressure (bar)
Product
Isolated yield (%)
1
2
3
4
5
6
H
H
H
H
H
H
H
Cl
50
100
50
50
50
5a
5a
5b
5c
5d
5e
100
100
23
66
32
NO2(NH2)a
F
Cl
Cl
50
30
a
The NO2 was reduced to NH2.

M. Tarleton, A. McCluskey / Tetrahedron Letters 52 (2011) 1583–1586
1585
Table 3
Isolated yield of amines 5a–e obtained by the flow reduction of 3a–e using a Raney Ni hydrogenation catalyst at 70 °C and 70 bar H2 pressure
NH2
CN
R2
R1
1 M NH3 in MeOH
Ra/Ni, H2
R2
R1
N
N
H
H
3a - e
5a - e
Entry
R1
H
R2
Flow rate (mL/min)
Product
Yield (%)
1
2
3
4
5
H
H
H
H
Cl
0.5
1.0
0.5
0.5
0.5
5a
5b
5c
5d
5e
100
100
100
100
100
NO2(NH2)a
F
Cl
Cl
a
The NO2 was reduced to NH2.
O
O
H
N
O
H
N
N
O
H
i, ii
N
iii, iv
O
H
O
O
CO2H
CO2H
O
6
F
7
8
PP2A inhibition = 18.5 3.50 µM
PP1 inhibition = 14.1 7.90 µM
PP2A inhibition = 7.25 1.25 µM
PP1 inhibition = 4.5 1.55 µM
Scheme 2. Reagents and conditions: (i) 0.05 M solution of 6 (acetone), 50 °C, 50 bar H2, 1.0 mL/min (H-cube); (ii) 0.05 M solution of 5a (1 M NH3 in MeOH); (iii) 0.05 M
solution of 6 (acetone), 50 °C, 50 bar H2, 1.0 mL/min (H-cube); (iv) 0.055 M solution of 5c (1 M NH3 in MeOH), 50 °C, 50 bar H2, 1.0 mL/min (H-cube). Protein phosphatase
activity (IC50 values) of 7 and 8.
were smoothly and cleanly converted into the saturated nitrile
analogues, 4a–e.
quantitatively into the desired 2-phenyl-3-(1H-pyrrol-2-yl)pro-
pan-1-amine (5a) under these conditions. Poor conversion of the
other analogues was noted, ranging from 23% (Table 2, entry 3)
to 66% (Table 2, entry 4). We also noted simultaneous reduction
of the aromatic NO2 moiety to NH2 under these conditions (Table
2, entry 3). The failure to achieve complete conversion into the
bis-aromatic amines significantly complicated product isolation
and purification.
Given the poor yields observed and the low conversion rates we
initiated an additional evaluation and optimisation cycle. Repeat-
ing the flow reduction of 3a–e (as 0.05 M solutions) in 1 M NH3/
MeOH at 70 bar H2 pressure, 70 °C and 1.0 (or 0.5) mL/min allowed
Having established that the 10% Pd-C and Ra/Ni catalysts affor-
ded two different products, and that we were unable to determine
reaction conditions under which only the nitrile group was re-
duced (data not shown), we sought to optimise the flow hydroge-
nation conditions that would most expediently allow the synthesis
of the desired bis-aromatic amines (see Fig. 1). In this evaluation
process we did not isolate the reduced product, but conducted a ra-
pid scan of multiple reaction conditions. With our initial efforts
conducted at 100 °C, we commenced our evaluation at this tem-
perature and reduced the H2 pressure. The reaction flow rate was
fixed at 1.0 mL/min. Table 1, entries 1–6; stepped the hydrogen
pressure downwards in 10 bar increments at a constant 100 °C,
and it is clear from the data presented that all H2 pressures evalu-
ated gave the desired product. Next we fixed the H2 pressure at
100 bar and stepped the reaction temperature down in 10 °C incre-
ments from 90 to 40 °C. Here no product was observed at 40 or
50 °C, but a low conversion of 5% was noted at 60 °C (Table 1, en-
tries 7–12).
Having rapidly surveyed the hydrogenation condition require-
ments for the phenyl analogue (5a), we applied the mildest full
conversion conditions of 60 °C and 50 bar H2 pressure to the series
of acrylonitrile analogues of interest (3a–e; see Scheme 1 and Table
2 for details). In this series of experiments the reaction was al-
lowed to continue uninterrupted for ca. 20 min, which ensured
the collection of sufficient sample for purification, identification
and yield calculations. As can be seen from Table 2, only the parent
(Z)-2-phenyl-3-(1H-pyrrol-2-yl)acrylonitrile (3a) was converted
complete conversion of the
a,b-unsaturated nitriles into the de-
sired bis-aromatic amines (5a–e, Table 3).24
To demonstrate further the versatility of our approach, bis-aro-
matic amines 5a and 5c were dissolved in acetone (as 0.05 M solu-
tions) and subjected to flow hydrogenation conditions in the
presence of 5,6-dehydronorcantharidin (6) which gave the corre-
sponding ring-opened acid amides 7 and 8 (Scheme 2). These com-
pounds proved to be effective protein phosphatase 1 and 2A
inhibitors (see Scheme 2 for data). This demonstrated the versatil-
ity of flow chemistry approaches to the rapid development of bio-
logically active molecules.
In conclusion we have reported an elegantly simple flow chemis-
try approach to a series of bis-aromatic amines 5a–e that have been
further utilised in the development of novel norcantharidin deriva-
tives 7 and 8. Judicious choice of hydrogenation catalyst allows the
reduction of either the olefin double bond (10% Pd-C) (4a–e) or
reduction of the a,b-unsaturated nitrile (Raney Nickel) (5a–e). The

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M. Tarleton, A. McCluskey / Tetrahedron Letters 52 (2011) 1583–1586
16. Sonawane, Y. A.; Phadtare, S. B.; Borse, B. N.; Jagtap, A. R.; Shankarling, G. S. Org.
Lett. 2010, 12, 1456–1459.
17. Ryabukhin, S. V.; Plaskon, A. S.; Volochnyuk, D. M.; Pipko, S. E.; Shivanyuk, A.
N.; Tolmachev, A. A. J. Comb. Chem. 2007, 9, 1073–1078.
use of flow chemistry approaches allowed rapid surveying of the
reaction conditions and the ability to up-scale the quantity of the
product produced by simply increasing the reaction time.
18. McCluskey, A.; Robinson, P. J.; Hill, T.; Scott, J. L.; Edwards, J. K. Tetrahedron Lett.
2002, 43, 3117–3120.
19. Correa, W. H.; Edwards, J. K.; McCluskey, A.; McKinnon, I.; Scott, J. L. Green
Chem. 2003, 5, 30–33.
Acknowledgements
20. Example synthesis of pyrrole-2-ylacrylonitriles: (Z)-2-Phenyl-3-(1H-pyrrol-2-
yl)acrylonitrile (3a):10 1H-Pyrrole-2-carbaldehyde (1) (165 mg, 1.74 mmol) was
added to vigorously stirred H2O (10 mL) and heated to 50 °C upon which it
dissolved. Phenylacetonitrile (2a) (193 mg, 1.65 mmol) was then slowly added
forming a suspension. Heating was continued at 50 °C and once a clear solution
was evident, typically 5–10 min, 40% PhCH2NMe3(OH) (7 mL) was added
dropwise. The reaction vessel was sealed and the mixture stirred at 50 °C for
5 h, the solution filtered hot, washed with warm H2O and dried under suction
and recrystallised from EtOH to afford 3a as a brown solid; 73%; mp 94–96 °C.
1H NMR (CDCl3, 300 MHz): d 7.61–7.57 (m, 2H), 7.45–7.40 (m, 2H), 7.42 (s, 1H),
7.35–7.30 (m, 1H), 7.08–7.06 (m, 1H), 6.73 (dd, J = 1.4, 3.7 Hz, 1H), 6.37 (dd,
J = 1.4, 3.7, 1H); 13C NMR (CDCl3, 75 MHz): d 133.4, 130.7, 128.5, 127.6, 127.2,
124.4, 123.5, 120.1, 118.5, 110.3, 100.8.
21. Clapham, B.; Wilson, N. S.; Michmerhuizen, M. J.; Blanchard, D. P.; Dingle, D.
M.; Nemcek, T. A.; Pan, J. Y.; Sauer, D. R. J. Comb. Chem. 2008, 10, 88–93.
22. Available from http://www.thalesnano.com (accessed Nov 2010).
23. Example reduction of the olefin moiety: 2-Phenyl-3-(1H-pyrrol-2-
yl)propanenitrile (4a):11 (Z)-2-Phenyl-3-(1H-pyrrol-2-yl)acrylonitrile (3a)
(990 mg, 5.1 mmol) was dissolved in sufficient freshly distilled dry acetone
(100 mL) to form a 0.05 M solution. This solution was hydrogenated using the
ThalesNano H-cube™ using a 10% Pd/C catalyst at 1 mL/min flow rate, 50 °C
and 50 bar H2 pressure. The acetone was removed in vacuo and the crude oil
was subjected to flash silica chromatography (1:1 CHCl3/hexanes) to afford 4a
as a brown oil; 98%. 1H NMR (CDCl3, 300 MHz): d 8.03 (br s, 1H), 7.42–7.35 (m,
3H), 7.29–7.26 (m, 2H), 6.69–6.67 (m, 1H), 6.15–6.13 (m, 1H), 6.03–6.02 (m,
1H), 4.01 (t, J = 7.4 Hz, 1H), 3.28–3.14 (m, 2H). 13C NMR (CDCl3,75 MHz): d
134.5, 128.6, 127.8, 126.8, 125.7, 120.4, 117.3, 108.1, 107.4, 38.4, 34.0.
24. Example reduction of the olefin and nitrile moieties: 2-(4-Fluorophenyl)-3-
(1H-pyrrol-2-yl)propan-1-amine (5c): a solution of (Z)-2-(4-fluorophenyl)-3-
(1H-pyrrol-2-yl)acrylonitrile (3c) (0.05 M, 990 mg, 4.6 mmol) in 1 M NH3 in
MeOH (100 mL) was hydrogenated using the ThalesNano H-cube™ using a Ra/
Ni catalyst at 0.5 mL/min flow rate, 70 °C and 70 bar H2 pressure. The solvent
was removed in vacuo and the crude oil subjected to flash silica
chromatography (0.05:0.95 MeOH/CH2Cl2) to afford 5c as a clear oil; 100%.
1H NMR (CDCl3, 300 MHz): d 8.47 (br s, 1H), 7.15–7.10 (m, 2H), 7.04–6.98 (m,
2H), 6.59–6.58 (m, 1H), 6.08–6.06 (m, 1H), 5.84–5.83 (m, 1H), 2.97–2.85 (m,
5H), 2.41 (br s, 2H). 13C NMR (CDCl3, 75 MHz): d 162.8, 159.5, 138.0, 129.2,
128.7, 116.0, 115.1, 114.9, 107.5, 105.9, 47.9, 46.2, 32.0; HRMS calculated for
(M+H+): C13H16FN2, 219.1298; found 219.1307.
The authors acknowledge the financial support of the Australian
Research Council, the Australian Cancer Research and Ramaciotti
Foundations, and John Morris Scientific, Australia. M.T. acknowl-
edges the UNI-PRS postgraduate funding from the University of
Newcastle. Protein phosphatase inhibition data for 7 and 8 were
determined by Drs Jennette Sakoff and Jayne Gilbert, Calvary Mater
Hospital, Newcastle Australia.
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