An integrated microreactor for the multicomponent synthesis of α-aminonitriles

Article abstract of DOI:10.1021/op800025p

Initial steps have been taken to develop an integrated microreactor, capable of performing multicomponent reactions consisting of both solution phase and heterogeneously catalyzed steps. Using the multicomponent Strecker reaction as a model, five α-aminonitriles were synthesized in excellent yields (>99.5%) and analytical purity, under continuous flow conditions.

Full text of DOI:10.1021/op800025p

Organic Process Research & Development 2008, 12, 1001–1006
Communications to the Editor
An Integrated Microreactor for the Multicomponent Synthesis of r-Aminonitriles1
Charlotte Wiles* and Paul Watts*
Department of Chemistry, The UniVersity of Hull, Cottingham Road, Hull HU6 7RX, U.K.
Scheme 2. Illustration of the model reaction evaluated
within an integrated microreactor and the competing
cyanohydrin formation found to occur in conventional batch
reactors
Abstract:
Initial steps have been taken to develop an integrated microreactor,
capable of performing multicomponent reactions consisting of both
solution phase and heterogeneously catalyzed steps. Using the
multicomponent Strecker reaction as a model, five r-aminonitriles
were synthesized in excellent yields (>99.5%) and analytical purity,
under continuous flow conditions.
Introduction
With interest in nonproteinogenic R-amino acids on the
increase, there is a growing demand for novel and efficient
techniques that enable the synthesis of such non-natural
compounds. Although many synthetic procedures have been
reported, few are suitable for the incorporation of alkyl imine
substrates, often resulting in low yields and selectivities. One
synthetically useful approach is the Strecker reaction, which as
Scheme 1illustrates, is a three-component reaction between a
its synthetic utility, the use of expensive Lewis acid catalysts,
harsh reaction conditions and somewhat variable yields preclude
the use of the Strecker reaction on a production scale. In addition
a major drawback of the one-pot Strecker reaction is the
competing cyanohydrin formation, as illustrated in Scheme 2,
which is particularly problematic when employing aromatic
aldehyde precursors; as the respective aldimine forms slowly,
leaving the aldehyde available for competing cyanohydrin
formation, resulting in poor reaction selectivity.
Scheme 1. Schematic illustrating the synthesis of
r-aminonitriles and their subsequent use in the preparation
of non-natural amino acids
Owing to the new and interesting opportunities for the
management of chemical reactions that microreaction technol-
ogy offers, such as enhanced process safety and rapid reaction
optimization, efficient catalyst recycle and production volume
flexibility,5 we embarked upon the development of a microf-
luidic system capable of integrating solution-phase and hetero-
geneously catalyzed reaction steps in a single reactor. By using
this approach we aimed to evaluate if sequential reactant
addition, coupled with the use of a solid-supported Lewis acid
catalyst, would allow for the efficient and selective synthesis
of R-aminonitriles (Figure 1), compared to the conventional one-
pot methodology.
carbonyl-containing compound, an amine, and a cyanide
source.2 The resulting R-aminonitrile can then be hydrolysed,
followed by deprotection, to afford an array of non-natural
amino acids, or be used as a precursor in the preparation of
nitrogen-containing heterocycles and 1,2-diamines.3,4 Despite
(5) (a) For recent reviews of the technology, see: Fukuyama, T.; Rahman,
M. T.; Sato, M.; Ryu, I. Synlett 2008, 2, 151. (b) Wiles, C.; Watts, P.
Eur. J. Org. Chem. 2008, http://dx.doi.org/10.1002/ejoc.200701041. (c)
Wiles, C.; Watts, P. Chem. Commun. 2007, 443. (d) Mason, B. P.; Price,
K. E.; Steinbacher, J. L.; Bogdan, A. R.; McQuade, D. T. Chem. ReV.
2007, 107, 2300. (e) Geyer, K.; Codee, J. D. C.; Seeberger, P. H. Chem.
Eur. J. 2006, 12, 8434.
* Corresponding authors. (C.W.) E-mail: c.wiles@chem.hull.ac.uk; (P.W.)
E-mail: p.watts@hull.ac.uk.
(1) Presented in part at the 234th American Chemical Society National
Meeting, Boston, MA, 2007. Wiles, C. Abstr. Pap. Am. Chem. 2007,
ORGN 105.
(2) Strecker, A. Liebigs Ann. Chim. 1850, 75, 27.
(3) Groger, H. Chem. ReV. 2003, 103, 2795.
(4) Weinstock, L. M.; Davis, P.; Handelsman, B.; Tull, R. J. Org. Chem.
1967, 32, 2823.
(6) Caution! All experiments should be performed within a fumecupboard
in order to avoid inhalation of HCN, which may be liberated upon
hydrolysis of trimethylsilylcyanide (TMSCN) should the reaction not
go to completion.
10.1021/op800025p CCC: $40.75
Published on Web 05/17/2008
2008 American Chemical Society
Vol. 12, No. 5, 2008 / Organic Process Research & Development
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within the catalyst bed (0.3 cm (wide) × 200 µm (deep) × 2.1
cm (long)) which was dry-packed with polymer-supported
ethylenediaminetetraacetic acid ruthenium (III) chloride (PS-
RuCl3) (0.01 g, 0.26 mmol g-1, 50 to 100 mesh), (Figure 2).
PEEK tubing (360 µm o.d. × 150 µm i.d. × 10 cm) and FEP
tubing (1/16 in. o.d. × 380 µm i.d. × 4 cm) was subsequently
glued in place, using epoxy resin (Bondmaster, UK), at the inlets
and outlet, respectively. As Figure 3 illustrates, fluidic intercon-
nections were made between the reactor and syringes (Hamilton,
Switzerland) using a series of commercially available connectors
(Supelco, UK).
Prior to evaluating the performance of the reactor for the
multicomponent reaction illustrated in Scheme 2, the reaction
conditions required for the in situ preparation of the aldimines
was first investigated. To achieve this, solutions of 2-phenyl-
ethylamine (0.4 M in MeCN) and 4-bromobenzaldehyde (0.4
M in MeCN) were introduced from separate inlets (A and B)
into the microchannel network, under pressure-driven flow
(5-100 µL min-1), where they were reacted for a specified
period of time prior to collection and analysis of the reaction
mixture (at outlet C, 0.2 M in MeCN) by GC-MS. As
illustrated in Figure 4a, employing a flow rate of 100 µL min-1
(residence time <0.2 s) afforded incomplete conversion of
4-bromobenzaldehyde to the respective imine, [1-(4-bromophe-
nyl)meth-(E)-ylidene]phenethylamine. Further optimization of
the reaction conditions, however, afforded quantitative synthesis
of [1-(4-bromophenyl)meth-(E)-ylidene]phenethylamine, when
operating over a flow rate range of 1-25 µL min-1, which
corresponds to a residence time of between 21.6 and 0.9 s.
Having successfully achieved our first aim, which was to
efficiently prepare an imine, the next step of the investigation
was to evaluate the synthesis of the respective R-aminonitrile
under continuous flow.
In order to determine the optimal flow rate required to
perform the nucleophilic addition step and identify the rate-
limiting step, we initially focused on the use of a preformed
imine, [1-(4-bromophenyl)meth-(E)-ylidene]phenethylamine.
Using the reactor illustrated in Figure 1, a solution of [1-(4-
bromophenyl)meth-(E)-ylidene]phenethylamine (0.2 M in MeCN)
was introduced from inlet A and a solution of TMSCN (0.2 M
in MeCN) from inlet C; the reactants mixed in the central
channel prior to reaction within the catalyst bed, which
contained PS-RuCl3. The resulting reaction products were
collected at outlet D (0.1 M) after 2.5 h, concentrated in vacuo,
prior to dissolution of the resulting solid in CDCl3 and analysis
by NMR spectroscopy, whereby comparison of the integrals
Figure 1. Schematic illustrating the reactor manifold designed
for the evaluation of the multicomponent Strecker reaction,
under continuous flow.6
Figure 2. Polymer-supported ethylenediaminetetraacetic acid
ruthenium (III) chloride (PS-RuCl3), the Lewis acid catalyst
evaluated within the microreactor.
Results and Discussion
As a result of the hydrolytic instability of many imines,
which often leads to difficulties in their isolation and purifica-
tion, it was desirable to generate these reactive intermediates
in situ in order to achieve our aim of providing a simple and
efficient route to the selective synthesis of R-aminonitriles. With
this in mind, a borosilicate glass microreactor with an overall
footprint of 3.0 cm × 3.0 cm × 0.6 cm was fabricated. As
Figure 1 illustrates, the reaction manifold consists of a T-
intersection where the aldehyde (inlet A) and amine (inlet B)
are mixed under diffusion and reacted within a central channel
(150 µm (wide) × 50 µm (deep) × 5.6 cm (long)) to afford
the aldimine. Subsequent introduction of the cyanide source,
in this case trimethylsilyl cyanide (TMSCN), through inlet C
enables the reagents to mix, again under diffusion, before
nucleophilic addition of the cyanide anion to the imine occurs
Figure 3. Interconnection strategy used to deliver/remove solutions to/from the microreactor.
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lowed by the synthesis of 2-(4-bromophenyl)-2-(phenethylami-
no)acetonitrile was investigated in series.
As Figure 4 illustrates, quantitative conversion is attainable
for both steps and in line with this observation, the multicom-
ponent reaction was performed at a total flow rate of 10 µL
min-1. To conduct a reaction, 4-bromobenzaldehyde (0.4 M)
was introduced from inlet A, 2-phenylethylamine (0.4 M) from
inlet B, and TMSCN (0.2 M) from inlet C (1:1:1). The reaction
products were collected at outlet D, over a period of 2.5 h, and
concentrated in vacuo to afford 2-(4-bromophenyl)-2-(phen-
ethylamino)acetonitrile as a pale-yellow solid (0.047 g, 99.5%).
Analysis of the material by 1H NMR spectroscopy confirmed
quantitative conversion to the desired product, and unlike
analogous batch reactions, whereby 18% cyanohydrin formation
was observed, no competing cyanation of the aldehyde was
detected (Figure 5). To further evaluate the purity of the
R-aminonitrile synthesized under continuous flow conditions,
the material was also evaluated by 13C NMR, IR spectroscopy,
MS and elemental analysis. To compare the purity of products
synthesized under flow conditions with those prepared in batch,
a sample of 2-(4-bromophenyl)-2-(phenethylamino)acetonitrile
was evaluated by Inductively Coupled Plasma-Mass Spectrom-
etry (ICP-MS) as a means of determining the proportion of Ru
leached from the catalyst. Using this approach, the material
synthesized in batch was found to contain 440 ppm of Ru,
compared to that prepared within the flow reactor that contained
a proportion of Ru below the instruments limit of detection and
Figure 4. Summary of the reaction conditions evaluated for
the synthesis of (a) [1-(4-bromophenyl)meth-(E)-ylidene]phen-
ethyl-amine and (b) 2-(4-bromophenyl)-2-(phenethylamino)-
acetonitrile.
(imine δ 8.1 ppm and R-aminonitrile δ 4.8 ppm) afforded
quantification of the percentage conversion achieved. As Figure
4b illustrates, employing a flow rate of 100 µL min-1 afforded
70.0% conversion to the desired R-aminonitrile, which was
subsequently improved upon by increasing the reactant resi-
dence time, as a function of flow rate, to afford quantitative
conversion of the imine to 2-(4-bromophenyl)-2-(phenethy-
lamino)acetonitrile. Having confirmed that both reaction steps
could be conducted under flow conditions and identified the
cyanation as the rate-limiting step, the in situ generation of the
imine, [1-(4-bromophenyl)meth-(E)-ylidene]phenethylamine fol-
Figure 5. 1H NMR spectra of 2-(4-bromophenyl)-2-(phenethylamino)acetonitrile synthesized in a microreactor (no additional
purification performed).
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comparable with the blank; an observation that is attributed to
mechanical degradation of the catalyst in a stirred reactor.
Finally to confirm that the PS-RuCl3 was acting as a catalyst,
the reaction was performed in its absence, packing the catalyst
bed with PS-EDTA7 Under the aforementioned reaction condi-
tions, no R-aminonitrile formation was observed; instead we
observed quantitative formation of the imine as expected.
Generality of the Technique. Having demonstrated the
ability to synthesize an R-aminonitrile with excellent selectivity
under continuous flow conditions, we subsequently evaluated
the preparation and reaction of a series of hydrolytically unstable
imines. As Table 1 illustrates, a further four amines were
investigated, ranging from aromatic derivatives to a cyclic
aliphatic amine, which afforded an iminium ion as the reactive
intermediate. Using this approach it was found that the optimal
flow rate for aromatic derivatives (entries 1-4) was 10 µL
min-1, compared to the more reactive pyrrolidine (entry 5)
which afforded quantitative conversion to the R-aminonitrile
at a flow rate of 20 µL min-1.
In an attempt to increase the throughput of the system,
conducting the reactions at an elevated temperature was
investigated. Employing the aforementioned reaction conditions,
the microreactor was placed in a silicone oil bath and heated
to 40 °C. Upon initial purging of the system with anhydrous
MeCN, at a total rate of 10 µL min-1, coloration of the solvent
stream was noted at outlet D, an observation that was attributed
to leaching of Ru from the catalyst. Consequently further
investigations will focus on other methods of increasing reactor
throughput such as increased reactant concentration and alterna-
tive catalysts.
amineacetic acid acetamide (3.0-4.0 mmol N g-1, 50-100
mesh, 1% cross-linked with DVB), polymer bound were sieved
to afford a particle size distribution of 38-75 µm (Endcotts,
UK).
Instrumentation. 1H and 13C NMR spectra were obtained
at room temperature as solutions in deuterochloroform (CDCl3)
using tetramethylsilane (TMS) as an internal standard. The
spectra were recorded using a Jeol GX400 spectrometer and
the chemical shifts given in parts per million (ppm) with
coupling constants reported in Hertz (Hz). The following
abbreviations are used to report NMR data, s ) singlet, d )
doublet, t ) triplet, brs ) broad singlet, m ) multiplet, and C0
) quaternary carbon. In the case of previously prepared
compounds, all spectral data obtained was consistent with the
literature. Gas chromatography-mass spectrometry (GC-MS)
was performed using a Varian GC (CP-3800) coupled to a
Varian MS (2000) with a CP-Sil 8 (30 m) column (Phenom-
enex, UK) and ultrahigh-purity helium (99.999%, Energas, UK)
carrier gas. Samples were analyzed using the following method,
injector temperature 200 °C, helium flow rate 1 mL min-1, oven
temperature 60 °C for 1 min then ramped to 270 at 25 °C min-1,
with a 2.5 min filament delay. Elemental analyses were
performed using a Carlo Erba EA1108 CHN analyzer. Infrared
spectra (4000-600 cm-1) were recorded using a Perkin-Elmer
Paragon 1000 FT-IR spectrometer and peaks reported in
wavenumbers (cm-1). Melting points were measured on a
Gallenkamp melting point apparatus and are reported uncor-
rected, based on three replicates. Mass spectra were obtained
using a Shimadzu QP5050A instrument and an EI ionization
source. Reactant delivery to the microreactor was controlled
by the use of a displacement pump (MD-1001, Bioanalytical
Systems Inc.), capable of delivering three solutions at flow rates
between 0.1 to 100 µL min-1 (calibrated for a 1 mL syringe).
The borosilicate glass microreactor was fabricated in-house
using photolithography, wet-etching and thermal annealing and
had channel dimensions of 150 µm (wide) × 50 µm (deep) ×
5.6 cm (long) and a catalyst bed of 3 mm (wide) × 150 µm
(deep) × 2.1 cm (long)).
Conclusions
In summary, we report herein a reactor capable of performing
multicomponent reactions consisting of both solution phase and
polymer-assisted steps. This approach, not only afforded
superior selectivity when compared to analogous batch reac-
tions, due to sequential reactant addition, but also enabled an
impressive catalytic turnover in excess of 289 for the five
examples reported herein. Furthermore, the technique described
affords a simple route to the synthesis of R-aminonitriles without
the need for additional purification steps, whilst preventing
catalyst leaching (compared to a typical stirred protocol where
degradation led to the release of 440 ppm of Ru into the reaction
product). With this in mind, further investigations are currently
underway within our laboratories in order to increase reactor
throughput, product diversity and chemoselectivity, the results
of which will be published in due course.
General Batch Protocol. To perform the Strecker reaction
under batch conditions, the aldehyde (0.15 mmol) and amine
(0.15 mmol) were added to a stirred vessel containing polymer-
supported ethylenediaminetetraacetic acid ruthenium (III) chlo-
ride (0.01 g, 0.026 mmol) in anhydrous MeCN (5 mL). After
20 min at room temperature, TMSCN (0.15 mmol) was added
and the reaction mixture stirred for an additional 24 h. After
which time the reaction mixture was filtered, under suction, to
remove the catalyst and the filtrate concentrated in vacuo. The
resulting reaction mixture was dissolved in CDCl3 (doped with
TMS) and analyzed by 1H NMR spectroscopy.
Experimental Section
Materials. All solvents were purchased as puriss grade
(>99.5%) over molecular sieves (H2O < 0.005%) from Fluka
(Gillingham, UK), and unless otherwise stated, chemicals were
purchased from Sigma-Aldrich (Gillingham, UK) and used as
received. Prior to use, polymer-supported ethylenediaminetet-
raacetic acid ruthenium (III) chloride (0.26 mmol Ru g-1,
50-100 mesh, 1% cross-linked with DVB) and ethylenedi-
General Microreaction Protocol. To perform a reaction,
the aldehyde and amine (0.4 M in MeCN) were introduced into
the reactor from inlets A and B, employing 500 µL syringes,
to afford, upon mixing, a 0.2 M solution of the respective imine.
TMSCN (0.2 M in MeCN) was subsequently introduced from
inlet C, using a 1 mL syringe, and the reaction mixture was
pumped through the catalyst bed, prior to collection within a
preweighed sample vial at outlet D. Varying the flow rate
enabled the effect of reactant residence time to be evaluated;
(7) Ethylenediaminetetraacetic acid acetamide polymer bound (3.62 mmol
N g-1, 50-100 mesh) is commercially available from Sigma-Aldrich.
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Table 1. Results obtained for the synthesis of five r-aminonitriles, derived from 4-bromobenzaldehyde (unless otherwise stated,
a run time of 2.5 h was employed)
a Based on the total flow obtained from three fluidic inputs. b Percent conversion determined via comparison of the 1H NMR integrals observed for the imine and
R-aminonitrile. c Run time ) 1.25 h.
once optimized, the reactor was operated for 2.5 h, after which
time the reaction products were concentrated in vacuo prior to
dilution with CDCl3 (doped with TMS) and analysis by H
NMR spectroscopy. In the case of previously unreported
compounds, the NMR sample was concentrated in vacuo and
the crude reaction product further evaluated by elemental
analysis, IR spectroscopy and mass spectrometry. It is important
to note that no additional product purification was performed
prior to analytical evaluation of the reaction products described
herein.
MHz, CDCl3/TMS) 1.85 (1H, brs, NH), 3.82 (1H, d, J 12.9,
CHH), 3.94 (1H, d, J 12.9, CHH), 4.81 (1H, s, CH), 7.28-7.41
(5H, m, 5 × ArH), 7.44 (2H, d, J 8.4, 2 × ArH) and 7.54 (2H,
d, J 8.4, 2 × ArH); 51.2 (CH2), 52.9 (CH), 118.3 (CN), 123.3
(C0Br), 127.8 (CH), 128.4 (2 × CH), 128.7 (2 × CH), 129.0
(2 × CH), 132.1 (2 × CH), 133.7 (C0) and 137.8 (C0); m/z
(E.I.) 303 (30), 302 (20), 301 (30), 274 (13), 272 (5), 195 (5),
194 (11), 106 (21), 92 (50), 91 (100) and 65 (20).
2-(4-Bromophenyl)-2-(phenethylamino)acetonitrile (En-
try 3). Conducting the reaction at a total flow rate of 10 µL
min-1 and employing 4-bromobenzaldehyde and 2-phenylethy-
lamine as reactants, the title compound was obtained as a pale
yellow solid (0.047 g, 99.5%); mpt. 91-92 °C; (Found C, 61.06;
H, 4.96; N, 8.69, C16H15N2Br requires C, 60.97; H, 4.80; N,
8.89%); νmax/cm-1 701.2, 750.6, 770.8, 811.9, 1419.6, 1450.0,
1542.2, 1581.0, 2347.4, 2896.1, 3002.7, 3056.1 and 3315.8; δH
(400 MHz, CDCl3/TMS) 1.54 (1H, brs, NH), 2.62-2.86 (2H,
m, CH2), 2.95-3.10 (2H, m, 2 × CH2), 4.75 (1H, s, CH), 7.12
(3H, m, 3 × ArH), 7.23 (2H, m, 2 × ArH), 7.43 (2H, d, J 8.4,
2 × ArH) and 7.50 (2H, d, J 8.4, 2 × ArH); δC (100 MHz,
CDCl3/TMS) 35.7 (CH2), 47.8 (CH2N), 53.6 (CH), 118.2 (CN),
122.9 (C0Br), 128.2 (C0), 128.5 (4 × CH), 128.6 (2 × CH),
131.8 (2 × CH), 133.6 (CH) and 138.8 (C0); m/z (E.I.) 317
(80), 316 (50), 315 (82), 290 (10), 288 (8), 197 (75), 196 (100),
170 (44), 169 (48), 91 (34), 90 (31), 89 (34), 77 (19) and 65
(21).
1
2-(4-Bromophenyl)-2-(phenylamino)acetonitrile (Entry
1).8 Employing 4-bromobenzaldehyde and aniline as precursors,
the microreaction was conducted at a total flow rate of 10 µL
min-1 to afford the title compound as a white crystalline solid
(0.043 g, 99.9%); δH (400 MHz, CDCl3/TMS) 3.65 (1H, brs,
NH), 5.32 (1H, d, J 3.7, CH), 6.66 (2H, d, J 8.4, 2 × ArH),
6.85 (1H, t, J 7.7, ArH), 7.20 (2H, t, J 7.7, 2 × ArH), 7.36
(2H, d, J 7.7, 2 × ArH) and 7.47 (2H, d, J 8.4, 2 × ArH); δC
(100 MHz, CDCl3/TMS) 49.8 (CH), 112.3 (2 × CH), 114.9
(CN), 116.9 (CH), 122.6 (C0Br), 128.3 (2 × CH), 129.1 (C0),
131.3 (2 × CH), 131.4 (2 × CH) and 143.7 (C0).
2-(Benzylamino)-2-(4-bromophenyl)acetonitrile (Entry 2).
Employing 4-bromobenzaldehyde and benzylamine as reactants,
the micro reaction was conducted at a total flow rate of 10 µL
min-1 to afford 2-(benzylamino)-2-(4-bromophenyl)acetonitrile
as a pale yellow oil (0.045 g, 99.9%); (Found C, 60.10; H, 4.56;
N, 9.06, C15H13N2Br requires C, 59.82; H, 4.35; N, 9.30%);
2-(4-Bromophenyl)-2-(3-phenylpropylamino)acetoni-
trile (Entry 4). Employing 4-bromobenzaldehyde and phenyl-
propylamine as reactants, the microreaction was conducted at
a total flow rate of 10 µL min-1, to afford 2-(4-bromophenyl)-
ν
max/cm-1 701.0, 736.7, 788.2, 823.5, 1454.1, 1488.2, 1551.6,
1591.1, 2303.6, 2846.5, 3030.4, 3053.5 and 3322.5; δH (400
(8) El-Ahl, S. A. Synth. Commun. 2003, 33, 989.
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2-(3-phenylpropylamino)acetonitrile as a pale-yellow gum
(0.049 g, 99.9%); (Found C, 61.95; H, 5.29; N, 8.48,
C17H17N2Br requires C, 62.02; H, 5.20; N, 8.51%); νmax/cm-1
699.7, 746.6, 817.7, 1453.0, 1487.2, 1573.3, 1589.1, 2226.6,
2855.9, 2935.0, 3025.1 and 3316.0; δH (400 MHz, CDCl3/TMS)
1.48 (1H, brs, NH), 1.76 (2H, m, CH2), 2.61-2.74 (4H, m, 2
× CH2), 4.61 (1H, s, CH), 7.12-7.30 (5H, m, 5 × ArH), 7.32
(2H, d, J 8.5, 2 × ArH) and 7.46 (2H, d, J 8.5, 2 × ArH); δC
(100 MHz, CDCl3/TMS) 30.8 (CH2), 32.9 (CH2), 46.2 (CH2),
53.5 (CH), 118.2 (CN), 122.6 (C0), 125.6 (CH), 128.0 (2 ×
CH), 128.1 (4 × CH), 131.1 (2 × CH), 133.7 (C0) and 141.8
(C0); m/z (E.I.) 329 (1), 328 (15), 304 (8), 303 (4), 301 (10),
199 (93), 198 (90), 197 (100), 196 (99), 169 (20), 118 (65), 91
(85), 77 (17) and 65 (25).
of 20 µL min-1, affording the title compound as a pale yellow
oil (0.040 g, 99.9%); δH (400 MHz, CDCl3/TMS) 1.82 (4H,
m, 2 × CH2), 2.57-2.67 (4H, m, 2 × CH2), 5.00 (1H, s, CH),
7.38 (2H, d, J 10.9, 2 × ArH) and 7.48 (2H, d, J 10.9, 2 ×
ArH), NH not observed; δC (100 MHz, CDCl3/TMS) 23.1 (2
× CH2), 49.8 (2 × CH2), 58.3 (CH), 115.3 (CN), 122.4 (C0Br),
128.9 (2 × CH), 131.9 (2 × CH) and 133.1 (C0).
Acknowledgment
Financial support provided by the EPSRC (RAIS Award)
and The University of Hull is gratefully acknowledged (C.W.).
Dr. Steve Clark and Mr. Bob Knight are thanked for assistance
with device fabrication and ICP-MS analysis, respectively. We
also thank Dr. Michael Singer (Sigma-Aldrich) for useful
discussions with regard to the supported catalyst, PS-RuCl3.
2-(4-Bromophenyl)-2-(pyrrolidin-2-yl)acetonitrile (Entry
5).9 Employing 4-bromobenzaldehyde and pyrrolidine as pre-
cursors, the micro reaction was conducted at a total flow rate
Received for review February 4, 2008.
OP800025P
(9) (a) Azizi, N.; Saidi, R. M. Synth. Commun. 2004, 34, 1207. (b) Ranu,
R. C.; Gey, S. S.; Hajra, A. Tetrahedron 2002, 58, 2529.
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