Evaluation of the heterogeneously catalyzed strecker reaction conducted under continuous flow

FULL PAPER

DOI: 10.1002/ejoc.200800751

Evaluation of the Heterogeneously Catalyzed Strecker Reaction Conducted

Under Continuous Flow

Charlotte Wiles*^[a]and Paul Watts^[a]

Keywords: Micro reactor / Strecker reaction / α-Aminonitriles / Heterogeneous catalysis / Solid-supported Lewis acid

Building on our experience of micro-reaction technology, we

present herein the evaluation of an integrated borosilicate

glass micro reactor in which 51 α-aminonitriles were synthe-

the presence of ketonic functionalities was also investigated,

concluding with the chemoselective synthesis of 2-(4-ace-

tylphenyl)-2-(phenethylamino)acetonitrile whereby the de-

sized via a series of continuous solution-phase and heteroge- sired product was obtained in 99.8% yield and quantitative

neously catalyzed reaction steps, affording analytically pure

products in yields Ͼ 99.6%. As an extension to this, the abil-

ity to selectivity synthesize aldehydic Strecker products in

purity.

Germany, 2008)

In its original form, the Strecker reaction consisted of

the condensation of carbonyl-containing compounds with

amine salts, in the presence of alkaline cyanides under buff-

ered aqueous conditions, with the resulting products under-

going hydrolysis to afford the desired α-amino acid.^[1]The

tedious nature of product isolation compared with the syn-

thetic utility of the resulting α-aminonitriles in the prepara-

tion of 1,2-diamines, 2-amino alcohols, imidazoles, thiadia-

zoles^[2,3]and pre-biotic precursors to nucleic acids and por-

phyrins,^[4]has, however, led to the development of a pleth-

ora of alternative methodologies. These range from the use

of organic solvents and alternative cyanide sources,^[5]to the

use of Lewis acid catalysts,^[6–9]guanidine HCl,^[10]ionic li-

quids,^[11,12]catalyst-free^[13]examples and even those con-

ducted at elevated pressures (0.6 GPa).^[14]Despite these ad-

vancements, the reaction still suffers from numerous draw-

backs including the use of elevated reaction temperatures,

extended reaction times, expensive homogeneous catalysts,

an excess of the cyanide source and variable yields, which

preclude the use of the Strecker reaction on a production

scale.

In addition, a major shortcoming of the multi-compo-

nent Strecker reaction is the competing cyanohydrin forma-

tion that can occur,^[15]as depicted in Scheme 1. When em-

ploying aliphatic aldehydes, the respective aldimines form

rapidly; therefore the potential of cyanohydrin formation is

low, leading to good/moderate selectivity for the α-aminoni-

trile. In comparison, however, the aldimines of aromatic al-

dehydes form slowly, leaving the aldehyde available for O-

TMS cyanohydrin formation, and possible hydrolysis to the

respective cyanohydrin, resulting in poor reaction selectiv-

ity. With this in mind, we postulated that in those cases

where rapid O-TMS cyanohydrin formation is favored, se-

quential reagent addition would allow for the selective syn-

thesis of the desired α-aminonitrile. However, to achieve

Introduction

Micro-reaction technology provides a new method of ex-

ecuting chemical reactions, affording a means of performing

synthetic transformations in such a way that lengthy opti-

mization stages are no longer required in order to obtain

production volumes traditionally met through the time-con-

suming route of scale-up. The technique not only enables

rapid transfer of processes, but also provides a simple an-

swer to variable production volumes through the implemen-

tation of few or many reactors depending on product de-

mand. With this in mind, the field of continuous flow syn-

thesis is growing year on year with many research groups

reporting alternative ways to perform common organic

transformations with increased control, safety and predict-

ability. Whilst several interesting molecules have been pre-

pared using such technology, the multiple reaction steps in-

vestigated have more often than not consisted of single

steps, performed in series i.e. where the reaction products

are purified off-line (batch-wise) between each reaction and

as such are not performed in a truly continuous manner.

Alternatively reactors have been devised where solution-

phase reactions are performed in separate modules to heter-

ogeneously catalyzed reactions, leading to the need for mul-

tiple interconnections, resulting in potential points of fail-

ure within the system. Building on experience gained

through performing an array of synthetic transformations

under continuous flow, we present herein the development

and evaluation of an integrated borosilicate glass micro re-

actor in which solution phase and heterogeneously cata-

lyzed reaction steps are performed in series to afford the

target molecules in excellent purity.

[a] Department of Chemistry, The University of Hull,

Cottingham Road, Hull, HU6 7RX, UK

Supporting information for this article is available on the

WWW under http://ww w .eurjoc.org or from the author.

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Scheme 1. Illustration of the model reaction selected for evaluation under continuous flow, depicting some of the possible by-products

obtained and the reaction pathways followed in a one-pot transformation.

this in a stirred reaction vessel would require careful moni- Strecker reaction. Employing polymer-supported (ethylene-

toring of the reaction, in order to confirm aldimine forma- diaminetetraacetic acid)ruthenium(III) chloride (1) (Fig-

tion was complete prior to the addition of the cyanide ure 2, a) as the Lewis acid catalyst and trimethylsilyl cya-

source; leading to reactant specific conditions rather than nide (TMSCN) 2 as the cyanide source, with the aim of

the development of a general methodology. Micro reaction providing a simple and efficient methodology for the syn-

technology,^[16]however, offers an interesting solution to this thesis of α-aminonitriles.^[26]As an extension to this, we re-

problem, affording enhanced control over physical proper- port herein the use of an alternative solid-supported Lewis

ties such as mixing, reaction time and temperature,^[17]en- acid catalyst, the polymer-bound scandium(III) bis(trifluor-

abling sequential reagent addition to be performed with omethanesulfonate) 3 (Figure 2, b), as a means of increas-

ease. The use of a homogeneous catalyst within a con- ing the throughput of the system and subsequently demon-

tinuous system would, however, mean that even if reaction strate the synthesis of 50 α-aminonitriles ranging from aro-

selectivity could be obtained, via sequential addition of rea- matic to aliphatic derivatives. The report is then concluded

gents, the reaction products would still require purification with an investigation into the chemoselective nature of the

in order to remove, and potentially recycle, the catalytic ma-

terial.^[18]To circumvent this problem, many authors have

reported the use of solid-supported catalysts,^[19]which has

been shown to increase the ease with which reaction prod-

ucts can be isolated from the activating agent; by enlarge,

however, the transfer of a reaction from homogeneous ca-

talysis to a heterogeneous environment leads to a profound

increase in reaction time. Additional optimization can

therefore be required in order to obtain acceptable yields

on the desired time scale; a process that is usually achieved

by the use of heat and/or excess catalytic material. In recent

years, it has been demonstrated that by conducting polymer

and silica-assisted reactions under continuous flow, small

quantities of catalytic material can be employed for the ef-

Figure 1. Diagrammatic representation of the reaction manifold

ficient synthesis of compounds such as acetals,^[20]carbox-

used to evaluate the Strecker reaction conducted under continuous

ylic acids/aldehydes,^[21]α,β-unsaturated compounds,^[22]sub-

flow.

stituted biphenyls,^[23]natural products such as (Ϯ)-oxomar-

itidine^[24]and even the enantioselective synthesis of

grossamide.^[25]As small volumes of the reaction mixture

(µL) are in contact with a relatively large volume of cata-

lytic material (mg), the result is that excellent conversions

can be obtained within short reaction times, typically in the

range of sec to min. Using this approach, the reaction times

attained compare more favorably with those employed in

homogeneous systems, whilst the ease with which reaction

products can be isolated from the solid-supported catalyst

Figure 2. Illustration of the two immobilized Lewis acid catalysts

is retained.

investigated within the borosilicate glass micro reactor (a). Poly-

With these factors in mind, we recently communicated

mer-supported (ethylenediaminetetraacetic acid)ruthenium(III)

chloride (PS-RuCl₃) (1) and (b). Polymer-bound scandium(III) bis-

(Figure 1) capable of performing the multi-component (trifluoromethanesulfonate) [PS-Sc(OTf)₂] (3).

our initial appraisal of a borosilicate glass micro reactor

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Catalyzed Strecker Reaction Conducted Under Continuous Flow

technique, employing 4-acetylbenzaldehyde (4) as a precur-

As depicted in Figure 3, the reaction manifold employed

sor to afford 2-(4-acetylphenyl)-2-(phenethylamino)acetoni- herein was a borosilicate glass micro reactor consisting of

trile (5) as the target molecule.

two etched layers, the first containing the reagent delivery

inlets along with the mixing channels and the second com-

prised of a larger etched region and the reactor outlet,

through which the reaction products are collected. Thermal

annealing of the two etched layers afforded the integrated

reactor, into which the solid-supported catalyst was dry-

packed (Figure 1), with interconnections made by means of

Microtight fittings and PEEK tubing, which as illustrated

in Figure 4 is secured using epoxy resin. Solutions of reac-

tants can then be delivered to the micro reactor via a series

of gas-tight syringes and reaction products collected from

the FEP tubing into a 2-mL glass sample vial at the outlet.

Results and Discussion

As Scheme 1 illustrates, initial investigations focused on

the reaction of 4-bromobenzaldehyde (6) with 2-phenylethyl-

amine (7) and TMSCN (2),^[27]catalyzed by polymer-

supported (ethylenediaminetetraacetic acid)ruthenium(III)

chloride (PS-RuCl₃) (1). Prior to evaluating the model reac-

tion under continuous flow, the reaction was conducted

using the conventional one-pot approach, which consisted

of the addition of TMSCN (2), to a stirred solution of 4-

bromobenzaldehyde (6) and 2-phenylethylamine (7) in

MeCN.^[28]The resulting reaction mixture was stirred under

N₂at room temperature for 24 h prior to filtration and re-

moval of solvent in vacuo, to afford a pale yellow oil. The

crude reaction product was subsequently dissolved in

CDCl₃and analyzed by ¹H NMR spectroscopy. After 24 h,

an appreciable quantity of the desired product 2-(4-bro-

mophenyl)-2-(phenethylamino)acetonitrile (8) had formed;

however, the reaction mixture also contained several by-

products or intermediates including 2-(4-bromophenyl)-2-

(trimethylsilyloxy)acetonitrile (9) and 2-(4-bromophenyl)-2-

hydroxyacetonitrile (10).

Figure 3. Schematic illustrating the components of the borosilicate

glass reactor employed for the investigations described herein (a)

top plate, (b) base plate and (c) bonded reactor.

Mechanistic Evaluation

Although the batch reaction served to illustrate the suit-

ability of PS-RuCl₃(1) as a catalyst for the transformation,

To evaluate the synthesis of an α-aminonitrile under con-

it did highlight some of the drawbacks associated with the tinuous flow, we must firstly consider the reaction mecha-

one-pot technique i.e. competing O-TMS cyanohydrin for- nism, from which the order of reactant addition to the

mation 9, resulting in incomplete cyanation and the pres- micro reactor can be determined. This not only ensures that

ence of residual amine within the reaction product. Conse- reactants are delivered to the reaction channel in the correct

quently, where rapid O-TMS cyanohydrin formation is fa- spatial and temporal manner, but also enables us to identify

vored, the reaction conditions must ensure that the imine the origin of side products, henceforth providing us with a

forms prior to the addition of the cyanide source. Therefore, means of preventing them. As Scheme 1 illustrates, there

rather than use a one-pot strategy, sequential reactant ad- are several possible products that could arise from the com-

dition would enable the formation of the desired intermedi- bination of an amine 7, aldehyde 6 and cyanide source 2

ate and subsequently ensure selective synthesis of the α-ami- in a one-pot system, firstly the formation of the O-TMS

nonitrile. In batch, however, this is difficult to achieve as cyanohydrin, 2-(4-bromophenyl)-2-(trimethylsilyloxy)aceto-

the reaction conditions must be tailored to take into ac- nitrile (9), with subsequent hydrolysis affording the cya-

count the reactivity of the particular precursors and as nohydrin, 2-(4-bromophenyl)-2-hydroxyacetonitrile (10),

such, the reaction was investigated within a borosilicate and secondly the formation of the imine intermediate, (E)-

glass micro reactor under pressure-driven flow, whereby re- [1-(4-bromophenyl)methylidene]phenethylamine (11). As

action conditions can be rapidly evaluated.

literature precedent exists for the Strecker reaction proceed-

Figure 4. Schematic illustrating the technique employed for the connection of the micro reactor to a syringe driver.

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C. Wiles, P. Watts

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ing via both of these intermediates, the mechanistic path-

From this example alone, it can be seen that when con-

way followed by the model reaction, the synthesis of 2-(4- ducting reactions in a one-pot, multi-component manner

bromophenyl)-2-(phenylethylamino)acetonitrile (8), was the route of a reaction is not always apparent, consequently

evaluated firstly using a pre-formed O-TMS cyanohydrin 9 side reactions can be prevalent resulting in a complex reac-

and then via the imine 11.

tion mixture. As such, these reactions often benefit from

The micro reactor was firstly charged with PS-RuCl₃(1, employing an excess of one reactant, in order to suppress

0.01 g, 0.26 mmolRug^–1) and the system purged with anhy- side reactions; even so, the resulting reaction products re-

drous MeCN, prior to performing a reaction. As depicted quire purification to remove any of the un-reacted material

in Figure 5, a, a solution of O-TMS cyanohydrin 9 (0.2  and/or by-products formed. Consequently, the use of a con-

in MeCN) was introduced into the micro reactor from inlet tinuous flow approach, such as the micro reactor described

A and 2-phenylethylamine (7, 0.2  in MeCN) from inlet B, herein, enables the user to perform rapid evaluation of a

the reactants mixed in the central channel prior to passing reaction, gaining a large amount of information from a

through the catalyst bed and collection at outlet D (0.1 ). small quantity of reactant, which is particularly useful if a

The reaction mixture was then analyzed by GC-MS, prior starting material is scarce or expensive. The technique is

1

to concentrating in vacuo and subsequent analysis by H also advantageous as the predictable nature of the mixing

NMR spectroscopy, whereby comparison of the integrals regime employed affords the ability to sequentially add re-

afforded the% conversion to be determined. Using this ap- actants, enabling the chemist to ensure that one-step is com-

proach, the reaction was evaluated over a range of flow plete prior to the addition of the next reactant; as such stoi-

rates (5 to 100 µLmin^–1) whereby no reaction to afford the chiometric quantities of reactant can often be employed,

desired α-aminonitrile 8 was observed, only recovery of the increasing reaction efficiency and the purity of the resulting

unreacted O-TMS cyanohydrin 9 and 2-phenylethylamine reaction product.

(7).

Multi-Component Synthesis of 2-(4-Bromophenyl)-2-

(phenylethylamino)acetonitrile

Having determined the reactive intermediate of interest

was the imine 11, our attention turned to its in-situ prepara-

tion, making the technique suitable for those reactions

where the reactive intermediate is hydrolytically unstable

and hence not isolatable in a pure form. With this in mind,

the synthesis of 2-(4-bromophenyl)-2-(phenylethylamino)-

acetonitrile (8) was investigated using the following pro-

cedure; a solution of 4-bromobenzaldehyde (6, 0.4  in

MeCN^[29]) was introduced from inlet A, followed by 2-

phenylethylamine (7, 0.4  in MeCN) from inlet B and fi-

nally TMSCN (2, 0.2  in MeCN) from inlet C, affording

Figure 5. Reaction manifolds used to evaluate the order of addition

for the synthesis of α-aminonitriles, catalyzed by PS-RuCl₃(1), un-

a total flow rate of 20 µLmin^–1, an overall reactant ratio of

der continuous flow via (a). the O-TMS cyanohydrin 9 and (b). the

imine 11.

1:1:1 and a final product concentration of 0.1 . The reac-

tion products were collected in a sample tube containing

MeCN (250 µL) and after 2.5 h, the reaction products were

With this in mind, the investigation turned to the evalu- concentrated in vacuo and the “crude” material 8 dissolved

ation of the imine 11 as the reactive intermediate. As illus- in CDCl₃and analyzed by ¹H NMR spectroscopy. Through

trated in Figure 5, b, (E)-[1-(4-bromophenyl)methylidene]- comparison of the integrals of the signals obtained for the

phenethylamine (11, 0.2  in MeCN) was introduced from intermediate imine 11 (δ = 8.1 ppm) and α-aminonitrile 8

inlet A, a solution of TMSCN (2, 0.2  in MeCN) from (δ = 4.8 ppm),^[30]the % conversion was found to be 95.9%,

inlet B and the reactants mixed in the central channel, prior reduction of the flow rate to 10 µLmin^–1, however, afforded

to reaction within the catalyst bed. The resulting reaction quantitative conversion (see Figure 6) to the desired prod-

mixture was collected at outlet D (0.1 ) and concentrated uct 8 and an isolated yield of 99.5% was obtained. Further

1

in vacuo, prior to dissolution in CDCl₃and analysis by H evaluation of the pale yellow solid 8 by ¹³C NMR spec-

NMR spectroscopy; whereby comparison of the integrals troscopy, IR spectroscopy, MS and elemental analysis con-

afforded quantification of the percentage conversion. Em- firmed the product was synthesized in analytical purity

ploying a flow rate of 100 µLmin^–1, afforded 25.9% conver- (Figure 7) and that no additional purification was found to

sion to the desired α-aminonitrile 8, which was sub- be necessary, unlike a typical batch reaction performed un-

sequently improved upon by reduction of the flow rate to der analogous conditions, over 24 h. In addition to the

20 µLmin^–1and then to 10 µLmin^–1, whereby the increased aforementioned analytical assessment of the flow-reaction

reactant residence time afforded 95.6% and 100.0% conver- product 8, the material was also analyzed by ICP-MS,

sion, of the imine 11 to 2-(4-bromophenyl)-2-(phenylethyl- which confirmed that no detectable Ru was present within

amino)acetonitrile (8), respectively.

the reaction product. This demonstrates an improvement in

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Catalyzed Strecker Reaction Conducted Under Continuous Flow

catalyst stability compared to the analogous batch reaction

Therefore not only does this example serve to illustrate

whereby 440 ppm of Ru was found to have been released the fact that under stoichiometric reaction conditions a

from the supported catalyst 1, an observation that is attrib- product 8 of superior purity can be obtained in a con-

uted to mechanical degradation of the catalyst, due to stir- tinuous flow micro reactor via the use of sequential reactant

ring of the material over the course of the reaction; leading addition, but reduced reaction times are also required in

to a dramatic reduction in the catalyst lifetime. Importantly, order to afford quantitative conversion of the starting mate-

when the reaction was performed in the absence of the cata- rials 6 and 7 to the desired α-aminonitrile 8, typically Ͻ

lyst, achieved by simply replacing the PS-RuCl₃(1) with 1 min cf. 24 h in batch. Furthermore, the notable reduction

PS-EDTA,^[31]no background reaction was observed when in catalyst degradation in the absence of mechanical stirring

operating the reactor at flow rates in the range of 1 to results in an extended catalyst lifetime and increased prod-

100 µLmin^–1, simply formation of the respective imine 11, uct purity.

as would be expected.

Generality of the Technique

Having demonstrated that the Strecker reaction between

4-bromobenzaldehyde (6) and 2-phenylethylamine (7) could

be conducted efficiently under continuous flow conditions,

the scope of the technique was evaluated through the reac-

tion of a further four amines with 4-bromobenzaldehyde

(6). The amines were selected to illustrate a range of reactiv-

ities i.e. from aromatic to aliphatic and cyclic derivatives

and as Table 1 illustrates, in the case of aniline (12), ben-

zylamine (13) and phenylpropylamine (14), excellent yields

were again obtained using analogous conditions to those

employed for 2-phenylethylamine (7). However, in the case

of pyrrolidine (15), which upon reaction with 4-bromobenz-

Figure 6. Illustration of the effect of flow rate on the synthesis of

aldehyde (6) affords an iminium ion as the reactive interme-

(o) (E)-[1-(4-bromophenyl)methylidene]phenethyl-amine (11) and

diate, quantitative conversion of the aldehyde 6 to (4-bro-

mophenyl)pyrrolidin-2-ylacetonitrile (16) was obtained at

(᭿) 2-(4-bromophenyl)-2-(phenethylamino)acetonitrile (8) in

micro reactor.

a

Figure 7. Typical ¹H NMR spectra obtained for 2-(4-bromophenyl)-2-(phenethylamino)acetonitrile (8) synthesized under continuous flow.

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the higher flow rate of 20 µLmin^–1, affording an increase in re-optimization steps usually associated with scale-up. This

the reaction throughput compared to the primary amines technique is particularly advantageous with respect to the

investigated.

production of pharmaceuticals and fine chemicals as it me-

ans that the reaction conditions employed at a development

stage are those that are later employed on a production

scale, all that changes is the number of reactors employed;

consequently the risk associated with moving a product

from development into production is removed. This in

mind, it is still desirable for a single reactor unit to be as

productive as possible and consequently, the next step of

the investigation was to evaluate techniques that would af-

ford a greater reaction throughput from a single micro reac-

tor, namely the use of elevated reaction temperatures and

alternative Lewis acid catalysts.

Table 1. Summary of the results obtained for the Strecker reaction

between 4-bromobenzaldehyde (6) and an array of amines using

PS-RuCl₃(1) as the catalyst and a run time of 2.5 h.

Elevated Reaction Temperatures

Employing the reaction conditions summarized in

Table 1, the micro reactor was placed in a silicone oil bath

and heated to 40 °C. Upon initial purging of the system

with anhydrous MeCN, at a total flow rate of 10 µLmin^–1,

orange coloration of the solvent stream was noted at outlet

D, an observation that was attributed to leaching of Ru

from the catalyst 1; as a result all further reactor evaluation

was conducted at room temperature.

Increased Reactant Concentrations

One facile route often employed to increase the produc-

tivity of reactions conducted under continuous flow is to

increase the concentration of the reactant feedstocks. As

previously mentioned the use of MeCN as reaction solvent

precludes the use of concentrations higher than 0.4  owing

to the precipitation of the imine 11 within the central reac-

tion channel. Consequently, in an attempt to increase the

throughput of the system, dichloromethane was evaluated

as an alternative solvent system, selected for its inert nature,

high volatility and its ability to solubilize large quantities

of organic material. It was therefore proposed that through

the increased solubilization of the imine intermediate, that

the reaction could be operated at a higher concentration,

to afford an increased reactor throughput i.e. double the

concentration, double the quantity of product synthesized

per unit time. Unfortunately, under analogous conditions

to those employed with MeCN as the reaction solvent, the

use of DCM led to swelling of the PS-RuCl₃(1), attributed

to the fact that the polymer used as a support was only

crosslinked with 1% DVB, resulting in blockage of the reac-

tor after only 20 min of operation. Clearly, this is unsuitable

for a system that is required to operate unaided and over

long periods; consequently, MeCN was retained as the reac-

tion solvent and a final product stream concentration of

[a] On the basis of the total flow obtained from 3 fluidic inputs.

[b]% Conversion determined via comparison of the ¹H NMR inte-

grals observed for the imine/α-aminonitrile. [c] Run time = 1.25 h.

From the examples discussed it can be seen that the use

of a micro reactor, such as the one illustrated in Figure 1,

has enabled us to validate the hypothesis that sequential

reactant addition facilitates the efficient synthesis of α-ami-

nonitriles, with Table 1 illustrating the excellent yields and

purities attainable within such a system. It must also be

noted that depending on the amine employed, the system

affords a throughput of between 17.2 and 31.8 mgh^–1

(equivalent to 0.06 and 0.12 mmolh^–1) and although batch

reactions can be performed on larger scales, and hence af-

forded greater throughputs, they result in the formation of

impure products that contain unreacted starting materials,

along with being contaminated with significant quantities

of trace metals, reducing the longevity of the catalysts em-

ployed and increasing the sophistication of purification

techniques required post reaction.

Increased Reactor Throughput

Whilst a perceived disadvantage of micro-reaction tech- 0.1  employed throughout. Further to this, reactant stoi-

nology is the relatively small quantity (mgh^–1) of material chiometry is another variable i.e. where the proportion of a

that can be prepared from a single reactor, techniques such reactant is increased in order to drive the reaction to com-

as numbering-up and scale-out enable the user to increase pletion. This approach is, however, disadvantageous when

throughput by employing multiple systems in parallel, an attempting to improve the atom efficiency of a reaction and

approach that does not incur the need to perform costly as such was not pursued as a solution herein.

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Catalyzed Strecker Reaction Conducted Under Continuous Flow

Alternative Lewis Acid Catalysts

to afford 2-(4-bromophenyl)-2-(phenylamino)acetonitrile

(17), 2-(benzylamine)-2-(4-bromophenyl)acetonitrile (18),

2-(4-bromophenyl)-2-(3-phenylpropylamino)acetonitrile (19)

and 2-(4-bromophenyl)-2-(pyrrolidin-2-yl)acetonitrile (16),

with isolated yields ranging from 99.8 to 99.9%. Again it

can be seen that in the case of the secondary amine pyr-

rolidine (15), an increased flow rate (40 µLmin^–1) can be

employed compared to the primary amines evaluated

(20 µLmin^–1), affording a throughput of 0.24 mmolh^–1cf.

the previously obtained 0.12 mmolh^–1.

As previously discussed, many Lewis acids have been re-

ported within the literature to act as catalysts for the

Strecker reaction, in particular rare earth (RE) metal tri-

flates have found widespread application, with a microen-

capsulated (MC) Sc(OTf)₃derivative reported by Kobaya-

shi and co-workers.^[32]The authors recently communicated

the catalyst in a flow reactor, whereby MC-Sc(OTf)₃con-

taining ca. 0.12 g of catalytic material was packed into a

circulating column and a mixture containing the imine and

TMSCN (2, 0.5 mmol in MeCN) pumped through the reac-

tor. Using this approach, the authors obtained 70% yield

on the first run, 71% on the second and finally 75% on

the third, illustrating the potential of the flow methodology.

Owing to the use of a circulating column reactor, where

reactants are added from a single inlet, the technique was

only suitable for the use of pre-formed imines or precursors

unlikely to result in by-product formation, when pre-mixed

in the absence of the catalyst. This is in comparison to the

technique described herein, whereby enhanced control and

reaction flexibility can be obtained through the ability to

introduce reactants from three separate inlets, prior to con-

tact with the catalytic material. With this in mind, we inves-

tigated the incorporation of the commercially available

polymer bound derivative PS-Sc(OTf)₂(3) (Figure 2, b),

within the aforementioned micro reactor and evaluated its

performance against PS-RuCl₃(1) and the MC-Sc(OTf)₃re-

ported by Kobayashi and co-workers.

Table 2. Summary of the results obtained for the Strecker reaction

between 4-bromobenzaldehyde 6 and an array of amines using PS-

Sc(OTf)₂3 as the catalyst (run time = 1 h unless otherwise stated).

The Continuous-Flow Evaluation of PS-Sc(OTf)₂

In order to compare the Lewis acid catalysts, PS-Sc(OTf)₂

(3, 0.01 g, 0.60 mmolScg^–1) was dry-packed into the cata-

lyst bed and the micro reactor purged with anhydrous

MeCN prior to performing a reaction. Again, 4-bro-

mobenzaldehyde (6, 0.4  in MeCN) was introduced from

inlet A, 2-phenylethylamine (7, 0.4  in MeCN) from inlet

B and TMSCN (0.2  in MeCN) from inlet C (1:1:1). The

imine 11 and TMSCN (2) were subsequently pumped

[a] On the basis of the total flow obtained from 3 fluidic inputs.

[b]% Conversion determined via comparison of the ¹H NMR inte-

grals observed for the imine/α-aminonitrile. [c] Run time = 0.5 h.

Evaluation of Aromatic Aldehydes

Having demonstrated the ability to increase reactor

through the catalyst bed at a total flow rate of 10 µLmin^–1throughput by employing an alternative Lewis acid catalyst,

and the reaction products collected at the outlet D in the scope of the reaction was subsequently investigated.

MeCN (250 µL). After 2.5 h, the reaction products were Again, the reactions were evaluated at room temperature

concentrated in vacuo to afford a pale yellow solid and the employing stoichiometric quantities of all reactants, with

1

material dissolved in CDCl₃prior to analysis by H and the focus being on the evaluation of an array of aldehydes

¹³C NMR spectroscopy; whereby quantitative conversion to [3,5-dimethoxybenzaldehyde (20), 4-chlorobenzaldehyde

α-aminonitrile 8 was confirmed. As Table 2 illustrates, in (21) and methyl 4-formylbenzoate (22)], demonstrating any

contrast to the previous system (See Table 1), PS-ScOTf₂electronic substituent effects, with benzaldehyde (23) serv-

(3) was found to be a more active catalyst, affording quanti- ing as a reference point (Table 3, Entries 1–5). To evaluate

tative conversion to 2-(4-bromophenyl)-2-(phenethylamino) this effect, micro reactions were conducted for 0.5 h at

acetonitrile (8) at double the flow rate (20 µLmin^–1) pre- 40 µLmin^–1and 1.0 h at 20 µLmin^–1, prior to removal of

viously found to be optimal for PS-RuCl₃(1), affording a the reaction solvent and analysis of the “crude” reaction

1

throughput of 0.12 mmolh^–1. Again, no cyanohydrin for- product. In the case of known compounds, H NMR, ¹³C

mation was observed and the desired product 8 was ob- NMR and MS were used to confirm the compounds struc-

1

tained in analytical purity. In addition to the synthesis of ture and for previously unreported compounds, H NMR,

α-aminonitrile 8, the catalyst was found to activate the reac- ¹³C NMR, MS, IR and CHN analysis were performed (See

tion between 4-bromobenzaldehyde 6 with aniline (12), ben- Experimental Section for details). We were again pleased to

zylamine (13), phenylpropylamine (14) and pyrrolidine (15) report that this mode of operation afforded, in all cases,

Eur. J. Org. Chem. 2008, 5597–5613

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C. Wiles, P. Watts

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analytically pure compounds with no sign of residual start- mation, the reaction can also yield the self-aldol product,

ing materials or the undesirable formation of the respective 3-hydroxy-2-methylbutanal, which has the potential to elim-

O-TMS cyanohydrin or cyanohydrin.

inate water to afford (E)-2-methylbut-2-enal, further com-

plicating the reaction mixture. In order to increase control

over the reaction pathway followed, the synthesis of 2-

(phenethylamino)butyronitrile (25) was subsequently inves-

tigated under continuous flow. To achieve this, propionalde-

hyde (24, 0.4  in MeCN) and 2-phenylethylamine (7, 0.4 

in MeCN) were introduced into the reactor from inlets A

and B respectively and a solution of TMSCN (2, 0.2  in

MeCN) from inlet C. Employing a total flow rate of

40 µLmin^–1, the reaction mixture was pumped through the

packed bed, containing PS-Sc(OTf)₂(3), and the reaction

products collected at outlet D, prior to concentrating in

vacuo. Using this approach afforded 2-(phenethylamino)-

butyronitrile (25) in excellent purity, confirming that en-

hanced reaction control can be obtained in microfluidic sys-

tems compared to the traditional one-pot approach where

complex reaction mixtures resulted.

Table 3. Summary of the results obtained for the multi-component

Strecker reaction of an array of aromatic aldehydes employing PS-

Sc(OTf)₂(3) as the catalyst.

Scheme 2. Schematic illustrating a selection of the reaction prod-

ucts encountered when attempting to synthesize 2-(phen-

ethylamino)butyronitrile (25) in a one-pot, batch reaction.

[a] On the baisis of the 3 fluidic i(nputs. [b] Isolated yield. [c] 1 h

run time. [d] 0.5 h run time. [e] 1:1:1 Stoichiometry [aldehyde/

amine/TMSCN (2)].

Having demonstrated that the aldol reaction could also

be avoided through the use of sequential reactant addition,

owing to the spatial control of reactive intermediates within

Investigation into the Reaction of Aliphatic Aldehydes

Having thoroughly evaluated the reaction of five aro- the micro channel, the generality of the reaction was sub-

matic aldehydes in the continuous flow reactor, the protocol sequently investigated, conducting the Strecker reaction of

was extended to the use of aliphatic aldehydes. Unlike their a further four aliphatic aldehydes, butyraldehyde (26), valer-

aromatic analogues, the use of aliphatic precursors adds an- aldehyde (27), hexanal (28) and heptanal (29), with amines

other dimension of complexity due to the competing reac- 7, 12–15. As Table 4 illustrates, owing to the increased reac-

tion pathway of the aldol reaction. Consequently, to further tivity of the aliphatic imines, to the nucleophilic attack of

demonstrate the synthetic utility of continuous flow reac- the CN anion, the reactions were successfully performed at

tors, such as the micro reactor described herein, the reac- higher flow rates (40 µLmin^–1) compared to that previously

tion of propionaldehyde (24) and 2-phenylethylamine (7), employed for the aromatic derivatives (20 µLmin^–1, Table 2

to afford 2-phenethylamino-butyronitrile (25), was em- and Table 3). Although using this approach, high-through-

ployed as a model reaction. As Scheme 2 illustrates, in ad- puts were obtained; the main advantage of the technique

dition to the previously encountered cyanohydrin forma- undoubtedly is the suppression of competing reactions,

tion, when conducted as a conventional one-pot transfor- which enables the desired α-aminonitrile to be synthesized

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Eur. J. Org. Chem. 2008, 5597–5613

Catalyzed Strecker Reaction Conducted Under Continuous Flow

in excellent yield and purity, negating the need to perform amines, we subsequently investigated the feasibility of per-

post reaction product purification. It must, however, be forming the ketonic Strecker reaction under continuous

noted that the investigation of aliphatic aldehydes was lim- flow. As Scheme 3 illustrates the model reaction selected in-

ited to the use of short chain aliphatic precursors due to volved the preparation of the ketoimine 30, formed via the

the immiscibility of compounds Ͼ C₈in MeCN. Compared reaction of 4-methylacetophenone (31) and 2-phenylethyla-

to analogous batch reactions, however, this approach is not mine (7), followed by the nucleophilic addition of the cya-

only rapid and facile, but also provides generic reaction nide anion to afford 2-(phenylethylamino)-2-p-tolylpro-

conditions with which plethoras of derivatives are prepared panenitrile (32) as the desired product.

with ease.

Table 4. Summary of the results obtained for the multi-component

Strecker reaction of aliphatic aldehydes under continuous flow con-

ditions, employing a run time of 0.5 h otherwise stated.

Scheme 3. Synthesis of 2-(phenylethylamino)-2-p-tolylpropaneni-

trile (32) investigated within a micro reactor.

To evaluate the reaction under continuous flow, the reac-

tion manifold illustrated in Figure 1 was again employed

along with working solutions of 4-methylacetophenone (31,

0.4  in MeCN), 2-phenylethylamine (7, 0.4  in MeCN)

and TMSCN (2, 0.2  in MeCN). Operating at the pre-

viously optimal flow rate of 20 µLmin^–1, we were surprised

to find that upon analysis of the resulting colorless oil that

no reaction, to afford the desired α-aminonitrile 32, had

occurred. Fully expecting the reaction to take longer than

the respective aldehydic Strecker reaction, the residence

time was increased via reduction of the flow rate to

1 µLmin^–1and again no reaction was observed, analysis of

the reaction products simply confirmed recovery of the

starting materials 31 and 7. In a final attempt to optimize

the reaction, the concentration of the TMSCN (2) solution

was increased from 0.2  (1 equiv.) to 0.6  (3 equiv.) and

again no conversion to 2-(phenylethylamino)-2-(p-tolyl)pro-

panenitrile (32) was observed. This led us to conclude that

the formation of the ketoimine 30 was the limiting step and

being less favorable than the previously observed aldimine

synthesis, would possibly require catalysis to afford the de-

sired intermediate 30. In accordance with this observation,

it was postulated that due to the catalyst free conditions

[a] On the basis of the3 fluidic inputs. [b] Isolated yield. [c] Run

employed within the first portion of the micro reactor that

time = 1 h. [d] 1:1:1 Stoichiometry [aldehyde/amine/TMSCN (2)].

it should be possible to perform the aldehydic Strecker reac-

tion in the presence of the ketone moiety, due to the prefer-

ential formation of the aldimine, as depicted by Scheme 4.

With this in mind, a solution of 4-bromobenzaldehyde

Evaluation of Carbonyl Selectivity Under Continuous Flow

(6) and 4-methylacetophenone (30) (0.4  respectively in

Having illustrated the efficient synthesis of fifty α-amino- MeCN) was introduced into the reactor at inlet A, a solu-

nitriles employing precursors ranging from aliphatic to aro- tion of 2-phenylethylamine 7 (0.4  in MeCN) from inlet B

matic aldehydes along with both primary and secondary and a solution of TMSCN (2, 0.2  in MeCN) from inlet

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5605

C. Wiles, P. Watts

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Scheme 4. Illustration of the model reaction used to evaluate reac-

tion selectivity under continuous flow and the potential reaction

products.

Scheme 5. Schematic illustrating the potential reaction products

obtained when employing 4-acetylbenzaldehyde (4) as a precursor.

C. In line with the optimization previously performed for

the synthesis of 2-(4-bromophenyl)-2-(phenylamino)aceto-

nitrile (8), a total flow rate of 20 µLmin^–1was employed

and the reaction products collected (1 h) and concentrated

in vacuo to afford a pale yellow oil. Analysis of the crude

reaction products by NMR confirming the quantitative

synthesis of 2-(4-bromophenyl)-2-(phenylamino)acetonitrile

(8), indicated by the appearance of the CH signal at

4.8 ppm, and the presence of the un-reacted 4-methylace-

tophenone (31), confirmed by the residual CH₃signals at δ

= 2.3 and 2.5 ppm, which is attributed to the reduced reac-

tivity of the ketonic moiety.

Figure 8. The bis-adduct 34 obtained when employing 4-acetyl-

benzaldehyde (4) in the Strecker reaction under batch conditions.

Having demonstrated the ability to synthesize 2-(4-bro-

mophenyl)-2-(phenylamino)acetonitrile (8) in the presence

of a ketone 31, the chemoselectivity of the reaction was

further evaluated for the synthesis of 2-(4-acetylphenyl)-2-

(phenethylamino)acetonitrile (5) (Scheme 5). Employing a

bifunctional compound, such as 4-acetylbenzaldehyde (4),

further increased the complexity of the reaction owing to

the potential to synthesize the respective cyanohydrins, ald-

imine and ketoimine, along with the aldehydic 5 or ketonic

Strecker product 33 and the bis-adduct 34 (Figure 8). It was

therefore proposed that by conducting the reaction under

2-(4-formylphenyl)-2-(phenethylamino)propionitrile (33) or

bis-adduct 34 formation, demonstrating excellent chemose-

lectivity compared to conventional methodology whereby

O-TMS-cyanohydrin formation dominated.

Summary

In recent years the use of continuous flow reactors, and

continuous flow, that the cyanohydrin formation would in particular micro reactors, has captured the attention of

again be suppressed as a result of sequential reagent ad- the modern day synthetic chemist, with uptake of the tech-

dition and that the desired aldehydic Strecker product nology increasing as the systems have become commercially

would be synthesized due to (i) the kinetically preferred for- available. Some sectors of the scientific community, how-

mation of the aldimine (1-{4-[(E)-phenethyliminomethyl]- ever, remain skeptical and as such our research focuses on

phenyl}ethanone), (ii) the short residence time employed comparing such emerging technologies with conventional

within such as system, and(iii) the use of stoichiometric batch-wise protocols, enabling any advantages and, poten-

quantities of the cyanide source 2.

tially most importantly, disadvantages/limitations to be

To explore this hypothesis, 4-acetylbenzaldehyde (4, identified. Through this practice, the aim is to develop novel

0.4 ) was introduced into the reactor as a solution in synthetic procedures using continuous flow processing as a

MeCN from inlet A, 2-phenylethylamine (7, 0.4  in means of improving the reproducibility of common syn-

MeCN) from inlet B and TMSCN (2, 0.2  in MeCN) from thetic transformations by providing operator independent

inlet C. Operating at the previously optimized flow rate for reaction methodologies.

aromatic aldehydes of 20 µLmin^–1, quantitative formation

To increase the complexity of reactions evaluated in this

of the aldehydic Strecker product was observed. Conse- way, the multi-component Strecker reaction was selected as

quently, the reactor was operated for a period of 1 h, which a model reaction and enabled us to develop a single reactor

upon concentrating in vacuo afforded 2-(4-acetylphenyl)-2- capable of performing solution phase and polymer-assisted

(phenylethylamino)acetonitrile (5) as a pale yellow oil in reactions in series. In contrast to conventional stirred reac-

99.8% yield (33 mgh^–1). Using this approach, the desired tor methodology, the development of an integrated micro

compound 5 was synthesized quantitatively, with no sign of fluidic system, such as the one described herein, is advan-

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Catalyzed Strecker Reaction Conducted Under Continuous Flow

points were determined using a Gallenkamp melting point appara-

tus and are reported uncorrected. Delivery of reactants to the micro

reactor was controlled using a displacement pump (MD-1001, Bio-

analytical Systems Inc.), capable of delivering three solutions at

flow rates of between 0.1 and 100 µLmin^–1(calibrated for a 1 mL

gastight syringe). Gas Chromatography-Mass Spectrometry (GC-

MS) was performed using a Varian GC (CP-3800) coupled to a

Varian MS (Saturn 2000) with a CP-Sil 8 column (30 m, Zebron

ZB-5, Phenomenex, UK) and ultra high purity helium (99.999%,

Energas, UK) carrier gas. Samples were analyzed using the follow-

tageous as the predictable nature of diffusion based mixing

enables a reaction manifold to be designed to afford com-

plete mixing of two precursors and subsequent generation

of an intermediate, prior to the addition of the third reac-

tant, followed by contact with the catalyst. As such, this

mode of operation offers a route to enhanced reaction selec-

tivity as by-product formation is prevented. Coupled with

the use of solid-supported catalysts and stoichiometric

quantities of precursors, this approach yields a synthetic

technique whereby post-reaction processing consists simply ing method; injector temperature 250 °C, 1.0 µL sample volume,

helium flow rate 1.0 mL min^–1, oven temperature 50 °C for 4 min,

of solvent removal, affording the desired product in analyti-

cal purity; an advantage, which is highlighted throughout

this report.

then ramped to 250 °C at 30 °C min^–1and held at 250 °C for

10 min, with a 3 min filament delay.

In conclusion, the integrated reactor reported herein of-

With the exception of 2-(4-bromophenyl)-2-(trimethylsilyloxy)ace-

fers significant operational advantages over batch-wise syn-

theses, ranging from shorter reaction times (Ͻ 1 min), in-

tonitrile

(9)

and

(E)-[1-(4-bromophenyl)methylidene]phen-

ethylamine (11), all characterization data reported was obtained

creased atom efficiency [1 equiv. of TMSCN (2)] and en- using compounds synthesized within the borosilicate glass micro

reactors and in all cases, no additional product purification was

performed.

hanced yields/purities (Ͼ99.6%), to efficient catalyst recycle

(turnover Ͼ 1050) and minimal exposure to hazardous re-

actants due to the use of a sealed reaction unit. The tech-

nique can also be scaled with ease through replication, as a

means of increasing the system throughput from the current

0.12–0.24 mmolh^–1. Owing to the success of this investiga-

Continuous-Flow Methodology: The borosilicate glass micro reactor

was fabricated in-house using a series of photolithography, wet-

etching and thermal annealing steps resulting in a reactor with an

overall footprint of 3.0 cm (wide)ϫ3.0 cm (long)ϫ0.3 cm (deep).

tion, further studies will be directed towards the develop- The first of the two etched layers had channel dimensions of

150 µm (wide)ϫ50 µm (deep) ϫ5.6 cm (long), with a catalyst bed

of 3 mm (wide)ϫ50 µm (deep) and 2.0 cm (long) (Figure 3, a) and

the second plate contained a catalyst bed of 3 mm (wide)ϫ150 µm

(deep)ϫ2.1 cm (long) (Figure 3, b). Thermal annealing of the two

etched layers afforded a catalyst bed with dimensions of 3 mm

(wide)ϫ200 µm (deep)ϫ2.0 cm (long) (Figure 3, c) and an overall

reactor dimension of 3.0 cm (wide)ϫ3.0 cm (long)ϫ0.6 cm (deep).

ment and evaluation of a solid-supported Lewis acid cap-

able of catalyzing the ketonic Strecker reaction under con-

tinuous flow conditions.

Experimental Section

The borosilicate glass reactor was then packed with the polymer

supported catalyst under evaluation and a series of PEEK (360 µm

o.d. ϫ150 µm i.d.ϫ10 cm) and FEP tubes (1/16” o.d.ϫ380 µm

i.d.ϫ4 cm), glued in place [using epoxy resin (Bondmaster, UK)]

to enable the introduction and removal of reactants and products

to and from the micro reactor. As Figure 4 illustrates, fluidic con-

nections were made using a series of commercially available connec-

tors (Supleco, UK), inlets A and B were fed with 500 µL syringes

and inlet C with a 1000 µL syringe to afford a stoichiometric ratio

of reactants.

Materials: All solvents were purchased as puriss grade (Ͼ99.5%)

over molecular sieves (H₂O Ͻ 0.005%) from Fluka and unless

otherwise stated, reagents were purchased from Sigma–Aldrich and

used as received. The polymer-bound scandium(III) bis(trifluoro-

methanesulfonate) [PS-ScOTf₂], 3) (0.60 mmolScg^–1, 250–600 µm)

was ground in a pestle and mortar to reduce the overall particle

size and sieved to afford a particle size distribution of 38 to 75 µm

(Endcotts, UK). The polymer-supported (ethylenediaminetetraace-

tic acid)ruthenium(III) chloride (PS-RuCl₃, 1) (0.26 mmolRug^–1,

50–100 mesh) and polymer-bound ethylenediaminetetraacetamide

(PS-EDTA) (3.62 mmolNg^–1) were also sieved to afford the narrow

particle size distribution required (see PS-ScOTf₂, 3) to enable the

preparation of uniform packed beds.

Preparation of (E)-[1-(4-Bromophenyl)methylidene]phenethylamine

(11) in Batch: 2-Phenylethylamine (7, 1.21 g, 10.0 mmol) was added

to a solution of 4-bromobenzaldehyde (6, 1.85 g, 10.0 mmol) in an-

hydrous MeCN (10 mL) and stirred for 24 h. Over the course of

the reaction a white crystalline solid precipitated from the reaction

mixture, this was filtered under suction and recrystallized from

DCM/hexane to afford the title compound 11 as a white, crystalline

solid; (0.0361 g, 99.9%). C₁₅H₁₄BrN (288.19): calcd. C 62.52, H

Instrumentation: All ¹H and ¹³C NMR spectra were recorded as

solutions in deuteriochloroform (CDCl₃) using tetramethylsilane

(TMS) as an internal standard. The spectra were recorded on a

Jeol GX400 spectrometer and the chemical shifts reported in parts

per million (ppm) with coupling constants given in Hertz (Hz). The

following abbreviations are used to report NMR spectroscopic

data; s = singlet, d = doublet, t = triplet, br. s = broad singlet, q

= quartet, sext = sextet, dd = double doublet, dt = doublet of

triplets, m = multiplet, ArH = aromatic proton and C₀= quater-

nary carbon. Elemental analyses were performed using a Fisons

Carlo–Erba CHN analyzer (EA1108) and infrared spectra (4000 to

600 cm^–1) were obtained in the solid state (KBr disks) using a Per-

4.90, N 4.86; found C 62.31, H 4.92, N 4.64. IR: ν

= 691.1,

˜

max

738.2, 851.0, 1457.2, 1507.2, 1653.2, 2360.4 and 3350.1 cm^–1. ¹H

NMR (400 MHz, CDCl₃/TMS): δ = 3.03 (t, J = 7.4 Hz, 2 H,

CH₂Ph), 3.89 (t, J = 7.4 Hz, 2 H, NCH₂CH₂), 7.21–7.39 (m, 5 H,

5ϫ ArH), 7.57 (m, 4 H, 4ϫ ArH) and 8.20 (s, 1 H, CH) ppm.

¹³C NMR (100 MHz, CDCl₃/TMS): δ = 37.5 (CH₂CH₂N), 63.2

(CH₂CH₂N), 125.1 (C₀Br), 126.3 (CH), 128.5 (2ϫ CH), 129.2 (2ϫ

CH), 129.6 (2ϫ CH), 131.9 (2ϫ CH), 135.2 (C₀), 139.9 (C₀) and

160.3 (CH) ppm. MS (EI): m/z = 290 (35), 289 (15), 288 (60), 198

(90), 197 (10), 196 (100), 171 (5), 169 (5), 105 (20) and 76 (15). GC-

MS R_T= 12.40 min.

kin–Elmer Optima 5300DV instrument, with peaks (ν_max) reported

in wavenumbers. Mass spectrometry data was obtained using a Shi-

madzu QP5050A instrument with an EI ionization source. Melting

˜

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5607

C. Wiles, P. Watts

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Continuous-Flow Synthesis of 2-(4-Bromophenyl)-2-(phenethyl-

amino)acetonitrile (8) via the Cyanohydrin Intermediate: Employing

51.2 (CH₂), 52.9 (CH), 118.3 (CN), 123.3 (C₀Br), 127.8 (CH), 128.4

(2ϫ CH), 128.7 (2ϫ CH), 129.0 (2ϫ CH), 132.1 (2ϫ CH), 133.7

(C₀) and 137.8 (C₀) ppm. MS (EI): m/z = 303 (30), 302 (20), 301

polymer-supported

(ethylenediaminetetraacetic

acid)rutheni-

um(III) chloride (1, 0.01 g, 0.26 mmol Ru g^–1) as the catalyst, solu- (30), 274 (13), 272 (5), 195 (5), 194 (11), 106 (21), 92 (50), 91 (100)

tions of 2-(4-bromophenyl)-2-(trimethylsilyloxy)acetonitrile (9,

0.2  in MeCN) and 2-phenylethylamine (7, 0.2  in MeCN) were

introduced into the reactor from inlets A and B respectively, where

they mixed in the central channel prior to passing through the cata-

lyst bed in a 1:1 ratio and an overall concentration of 0.1 . The

reaction products were collected at outlet D, into a pre-weighed

sample vial, over a period of 2.5 h and concentrated in vacuo prior

and 65 (20).

2-(4-Bromophenyl)-2-(phenethylamino)acetonitrile (8): (Table 2, En-

try 3) Conducting the reaction at a total flow rate of 20 µLmin^–1

and employing 4-bromobenzaldehyde (6) and 2-phenylethylamine

(7) as reactants, the title compound 8 was obtained as a pale yellow

solid (0.038 g, 99.9%); mpt. 91–92 °C. C₁₆H₁₅BrN₂(315.21): calcd.

C 60.97, H 4.80, N 8.89; found C 61.06, H 4.96, N 8.69]. IR: ν

˜

max

1

to analysis by H NMR spectroscopy. Comparison of the integrals

= 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 cm^–1. ¹H NMR (400 MHz,

CDCl₃/TMS): δ = 1.54 (br. s, 1 H, NH), 2.62–2.86 (m, 2 H, CH₂),

2.95–3.10 (m, 2 H, 2ϫ CH₂), 4.75 (s, 1 H, CH), 7.12 (m, 3 H, 3ϫ

ArH), 7.23 (m, 2 H, 2ϫ ArH), 7.43 (d, J = 8.4 Hz, 2 H, ArH) and

7.50 (d, J = 8.4 Hz, 2 H, 2ϫ ArH) ppm. ¹³C NMR (100 MHz,

CDCl₃/TMS): δ = 35.7 (CH₂), 47.8 (CH₂N), 53.6 (CH), 118.2

(CN), 122.9 (C₀Br), 128.2 (C₀), 128.5 (4ϫ CH), 128.6 (2ϫ CH),

131.8 (2ϫ CH), 133.6 (CH) and 138.8 (C₀) ppm. MS (EI): m/z =

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).

obtained for the signals arising from the O-TMS cyanohydrin 9, at

δ = 5.38 ppm, and α-aminonitrile 8, at δ = 4.8 ppm, enabled the %

conversion to be quantified.

Continuous-Flow Synthesis of 2-(4-Bromophenyl)-2-(phenethyl-

amino)acetonitrile (8) via the Imine Intermediate 11: Employing

polymer-supported

(ethylenediaminetetraacetic

acid)rutheni-

um(III) chloride (0.01 g, 0.26 mmol Ru g^–1) as the catalyst, solu-

tions of (E)-[1-(4-bromophenyl)methylidene]phenethylamine (11,

0.2  in MeCN) and TMSCN (2, 0.2  in MeCN) were introduced

into the reactor from inlets A and B respectively, where they mixed

in the central channel prior to passing through the packed bed at

an overall concentration of 0.1  (1:1). The reaction products were

collected at outlet D, into a pre-weighed sample vial, over a period

2-(4-Bromophenyl)-2-(3-phenylpropylamino)acetonitrile

(19):

(Table 2, Entry 4) Employing 6 and 14 as reactants, the micro reac-

tion was conducted at a total flow rate of 20 µLmin^–1, to afford 19

as a pale yellow gum (0.0394 g, 99.9%). C₁₇H₁₇BrN₂(329.24):

calcd. C 62.02, H 5.20, N 8.51; found C 61.95, H 5.29, N 8.48].

1

of 2.5 h and concentrated in vacuo prior to analysis by H NMR

spectroscopy. Comparison of the integrals obtained for the signals

arising from the imine 11, at δ = 8.20 ppm, and α-aminonitrile 8,

δ = 4.75 ppm, enabled quantification of the % conversion.

IR: ν

= 699.7, 746.6, 817.7, 1453.0, 1487.2, 1573.3, 1589.1,

˜

max

2226.6, 2855.9, 2935.0, 3025.1 and 3316.0 cm^–1. ¹H NMR

(400 MHz, CDCl₃/TMS): δ = 1.48 (br. s, 1 H, NH), 1.76 (m, 2 H,

CH₂), 2.61–2.74 (m, 4 H, 2ϫ CH₂), 4.61 (s, 1 H, CH), 7.12–7.30

(m, 5 H, 5ϫ ArH), 7.32 (d, J = 8.5 Hz, 2 H, 2ϫ ArH) and 7.46 (d,

J = 8.5 Hz, 2 H, 2ϫ ArH) ppm. ¹³C NMR (100 MHz, CDCl₃/

TMS): δ = 30.8 (CH₂), 32.9 (CH₂), 46.2 (CH₂), 53.5 (CH), 118.2

(CN), 122.6 (C₀), 125.6 (CH), 128.0 (2ϫ CH), 128.1 (4ϫ CH),

131.1 (2ϫ CH), 133.7 (C₀) and 141.8 (C₀) ppm. MS (EI): m/z =

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).

General Procedure for the Continuous-Flow Synthesis of α-Aminoni-

triles via an Imine Intermediate (Prepared in-Situ): Employing 1

(0.01 g, 0.26 mmolRug^–1) or 3 (0.010 g, 0.60 mmolScg^–1), solu-

tions of the aldehyde (0.4  in MeCN) and amine (0.4  in MeCN)

were introduced into the reactor from inlets A and B respectively,

to afford the respective imine within the central channel at a con-

centration of 0.2 . TMSCN (2, 0.2  in MeCN) was subsequently

introduced into the reactor, where it mixed with the in-situ gener-

ated imine, prior to passing through the catalyst bed at a total flow

rate of 20 to 40 µLmin^–1.^[33]The reaction mixture was collected at

outlet D, in a pre-weighed sample vial, and concentrated in vacuo,

prior to dissolution in CDCl₃and analysis by ¹H NMR spec-

troscopy. Comparison of the integrals from the residual CH signal

of the imine and that of the CH from the desired α-aminonitrile

enabled quantification of the% conversion and hence the relative

success of the reaction. All known compounds were identified by

comparison of their spectroscopic data and physical properties with

those of authentic samples (See Supporting Information for further

details) and for those compounds that were previously unknown,

full characterization was performed on the compounds synthesized

under continuous flow using PS-ScOTf₂(3) as the catalyst; in all

cases, no additional product purification was performed.

2-Phenyl-2-(3-phenylpropylamino)acetonitrile: (Table 3, Entry 4)

Employing benzaldehyde 23 and phenylpropylamine (14) as reac-

tants, the micro reactor was operated at a total flow rate of

20 µLmin^–1, to afford 2-phenyl-2-(3-phenylpropylamino)acetoni-

trile as a pale yellow gum (0.0300 g, 99.9%). C₁₇H₁₈N₂(250.34):

calcd. C 81.56, H 7.25, N 11.19; found C 81.50, H 7.23, N 11.10].

IR: ν

= 689.9, 738.0, 1452.5, 1496.1, 1580.3, 1600.9, 1643.6,

˜

max

202.6, 2856.0, 2937.6, 3027.3 and 3317.8 cm^–1. ¹H NMR

(400 MHz, CDCl₃/TMS): δ = 1.89 (m, 2 H, CH₂), 2.67–2.86 (m, 4

H, 2ϫ CH₂), 4.76 (s, 1 H, CH), 7.26–7.38 (m, 10 H, 10ϫ ArH)

ppm and NH not observed. ¹³C NMR (100 MHz, CDCl₃/TMS): δ

= 31.1 (CH₂), 33.2 (CH₂), 46.7 (CH₂), 54.4 (CH), 118.8 (CN), 125.8

(CH), 128.2 (2ϫ CH), 128.3 (CH), 128.4 (4ϫ CH), 128.8 (2ϫ CH),

132.3 (C₀) and 141.6 (C₀) ppm. MS (EI): m/z = 251 (4), 250 (8),

224 (7), 145 (14), 131 (20), 119 (48), 118 (100), 116 (70), 105 (14),

91 (47), 90 (10), 77 (12) and 65 (11).

2-Benzylamino-2-(4-bromophenyl)acetonitrile (18): (Table 2, Entry

2) Employing 4-bromobenzaldehyde (6) and benzylamine (13) as

reactants, the micro reaction was conducted at a total flow rate of

20 µLmin^–1to afford 18 as a pale yellow oil (0.0361 g, 99.9%).

C₁₅H₁₃BrN₂(301.19): calcd. C 59.82, H 4.35, N 9.30; found C

2-(Benzylamino)-2-(3,5-dimethoxyphenyl)acetonitrile: (Table 3, En-

try 7) Employing 3,5-dimethoxybenzaldehyde (20) and benzyla-

mine (13) as reactants, the micro reactor was operated at a total

flow rate of 20 µLmin^–1, affording 2-(benzylamino)-2-(3,5-dimeth-

60.10, H 4.56, N 9.06]. IR: ν

= 701.0, 736.7, 788.2, 823.5,

˜

max

1454.1, 1488.2, 1551.6, 1591.1, 2303.6, 2846.5, 3030.4, 3053.5 and

1

3322.5 cm^–1. H NMR (400 MHz, CDCl₃/TMS): δ = 1.85 (br. s, 1

oxyphenyl)acetonitrile as

99.9%). C₁₇H₁₈N₂O₂(282.34): calcd. C 72.30, H 6.43, N 8.51;

= 691.3, 720.4, 810.3,

a white crystalline solid (0.0338 g,

H, NH), 3.82 (d, J = 12.9 Hz, 1 H, CHH), 3.94 (d, J = 12.9 Hz, 1

H, CHH), 4.81 (s, 1 H, CH), 7.28–7.41 (m, 5 H, 5ϫ ArH), 7.44 (d, found C 72.23, H 6.62, N 9.69]. IR: ν

˜

max

1

J = 8.4 Hz, 2 H, 2ϫ ArH) and 7.54 (d, J = 8.4 Hz, 2 H, 2ϫ ArH),

1445.2, 2260.6, 2820.6, 2866.3, 2938.1 and 3029.4 cm^–1. H NMR

5608

www.eurjoc.org

Eur. J. Org. Chem. 2008, 5597–5613

Catalyzed Strecker Reaction Conducted Under Continuous Flow

(400 MHz, CDCl₃/TMS): δ = 1.93 (br. s, 1 H, NH), 3.76 (s, 6 H,

2ϫ OCH₃), 3.90 (d, J = 12.9 Hz, 1 H, CHH), 4.00 (d, J = 12.9 Hz,

1 H, CHH), 4.79 (s, 1 H, CH), 6.42 (t, J = 2.2 Hz, 1 H, ArH), 6.67

(d, J = 2.2 Hz, 2 H, 2ϫ ArH) and 7.32–7.36 (m, 5 H, 5ϫ ArH)

ppm. ¹³C NMR (100 MHz, CDCl₃/TMS): δ = 50.9 (CH), 53.2

20 µLmin^–1and employing 4-chlorobenzaldehyde (21) and 2-phen-

ylethylamine (7) as reactants, afforded the title compound as a col-

orless oil (0.0323 g, 99.8%). C₁₆H₁₅ClN₂(270.76): calcd. C 70.98,

H 5.58, N 10.35; found C 70.95, H 5.62, N 10.42]. IR: ν_max= 743.4,

˜

792.1, 853.2, 2254.5, 2870.6, 2925.7 and 2962.3 cm^–1. ¹H NMR

(CH₂), 55.3 (2ϫ OCH₃), 100.6 (CH), 105.2 (2ϫ CH), 118.6 (CN), (400 MHz, CDCl₃/TMS): δ = 1.93 (br. s, 1 H, NH), 2.83 (m, 2 H,

127.5 (CH), 128.3 (2ϫ CH), 128.4 (2ϫ CH), 130.8 (C₀), 138.0 (C₀) CH₂), 2.98 (m, 2 H, CH₂), 4.75 (s, 1 H, CH), 7.23 (m, 3 H, 3ϫ

and 161.0 (2ϫ C₀OCH₃) ppm. MS (EI): m/z = 283 (8), 282 (16), ArH), 7.32 (m, 2 H, 2ϫ ArH), 7.33 (d, J = 8.5 Hz, 2 H, 2ϫ ArH)

281 (17), 255 (38), 240 (5), 224 (10), 106 (20), 91 (100), 77 (20) and and 7.41 (d, J = 8.5 Hz, 2 H, 2ϫ ArH) ppm. ¹³C NMR (100 MHz,

75 (5).

CDCl₃/TMS): δ = 35.8 (CH₂), 42.6 (CH₂N), 53.6 (CH), 118.3

(CN), 126.4 (C₀), 128.5 (4ϫ CH), 128.6 (4ϫ CH), 133.1 (CH),

134.8 (C₀) and 138.8 (C₀) ppm.

2-(3,5-Dimethoxyphenyl)-2-(phenethylamino)acetonitrile: (Table 3,

Entry 8) Conducting the reaction at a total flow rate of 20 µLmin^–1

and employing 3,5-dimethoxybenzaldehyde (20) and 2-phenylethyl-

amine (7) as reactants, title compound was obtained as a white

crystalline solid (0.0355 g, 99.9%). C₁₈H₂₀N₂O₂(296.37): calcd. C

2-(4-Chlorophenyl)-2-(3-phenylpropylamino)acetonitrile:

(Table 3,

Entry 14) Employing 4-chlorobenzaldehyde (21) and phenylpropyl-

amine (14) as reactants, the micro reaction was conducted at a total

flow rate of 20 µLmin^–1, affording the title compound as a colorless

oil (0.0342 g, 100.0%). C₁₇H₁₇ClN₂(284.91): calcd. C 71.70, H

72.95, H 6.80, N 9.45; found C 72.75, H 6.81, N 9.39]. IR: ν

=

˜

max

740.7, 1156.3, 1265.5, 1429.7, 1457.6, 1598.2, 2305.7, 2841.5,

2986.5 and 3054.5 cm^–1. ¹H NMR (400 MHz, CDCl₃/TMS): δ =

2.62 (m, 2 H, CH₂), 2.91 (m, 2 H, CH₂), 3.73 (s, 6 H, 2ϫ OCH₃),

5.39 (s, 1 H, CH), 6.40 (t, J = 2.2 Hz, 1 H, ArH), 6.59 (m, 2 H,

2ϫ ArH), 7.12–7.29 (m, 5 H, 5ϫ ArH) ppm. and NH not observed.

6.02, N 9.84; found C 71.65, H 6.10, N 9.82]. IR: ν

= 690.1,

˜

max

736.2, 792.1, 1453.0, 1496.6, 1580.3, 1601.3, 1644.2, 2304.5, 2856.1,

2937.8, 3027.4 and 3317.9 cm^–1. ¹H NMR (400 MHz, CDCl₃/

TMS): δ = 1.85 (m, 2 H, CH₂), 2.69–2.84 (m, 4 H, 2ϫ CH₂), 4.74

¹³C NMR (100 MHz, CDCl₃/TMS): δ = 37.1 (CH₂), 47.9 (CH₂N), (s, 1 H, CH), 7.14–7.20 (m, 5 H, 5ϫ ArH), 7.27 (d, J = 7.8 Hz, 2

50.1 (CH), 56.3 (2ϫ OCH₃), 99.2 (CH), 107.1 (2ϫ CH), 114.7

H, 2ϫ ArH), 7.48 (m, 2 H, 2ϫ ArH) ppm and NH not observed.

(CN), 126.3 (CH), 127.6 (2ϫ CH), 128.3 (2ϫ CH), 132.2 (C₀), ¹³C NMR (100 MHz, CDCl₃/TMS): δ = 33.1 (CH₂), 33.4 (CH₂),

139.5 (C₀) and 162.3 (2ϫ C₀OCH₃) ppm. MS (EI): m/z = 297 (5), 45.3 (CH₂N), 49.9 (CH), 117.6 (CN), 125.6 (CH), 128.1 (2ϫ CH),

296 (3), 234 (10), 208 (15), 178 (100), 163 (25), 147 (45), 116 (10),

105 (20), 91 (30) and 76 (25).

128.3 (2ϫ CH), 128.8 (2ϫ CH), 130.4 (2ϫ CH), 131.8 (C₀), 134.2

(C₀Cl) and 142.0 (C₀) ppm. MS (EI): m/z = 285 (3), 284 (2), 283

(4), 273 (5), 271 (10), 154 (100), 152 (95), 127 (14), 125 (40), 105

(20), 91 (30) and 76 (10).

2-(3,5-Dimethoxyphenyl)-2-(3-phenylpropylamino)acetonitrile: (Table

3, Entry 9) Employing 3,5-dimethoxybenzaldehyde (20) and phen-

ylpropylamine (14) as reactants, the micro reactor was operated at

a total flow rate of 20 µLmin^–1, affording the title compound as a

2-(4-Chlorophenyl)-2-(pyrrolidin-1-yl)acetonitrile: (Table 3, Entry

15) Operating the micro reactor at a total flow rate of 40 µLmin^–1

colorless oil (0.0372 g, 100.0%). C₁₉H₂₂N₂O₂(310.39): calcd. C and employing 4-chlorobenzaldehyde (21) and pyrrolidine (15) as

73.52, H 7.14, N 9.03; found C 73.50, H 7.16, N 9.10]. IR: ν

reactants, the title compound was obtained as a pale yellow oil

(0.0264 g, 100.0%). C₁₂H₁₃ClN₂(221.63): calcd. C 65.31, H 5.94,

˜

max

= 650.2, 680.4, 720.5, 1360.1, 1450.2, 2255.3, 2815.5, 2850.2 and

2920.5 cm^–1. ¹H NMR (400 MHz, CDCl₃/TMS): δ = 1.82 (m, 2 H,

N 12.70; found C 65.65, H 6.23, N 12.57]. IR: ν_max= 720.1, 750.2,

˜

CH₂), 2.67–2.69 (m, 4 H, 2ϫ CH₂), 3.76 (s, 6 H, 2ϫ OCH₃), 4.65 860.2, 1540.5, 1616.4, 2302.6, 2801.3 and 2915.4 cm^–1. ¹H NMR

(s, 1 H, CH), 6.43 (t, J = 2.2 Hz, 1 H, ArH), 6.65 (d, J = 2.2 Hz, (400 MHz, CDCl₃/TMS): δ = 1.83 (m, 4 H, 2ϫ CH₂), 2.61 (m, 4

2 H, 2ϫ ArH), 7.15–7.27 (m, 5 H, 5ϫ ArH) ppm and NH not H, 2ϫ CH₂), 5.02 (s, 1 H, CH), 7.36 (d, J = 8.2 Hz, 2 H, 2ϫ ArH)

observed. ¹³C NMR (100 MHz, CDCl₃/TMS): δ = 31.1 (CH₂), 33.1

and 7.47 (d, J = 8.2 Hz, 2 H, 2ϫ ArH) ppm. ¹³C NMR (100 MHz,

(CH₂), 46.6 (CH₂), 54.3 (CH), 55.3 (2ϫ OCH₃), 100.6 (CH), 105.6 CDCl₃/TMS): δ = 23.2 (2ϫ CH₂), 48.2 (2ϫ CH₂N), 51.3 (CH),

(2ϫ CH), 118.7 (CN), 125.8 (CH), 128.2 (4ϫ CH), 137.0 (C₀), 115.4 (CN), 128.1 (2ϫ CH), 128.2 (CH), 130.4 (2ϫ CH) and 133.2

141.5 (C₀), 161.0 (2ϫ C₀OCH₃) ppm. MS (EI): m/z = 311 (18), 310

(8), 284 (100), 253 (10), 222 (15), 179 (90), 178 (85), 148 (50), 119

(45), 91 (65), 77 (15) and 75 (10).

(C₀Cl) ppm. MS (EI): m/z = 222 (5), 221 (10), 220 (15), 219 (12),

194 (5), 85 (13), 84 (15), 83 (38), 70 (50) and 51 (25).

Methyl 4-[Cyano(phenylamino)methyl]benzoate: (Table 3, Entry 16)

Employing methyl 4-formylbenzoate (22) and aniline (12) as reac-

tants, the micro reaction was conducted at a total flow rate of

20 µLmin^–1, to afford the title compound as a colorless oil

(0.0318 g, 99.8%). C₁₆H₁₄N₂O₂(266.42): calcd. C 72.17, H 5.30, N

2-(3,5-Dimethoxyphenyl)-2-(pyrrolidin-1-yl)acetonitrile:

(Table 3,

Entry 10) Operating the micro reactor at a total flow rate of

40 µLmin^–1, employing 3,5-dimethoxybenzaldehyde (20) and pyr-

rolidine (15) as reactants, 2-(3,5-dimethoxyphenyl)-2-(pyrrolidin-1-

yl)acetonitrile was obtained as a pale yellow oil (0.0295 g, 100.0%).

C₁₄H₁₈N₂O₂(246.31): calcd. C 68.27, H 7.40, N 11.38; found C

10.52; found C 71.89, H 5.53, N 10.28]. IR: ν

= 690.2, 745.0,

˜

max

840.3, 1250.2, 1752.1, 2253.6, 2835.2 and 2905.3 cm^–1. ¹H NMR

68.27, H 7.60, N 11.64]. IR: ν

= 650.2, 683.6, 720.1, 740.7,

(400 MHz, CDCl₃/TMS): δ = 3.95 (s, 3 H, OCH₃), 4.13 (d, J =

˜

max

896.0, 1429.3, 1508.0, 1598.3, 2240.1, 2820.3 and 3055.4 cm^–1. H 8.4 Hz, 1 H, NH), 5.52 (d, J = 8.4 Hz, 1 H, CH), 6.78 (m, 2 H, 2ϫ

1

NMR (400 MHz, CDCl₃/TMS): δ = 1.83 (m, 4 H, 2ϫ CH₂), 2.66

(m, 4 H, 2ϫ CH₂), 3.80 (s, 6 H, 2ϫ OCH₃), 4.97 (s, 1 H, CH), 6.43

ArH), 6.98 (m, 1 H, ArH), 7.26–7.30 (m, 2 H, 2ϫ ArH), 7.71 (d,

J = 8.3 Hz, 2 H, 2ϫ ArH) and 8.11 (d, J = 8.3 Hz, 2 H, 2ϫ ArH)

(t, J = 2.2 Hz, 1 H, ArH) and 6.89 (d, J = 2.2 Hz, 2 H, 2ϫ ArH) ppm. ¹³C NMR (100 MHz, CDCl₃/TMS): δ = 50.0 (CH), 52.4

ppm. ¹³C NMR (100 MHz, CDCl₃/TMS): δ = 23.1 (2ϫ CH₂), 48.2 (OCH₃), 114.3 (2ϫ CH), 118.2 (CN), 120.6 (CH), 127.2 (2ϫ CH),

(2ϫ CH₂), 51.0 (CH), 55.3 (2ϫ OCH₃), 100.6 (CH), 105.2 (2ϫ 129.6 (2ϫ CH), 130.5 (2ϫ CH), 139.2 (C₀), 144.3 (C₀) and 168.3

CH), 118.6 (CN), 136.8 (C₀) and 161.1 (2ϫ C₀OCH₃) ppm. MS (C₀CO₂CH₃) ppm. MS (EI): m/z = 267 (5), 266 (15), 235 (15), 207

(EI): m/z = 247 (20), 246 (10), 220 (40), 194 (20), 177 (65), 109 (40), (25), 189 (20), 175 (75), 135 (100), 131 (10), 77 (15) and 76 (10).

84 (35), 70 (100) and 49 (50).

Methyl 4-[Cyano(benzylamino)methyl]benzoate: (Table 3, Entry 17)

2-(4-Chlorophenyl)-2-(phenethylamino)acetonitrile: (Table 3, Entry

13) Conducting the micro reaction at a total flow rate of

Conducting the micro reaction at a total flow rate of 20 µLmin^–1

and employing methyl 4-formylbenzoate (22) and benzylamine 13

Eur. J. Org. Chem. 2008, 5597–5613

www.eurjoc.org

5609

C. Wiles, P. Watts

FULL PAPER

as precursors, afforded the title compound as a colorless oil

(0.0335 g, 99.9%). C₁₇H₁₆N₂O₂(280.33): calcd. C 72.84, H 5.75, N

2-(3-Phenylpropylamino)butanenitrile: (Table 4, Entry 4) Employing

propionaldehyde (24) and phenylpropylamine (14) as reactants, the

micro reaction was conduced at a total flow rate of 40 µLmin^–1,

affording the title compound as a colourless oil (0.0242 g, 99.9%).

C₁₃H₁₈N₂(202.30): calcd. C 77.18, H 8.97, N 13.85; found C 77.20,

9.99; found C 72.63, H 5.65, N 5.65]. IR: ν_max= 720.3, 741.2, 841.2,

˜

1

1252.3, 1457.0, 1719.6, 2254.1, 2987.0 and 3054.5 cm^–1. H NMR

(400 MHz, CDCl₃/TMS): δ = 1.96 (br. s, 1 H, NH), 3.90 (s, 3 H,

OCH₃), 3.90 (d, J = 12.9 Hz, 1 H, CHH), 4.02 (d, J = 12.9 Hz, 1 H 8.99, N 13.82]. IR: ν

= 695.3, 720.6, 1565.2, 2232.1, 2801.5,

˜

max

H, CHH), 4.77 (s, 1 H, CH), 7.28 (m, 5 H, 5ϫ ArH), 7.60 (d, J = 2865.1, 2886.1, 2905.6, 2986.1 and 3456.2 cm^–1. ¹H NMR

8.4 Hz, 2 H, 2ϫ ArH) and 8.05 (d, J = 8.4 Hz, 2 H, 2ϫ ArH) ppm. (400 MHz, CDCl₃/TMS): δ = 0.98 (t, J = 7.6 Hz, 3 H, CH₃), 1.67–

¹³C NMR (100 MHz, CDCl₃/TMS): δ = 51.0 (CH), 52.1 (OCH₃)

52.9 (CH₂), 118.1 (CN), 127.2 (2ϫ CH), 127.6 (CH), 128.3 (2ϫ

CH), 128.5 (2ϫ CH), 129.9 (2ϫ CH), 130.6 (C₀), 137.7 (C₀), 139.3

1.74 (m, 2 H, CH₂), 2.50–2.76 (m, 4 H, 2ϫ CH₂), 2.57 (t, J =

7.6 Hz, 2 H, CH₂), 2.78–2.84 (m, 1 H, NH), 3.34 (t, J = 7.6 Hz, 1

H, CH), 7.08–7.10 (m, 3 H, 3ϫ ArH) and 7.41–7.52 (m, 2 H, 2ϫ

(C₀) and 166.2 (C₀COCH₃) ppm. MS (EI): m/z = 281 (5), 280 (10), ArH) ppm. ¹³C NMR (100 MHz, CDCl₃/TMS): δ = 10.1 (CH₃),

254 (25), 135 (75), 91 (100), 77 (15) and 76 (5).

26.9 (CH₂), 31.3 (CH₂), 33.4 (CH₂), 47.2 (CH₂), 51.1 (CH), 120.3

(CN), 125.8 (CH), 128.3 (2ϫ CH), 128.4 (2ϫ CH) and 141.6 (C₀)

ppm. MS (EI): m/z = 203 (5), 202 (6), 187 (15), 173 (100), 134 (20),

120 (15), 105 (75), 91 (65) and 77 (10).

Methyl 4-[Cyano(phenethylamino)methyl]benzoate: (Table 3, Entry

18) Conducting the micro reaction at a total flow rate of

20 µLmin^–1and employing methyl 4-formylbenzoate (22) and 2-

phenylethylamine (7) as reactants, afforded the title compound as

a pale yellow oil (0.0352 g, 99.9%). C₁₈H₁₈N₂O₂(294.35): calcd. C

2-(3-Phenylpropylamino)pentanenitrile: (Table 4, Entry 9) Em-

ploying butyraldehyde (26) and phenylpropylamine (14) as precur-

sors, the micro reactor was operated at a total flow rate of

40 µLmin^–1to afford the title compound as a colorless oil

(0.0258 g, 99.6%). C₁₄H₂₀N₂(216.33): calcd. C 77.73, H 9.32, N

73.45, H 6.16, N 9.52; found C 73.52, H 6.48, N 9.37]. IR: ν

=

˜

max

738.7, 908.9, 1262.9, 1437.6, 1456.0, 1543.3, 1718.1, 2254.1, 2986.9

1

and 3540.3 cm^–1. H NMR (400 MHz, CDCl₃/TMS): δ = 2.89 (m,

2 H, CH₂), 3.01 (m, 2 H, CH₂), 3.89 (s, 3 H, OCH₃), 4.21 (br. s, 1

12.95; found C 77.62, H 9.38, N 12.83]. IR: ν

= 692.6, 719.9,

˜

max

H, NH), 4.83 (s, 1 H, CH), 7.19 (m, 2 H, 2ϫ ArH), 7.52 (m, 3 H, 740.3, 1543.2, 2234.1, 2840.6, 2885.6, 2921.3, 2956.1 and

3ϫ ArH), 7.55 (d, J = 8.4 Hz, 2 H, 2ϫ ArH) and 8.02 (d, J =

3467.2 cm^–1. ¹H NMR (400 MHz, CDCl₃/TMS): δ = 0.89 (t, J =

8.4 Hz, 2 H, 2ϫ ArH) ppm. ¹³C NMR (100 MHz, CDCl₃/TMS): 7.3 Hz, 3 H, CH₃), 1.41–1.48 (2 H, m CH₂), 1.64 (q, J = 7.3 Hz, 2

δ = 35.7 (CH₂), 47.9 (CH₂), 52.1 (CH), 53.8 (OCH₃), 118.1 (CN), H, CH₂), 1.70–1.80 (m, 2 H, CH₂), 2.53–2.56 (m, 1 H, CH), 2.60

123.1 (CH), 127.1 (2ϫ CH), 128.4 (4ϫ CH), 129.4 (C₀), 129.7 (2ϫ

(t, J = 7.6 Hz, 2 H, CH₂), 2.82–2.86 (m, 1 H, CH), 3.42 (m, 1 H,

CH), 138.8 (C₀), 139.3 (C₀) and 166.2 (C₀CO₂CH₃) ppm. MS (EI): CH), 7.12 (m, 3 H, 3ϫ ArH), 7.19–7.24 (m, 2 H, 2ϫ ArH) ppm

m/z = 295 (8), 294 (4), 268 (28), 236 (5), 203 (49), 179 (100), 174 and NH not observed. ¹³C NMR (100 MHz, CDCl₃/TMS): δ =

(75), 117 (33), 105 (32), 91 (53) and 76 (25).

13.9 (CH₃), 19.4 (CH₂), 31.7 (CH₂), 33.8 (CH₂), 36.0 (CH₂), 47.6

(CH₂), 50.8 (CH), 120.8 (CN), 126.3 (CH), 128.8 (2ϫ CH), 128.8

(2ϫ CH) and 142.1 (C₀) ppm. MS (EI): m/z = 217 (5), 216 (10),

175 (15), 161 (15), 147 (20), 134 (15), 105 (100), 91 (75) and 77

(20).

Methyl 4-[Cyano(3-phenylpropylamino)methyl]benzoate: (Table 3,

Entry 19) Conducting the micro reaction at a total flow rate of

20 µLmin^–1and employing methyl 4-formylbenzoate (22) and

phenylpropylamine (14) as reactants, afforded the title compound

as a colorless oil (0.0369 g, 99.9%). C₁₉H₂₀N₂O₂(294.35): calcd. C

2-(Phenylamino)hexanenitrile: (Table 4, Entry 11) Conducting the

micro reaction at a total flow rate of 30 µLmin^–1and employing

valeraldehyde (27) and aniline (12) as reactants, 2-(phenylamino)-

hexanenitrile was obtained as a pale yellow oil (0.0338 g, 99.9%).

73.80, H 6.79, N 9.06; found C 74.01, H 6.54, N 9.09]. IR: ν

=

˜

max

738.7, 908.9, 1262.9, 1437.6, 1456.0, 1543.3, 1718.1, 2254.1, 2986.9

1

and 3054.3 cm^–1. H NMR (400 MHz, CDCl₃/TMS): δ = 1.89 (m,

2 H, CH₂), 2.21 (br. s, 1 H, NH), 2.65–2.70 (m, 4 H, 2ϫ CH₂), C₁₂H₁₆N₂(188.27): calcd. C 76.55, H 8.57, N 14.88; found C 76.35,

3.90 (s, 3 H, OCH₃), 4.79 (s, 1 H, CH), 7.16–7.25 (m, 5 H, 5ϫ

ArH), 7.59 (d, J = 8.7 Hz, 2 H, 2ϫ ArH) and 8.03 (d, J = 8.7 Hz,

H 8.49, N 14.72]. IR: ν

= 650.5, 732.7, 908.0, 1469.8, 1506.6,

˜

max

1603.1, 2254.5, 2870.6, 2925.8, 2962.6 and 3431.6 cm^–1. H NMR

1

2 H, 2ϫ ArH) ppm. ¹³C NMR (100 MHz, CDCl₃/TMS): δ = 31.0 (400 MHz, CDCl₃/TMS): δ = 0.89 (t, J = 7.3 Hz, 3 H, CH₃), 1.24–

(CH₂), 32.1 (CH₂), 46.6 (CH₂), 52.1 (CH), 54.0 (OCH₃), 118.3 1.37 (m, 4 H, 2ϫ CH₂), 1.72–1.93 (m, 2 H, CH₂), 3.52 (m, 1 H,

(CN), 126.5 (CH), 127.1 (2ϫ CH), 128.2 (4ϫ CH), 128.6 (2ϫ CH), CH), 4.31 (br. s, 1 H, NH), 6.63–6.81 (m, 3 H, 3ϫ ArH) and 7.34–

129.6 (C₀), 139.4 (C₀), 141.4 (C₀) and 166.2 (C₀CO₂CH₃) ppm. MS 7.43 (m, 2 H, 2ϫ ArH) ppm. ¹³C NMR (100 MHz, CDCl₃/TMS):

(EI): m/z = 309 (5), 308 (8), 277 (10), 249 (25), 223 (28), 147 (50),

134 (25), 105 (35) and 91 (100).

δ = 14.0 (CH₃), 21.9 (CH₂), 31.0 (CH₂), 33.2 (CH₂), 52.6 (CH),

112.5 (2ϫ CH), 118.5 (CN), 119.2 (CH), 129.2 (2ϫ CH) and 146.3

(C₀) ppm. MS (EI): m/z = 189 (5), 188 (100), 172 (17), 143 (13),

131 (18), 118 (30), 105 (20), 93 (58) and 77 (15).

2-(Benzylamino)butanenitrile: (Table 4, Entry 2) Employing propi-

onaldehyde (24) and benzylamine (13) as reactants, the micro reac-

tion was performed at a total flow rate of 40 µLmin^–1to afford

the title compound as a colorless oil (0.0208 g, 99.6%). C₁₁H₁₄N₂

(175.24): calcd. C 75.82, H 8.10, N 16.08; found C 75.80, H 8.11,

2-(Benzylamino)hexanenitrile: (Table 4, Entry 12) Conducting the

micro reaction at a total flow rate of 40 µLmin^–1and employing

valeraldehyde (27) and benzylamine (13) afforded 2-(benzylamino)-

hexanenitrile as a colorless oil (0.0242 g, 99.9%). C₁₃H₁₈N₂

N 16.07]. IR: ν

= 720.2, 741.2, 863.2, 1395.2, 1502.3, 1523.4,

˜

max

2245.3, 2853.1, 2936.1 and 3346.1 cm^–1. ¹H NMR (400 MHz, (202.30): calcd. C 77.18, H 8.97, N 13.85; found C 77.25, H 9.01,

CDCl₃/TMS): δ = 1.00 (t, J = 7.3 Hz, 3 H, CH₃), 1.58 (br. s, 1 H,

NH), 1.67–1.76 (m, 2 H, CH₂), 3.35 (dt, J = 7.3 Hz, 1 H and 0.8,

CH), 3.74 (d, J = 12.9 Hz, 1 H, CHH), 3.96 (d, J = 12.9 Hz, 1 H,

N 13.72]. IR: ν

= 720.2, 741.2, 863.2, 1395.2, 1502.3, 1523.4,

˜

max

2245.3, 2853.1 and 3346.1 cm^–1. ¹H NMR (400 MHz, CDCl₃/

TMS): δ = 0.90 (t, J = 7.0 Hz, 3 H, CH₃), 1.30–1.47 (m, 5 H, 2ϫ

CHH) and 7.15–7.62 (m, 5 H, 5ϫ ArH) ppm. ¹³C NMR (100 MHz, CH₂and NH), 1.74–1.78 (m, 2 H, CH₂), 3.49 (dt, J = 7.0 Hz, 1 H

CDCl₃/TMS): δ = 10.1 (CH₃), 26.8 (CH₂), 51.1 (CH), 51.6 (CH₂), and 0.8, CH), 3.80 (d, J = 12.9 Hz, 1 H, CHH), 4.05 (d, J =

120.1 (CN), 127.5 (CH), 128.3 (2ϫ CH), 128.5 (2ϫ CH) and 138.3 12.9 Hz, 1 H, CHH) and 7.22–7.74 (m, 5 H, 5ϫ ArH) ppm. ¹³C

(C₀) ppm. MS (EI): m/z = 175 (10), 174 (15), 148 (25), 105 (75), 91

NMR (100 MHz, CDCl₃/TMS): δ = 13.8 (CH₃), 22.1 (CH₂), 27.7

(100) and 77 (15).

(CH₂), 33.2 (CH₂), 49.8 (CH), 51.6 (CH₂), 120.3 (CN), 127.5 (CH),

5610

www.eurjoc.org

Eur. J. Org. Chem. 2008, 5597–5613

Catalyzed Strecker Reaction Conducted Under Continuous Flow

128.5 (2ϫ CH), 128.6 (2ϫ CH) and 138.4 (C₀) ppm. MS (EI): m/z NH), 1.63 (q, J = 7.0 Hz, 2 H, CH₂), 2.69–2.83 (m, 3 H, CH₂and

= 203 (5), 202 (15), 187 (30), 173 (75), 159 (30), 120 (16), 106 (5),

91 (100) and 77 (12).

NCH), 3.04–3.10 (m, 1 H, NCH), 3.43 (t, J = 7.0 Hz, 1 H, CH),

7.09–7.18 (m, 3 H, 3ϫ ArH) and 7.20–7.24 (m, 2 H, 2ϫ ArH) ppm.

¹³C NMR (100 MHz, CDCl₃/TMS): δ = 14.0 (CH₃), 22.5 (CH₂),

25.4 (CH₂), 31.3 (CH₂), 33.5 (CH₂), 36.1 (CH₂), 48.8 (CH₂), 50.8

(CH), 120.4 (CN), 126.6 (CH), 128.7 (2ϫ CH), 128.8 (2ϫ CH) and

139.2 (C₀) ppm. MS (EI): m/z = 231 (6), 230 (10), 215 (7), 201 (10),

187 (15), 173 (100), 159 (30), 145 (45), 105 (100) and 77 (45).

2-(Phenethylamino)hexanenitrile: (Table 4, Entry 13) Employing va-

leraldehyde (27) and 2-phenylethylamine (7) as precursors, the

micro reaction was conducted at a total flow rate of 40 µLmin^–1,

to afford 2-phenethylamino-hexanenitrile as a pale yellow oil

(0.0259 g, 100.0%). C₁₄H₂₀N₂(216.33): calcd. C 77.73, H 9.32, N

12.95; found C 77.69, H 9.31, N 12.97]. IR: ν

= 704.2, 743.4,

2-(3-Phenylpropylamino)heptanenitrile: (Table 4, Entry 19) Em-

˜

max

1268.3, 1459.6, 2302.6, 2861.7, 2930.6, 2959.5 and 3649.5 cm^–1. ¹H ploying hexanal (28) and phenylpropylamine (14) as reactants, the

NMR (400 MHz, CDCl₃/TMS): δ = 0.85 (t, J = 7.3 Hz, 3 H, CH₃),

1.23–1.43 (m, 2 H, CH₂), 1.56 (br. s, 1 H, NH), 1.65 (q, J = 7.3 Hz,

micro reaction was performed at a total flow rate of 40 µLmin^–1,

to afford 2-(3-phenylpropylamino)heptanenitrile as a pale yellow

2 H, CH₂), 1.71–1.81 (m, 2 H, CH₂), 2.52–2.57 (dq, J = 7.3 Hz, 1 oil (0.0293 g, 99.9%). C₁₆H₂₄N₂(244.38): calcd. C 78.64, H 9.90,

H and 1.4, CHH), 2.59 (t, J = 7.3 Hz, 2 H, CH₂), 2.81–2.86 (dq, 1

H, 7.3 and 1.4, CHH), 3.41 (dt, J = 7.3 Hz, 1 H and 0.8, CH), 7.12

N 11.46; found C 78.61, H 9.92, N 11.43]. IR: ν_max= 695.1, 723.1,

˜

1382.6, 1542.1, 2245.6, 2854.6, 2891.6, 910.7, 2986.1 and

(m, 2 H, 2ϫ ArH) and 7.18 –7.25 (m, 3 H, 3ϫ ArH) ppm. ¹³C 3461.3 cm^–1. ¹H NMR (400 MHz, CDCl₃/TMS): δ = 0.77 (t, J =

NMR (100 MHz, CDCl₃/TMS): δ = 14.2 (CH₃), 22.6 (CH₂), 28.1

7.4 Hz, 3 H, CH₃), 1.16–1.24 (m, 5 H, 2ϫ CH₂and CHH), 1.35–

(CH₂), 31.7 (CH₂), 33.7 (CH₂), 47.6 (CH₂N), 51.1 (CH), 120.9 1.39 (m, 1 H, CHH), 1.63 (q, J = 7.4 Hz, 2 H, CH₂), 1.65–1.76 (m,

(CN), 126.3 (CH), 128.7 (2ϫ CH), 128.8 (2ϫ CH) and 142.1 (C₀) 2 H, CH₂), 2.49–2.53 (m, 1 H, CHH), 2.56 (t, J = 7.9 Hz, 2 H,

ppm. MS (EI): m/z = 217 (6), 216 (10), 201 (30), 187 (80), 173 (60),

CH₂), 2.77–2.84 (m, 1 H, CHH), 3.37 (dt, J = 7.4 Hz, 1 H and 1.4,

159 (20), 145 (5), 133 (20), 120 (10), 105 (100), 91 (75) and 77 (20). CH), 7.04–7.22 (m, 5 H, 5ϫ ArH) ppm and NH not observed. ¹³

C

NMR (100 MHz, CDCl₃/TMS): δ = 13.9 (CH₃), 22.4 (CH₂), 25.3

(CH₂), 31.2 (CH₂), 31.3 (CH₂), 33.4 (CH₂), 33.5 (CH₂), 47.2 (CH),

50.7 (CH₂N), 120.4 (CN), 125.9 (CH), 128.3 (2ϫ CH), 128.4 (2ϫ

CH) and 141.6 (C₀) ppm. MS (EI): m/z = 245 (5), 244 (15), 215

(20), 187 (15), 173 (100), 159 (75), 135 (50), 105 (20), 91 (45) and

76 (10).

2-(3-Phenylpropylamino)hexanenitrile: (Table 4, Entry 14) Op-

erating the micro reactor at a total flow rate of 40 µLmin^–1and

employing valeraldehyde (27) and phenylpropylamine (14) as reac-

tants afforded the title compound as a pale yellow oil (0.0276 g,

99.9%. C₁₅H₂₂N₂(230.35): calcd. C 78.21, H 9.63, N 12.16; found

C 78.27, H 9.83, N 12.25]. IR: ν_max= 695.1, 745.2, 1565.3, 2255.6,

˜

2880.6, 2885.6, 2915.3, 2976.1 and 3469.2 cm^–1. ¹H NMR 2-(Benzylamino)octanenitrile: (Table 4, Entry 22) Conducting the

(400 MHz, CDCl₃/TMS): δ = 0.85 (t, J = 7.3 Hz, 3 H, CH₃), 1.25–

1.36 (sext, J = 7.3 Hz, 2 H, CH₂), 1.37–1.41 (m, 2 H, CH₂), 1.65

(q, J = 7.3 Hz, 2 H, CH₂), 1.71–1.79 (m, 2 H, 7.3, CH₂), 2.55–2.57

micro reaction at a total flow rate of 40 µLmin^–1and employing

heptanal (29) and benzylamine (13) as reactants, the title com-

pound was obtained as a pale yellow oil (0.0278 g, 99.9%).

(dq, J = 7.3 Hz, 1 H and 1.4, CH), 2.59 (t, J = 7.3 Hz, 2 H, CH₂), C₁₅H₂₂N₂(230.35): calcd. C 77.53, H 10.41, N 12.06; found C

2.81–2.86 (dq, J = 7.3 Hz, 1 H and 1.4, CH), 3.41 (dt, J = 7.3 Hz, 77.55, H 10.45, N 12.01]. IR: ν = 680.6, 725.2, 1454.3, 1488.6,

˜

max

2 H and 1.4, CH₂) and 7.10–7.12 (m, 5 H, 5ϫ ArH) ppm. ¹³C 1552.1, 1590.6, 2304.7, 2843.2, 3030.6, 3054.2 and 3324.0 cm^–1. ¹H

NMR (100 MHz, CDCl₃/TMS): δ = 14.2 (CH₃), 22.6 (CH₂), 28.1 NMR (400 MHz, CDCl₃/TMS): δ = 0.79 (t, J = 7.0 Hz, 3 H, CH₃),

(CH₂), 31.7 (CH₂), 33.7 (CH₂), 33.8 (CH₂), 47.6 (CH₂), 51.1 (CH), 1.23 (m, 8 H, 4ϫ CH₂), 1.51 (br. s, 1 H, NH), 1.69 (q, J = 7.0 Hz,

120.9 (CN), 126.3 (CH), 128.8 (4ϫ CH) and 142.1 (C₀) ppm. MS 2 H, CH₂), 3.41 (d, J = 12.9 Hz, 1 H, CHH), 3.62 (m, 1 H, CH),

(EI): m/z = 231 (6), 230 (10), 215 (20), 201 (15), 187 (65), 173 (100), 3.99 (d, J = 12.9 Hz, 1 H, CHH) and 7.26–7.28 (m, 5 H, 5ϫ ArH)

135 (25), 105 (75), 91 (45) and 77 (20).

ppm. ¹³C NMR (100 MHz, CDCl₃/TMS): δ = 14.0 (CH₃), 22.4

(CH₂), 25.5 (CH₂), 28.6 (CH₂), 31.5 (CH₂), 33.5 (CH₂), 49.7 (CH),

51.6 (CH₂), 120.3 (CN), 127.5 (CH), 128.3 (2ϫ CH), 128.5 (2ϫ

CH) and 138.4 (C₀) ppm. MS (EI): m/z = 231 (3), 230 (17), 201

(15), 187 (20), 173 (75), 145 (10), 106 (25), 91 (100) and 76 (15).

2-(Pyrrolidin-1-yl)hexanenitrile: (Table 4, Entry 15) Conducting the

micro reaction at a total flow rate of 40 µLmin^–1and employing

valeraldehyde (27) and pyrrolidine (15) as reactants, afforded a col-

orless oil 40 µLmin^–1afforded 2-(benzylamino)hexanenitrile as a

colorless oil (0.0199 g, 100.0%). C₁₀H₁₈N₂(166.27): calcd. C 72.24,

2-(Phenylethylamino)octanenitrile: (Table 4, Entry 23) Employing

heptanal (29) and 2-phenylethylamine (7) as reactants, the micro

reaction was conducted at a total flow rate of 40 µLmin^–1, to afford

the title compound as a pale yellow oil (0.0293 g, 99.9%).

C₁₆H₂₄N₂(244.38): calcd. C 78.64, H 9.90, N 11.46; found C 78.65,

H 10.91, N 16.85; found C 72.14, H 10.87, N 16.81]. IR: ν

=

˜

max

1375.6, 2245.3, 2795.6, 2880.6, 2885.3 and 2960.7 cm^–1. H NMR

(400 MHz, CDCl₃/TMS): δ = 0.82 (t, J = 7.3 Hz, 3 H, CH₃), 1.19–

1.40 (m, 4 H, 2ϫ CH₂), 1.61–1.66 (m, 2 H, CH₂), 1.68–1.72 (m, 4

H, 2ϫ CH₂), 2.51–2.59 (m, 4 H, 2ϫ CH₂N) and 3.61 (t, J = 7.3 Hz,

1 H, CH) ppm. ¹³C NMR (100 MHz, CDCl₃/TMS): δ = 14.2

(CH₃), 22.5 (CH₂), 23.8 (2ϫ CH₂), 28.1 (CH₂), 32.8 (CH₂), 50.4

1

H 9.72, N 11.35]. IR: ν

= 620.5, 760.1, 1375.2, 1435.1, 1561.2,

˜

max

2246.7, 2801.6, 2880.2, 2906.1, 3101.6 and 3401.2 cm^–1. H NMR

1

(400 MHz, CDCl₃/TMS): δ = 0.83 (t, J = 7.2 Hz, 3 H, CH₃), 1.22

(2ϫ CH₂), 55.8 (CH) and 118.1 (CN) ppm. MS (EI): m/z = 167 (m, 8 H, 4ϫ CH₂), 1.66 (m, 2 H, CH₂), 2.69–2.86 (m, 4 H, 2ϫ

(5), 166 (10), 151 (5), 123 (20), 109 (25), 96 (25) and 70 (100).

CH₂), 3.09 (dt, J = 7.2 Hz, 1 H and 1.2, CH), 7.16–7.70 (m, 3 H,

3ϫ ArH), 7.70–7.23 (m, 2 H, 2ϫ CH) ppm and NH not observed.

¹³C NMR (100 MHz, CDCl₃/TMS): δ = 14.0 (CH₃), 22.4 (CH₂),

25.5 (CH₂), 28.6 (CH₂), 31.4 (CH₂), 33.4 (CH₂), 35.9 (CH₂), 48.6

(CH), 50.7 (CH₂N), 120.2 (CN), 126.4 (CH), 128.5 (2ϫ CH), 128.6

(2ϫ CH) and 139.0 (C₀) ppm. MS (EI): m/z = 245 (8), 244 (4), 218

(9), 153 (51), 139 (2), 126 (13), 105 (22), 91 (19), 77 (9), 69 (100)

and 56 (28).

2-(Phenethylamino)heptanenitrile: (Table 4, Entry 18) Employing

hexanal (28) and 2-phenylethylamine (7) as reactants, the micro

reaction was performed at a total flow rate of 40 µLmin^–1, to afford

the title compound as a pale yellow oil (0.0276 g, 99.9%).

C₁₅H₂₂N₂(230.35): calcd. C 78.21, H 9.63, N 12.16; found C 78.23,

H 9.65, N 12.14]. IR: ν

= 695.2, 765.3, 1376.6, 1495.6, 2245.3,

˜

max

2869.3, 2889.6, 2920.3 and 3467.1 cm^–1. ¹H NMR (400 MHz,

CDCl₃/TMS): δ = 0.80 (t, J = 7.0 Hz, 3 H, CH₃), 1.19–1.24 (m, 5 2-(3-Phenylpropylamino)octanenitrile: (Table 4, Entry 24) Em-

H, 2ϫ CH₂and CH), 1.32–1.43 (m, 1 H, CH), 1.55 (br. s, 1 H, ploying heptanal (29) and phenylpropylamine (14) as reactants, the

Eur. J. Org. Chem. 2008, 5597–5613

www.eurjoc.org

5611

C. Wiles, P. Watts

FULL PAPER

micro reactor was operated at a total flow rate of 40 µLmin^–1, af-

fording the title compound as a pale yellow oil (0.0310 g, 99.9%).

C₁₇H₂₆N₂(258.41): calcd. C 79.02, H 10.14, N 10.84; found C

[1]

A. Strecker, Liebigs Ann. Chim. 1850, 75, 27–45.

[2] Y. M. Shafran, V. A. Bakulev, V. S. Mokrushin, Russ. Chem.

Rev. 1989, 58, 148–162.

78.78, H 10.38, N 10.59]. IR: ν

= 720.1, 750.3, 1365.2, 1440.6,

˜

max

2251.6, 2890.3, 2922.6, 2980.5 and 3100.2 cm^–1. ¹H NMR

(400 MHz, CDCl₃/TMS): δ = 0.83 (t, J = 7.0 Hz, 3 H, CH₃), 1.20–

1.36 (m, 6 H, 3ϫ CH₂), 1.40–1.45 (m, 1 H, CH), 1.67 (q, J =

7.0 Hz, 2 H, CH₂), 1.72–1.83 (m, 2 H, CH₂), 2.55 (m, 1 H, CH),

2.63 (m, 2 H, CH₂), 2.55 (m, 2 H, CH₂), 3.42 (m, 1 H, CH), 7.27

(m, 2 H, 2ϫ ArH), 7.13 (m, 3 H, 3ϫ ArH) ppm and NH not

observed. ¹³C NMR (100 MHz, CDCl₃/TMS): δ = 14.4 (CH₃), 22.9

(CH₂) 26.0 (CH₂), 29.1 (CH₂), 31.7 (CH₂), 31.9 (CH₂), 33.8 (CH₂),

34.0 (CH₂), 47.7 (CH₂), 51.1 (CH), 120.9 (CN), 126.3 (CH), 128.8

(4ϫ CH) and 142.1 (C₀) ppm. MS (EI): m/z = 259 (6), 258 (20),

243 (5), 229 (6), 215 (10), 201 (5), 187 (16), 173 (100), 159 (16), 147

(5), 105 (45), 91 (65) and 77 (21).

[3] L. M. Weinstock, P. Davis, B. Handelsman, R. J. Tull, J. Org.

Chem. 1967, 32, 2823–2829.

[4] D. Enders, J. P. Shilvock, Chem. Soc. Rev. 2000, 29, 359–373.

[5] M. Suginome, A. Yamamoto, Y. Ito, Chem. Commun. 2002,

1392–1393.

[6] K. Kobayashi, H. Ishitani, Chem. Rev. 1999, 99, 1069–1094.

[7] S. K. De, R. A. Gibbs, Synth. Commun. 2005, 35, 961–966.

[8]

B. Das, R. Ramu, B. Ravikanth, K. R. Reddy, Synthesis 2006,

1419–1422.

[9] S. Kobayashi, H. Ishitani, M. Ueno, Synlett 1997, 115–116.

[10] A. Heydari, A. Arefi, S. Khaksar, R. K. Shiroodi, J. Mol. Ca-

tal. A 2007, 271, 142–144.

[11] J. S. Yadav, B. V. S. Reddy, B. Eshwaraiah, M. Srinivas, P. Vish-

numurthy, New J. Chem. 2003, 27, 462–465.

2-(Pyrrolidin-1-yl)octanenitrile: (Table 4, Entry 25) Conducting the

micro reaction at a total flow rate of 40 µLmin^–1and employing

heptanal (29) and pyrrolidine (15) as precursors, afforded 2-(pyrrol-

idin-1-yl)octanenitrile as a pale yellow oil (0.0233 g, 100.0%).

C₁₂H₂₂N₂(194.32): calcd. C 74.17, H 11.41, N 14.42; found C

[12] M. M. Mojtahedi, M. S. Abaee, H. Abbasi, J. Iranian. Chem.

Soc. 2006, 3, 93–97.

[13] R. Martinez, D. J. Ramon, M. Yus, Tetrahedron Lett. 2005, 46,

8471–8474; it must be noted, however, that in our hands, no

reaction to afford the α-aminonitrile was observed in the ab-

sence of a catalyst, only formation of the respective imine.

[14] K. Matsumoto, J. C. Lim, H. Iida, H. Hamana, K. Kumamoto,

H. Kotsuki, G. Jenner, Helv. Chim. Acta 2005, 88, 1734–1753.

[15] J. H. Atherton, J. Blacker, M. R. Crampton, C. Grosjean, Org.

Biomol. Chem. 2004, 2, 2567–2571.

[16] a) J. I. Yoshida, A. Nagaki, T. Yamada, Chem. Eur. J. 2008,

advanced article; b) T. Fukuyama, M. T. Rahman, M. Sato, I.

Ryu, Synlett 2008, 2, 151–163; c) C. Wiles, P. Watts, Eur. J.

Org. Chem. 2008, 10, 1655–1671; d) C. Wiles, P. Watts, Chem.

Commun. 2007, 443–467; e) B. P. Mason, K. E. Price, J. L. Ste-

inbacher, A. R. Bogdan, D. T. McQuade, Chem. Rev. 2007, 107,

2300–2318.

74.21, H 11.40, N 14.20]. IR: ν_max= 1385.6, 2259.1, 2803.2, 2889.6

˜

and 2915.4 cm^–1. ¹H NMR (400 MHz, CDCl₃/TMS): δ = 0.75 (t,

3 H, CH₃), 1.15–1.23 (m, 6 H, 3ϫ CH₂), 1.25–1.46 (m, 2 H, CH₂),

1.52–1.75 (m, 6 H, 3ϫ CH₂), 2.45–2.50 (m, 2 H, CH₂N), 2.55–2.60

(m, 2 H, CH₂) and 3.56 (dt, J = 7.8 Hz, 1 H and 1.4, CH) ppm.

¹³C NMR (100 MHz, CDCl₃/TMS): δ = 13.9 (CH₃), 22.4 (CH₂),

23.2 (2ϫ CH₂), 25.9 (CH₂), 28.5 (CH₂), 31.4 (CH₂), 32.6 (CH₂),

49.9 (2ϫ CH₂N), 55.3 (CH) and 117.6 (CN) ppm. MS (EI): m/z =

195 (2), 194 (6), 193 (10), 168 (10), 152 (2), 109 (100), 96 (20), 84

(30), 67 (10) and 55 (25).

2-(4-Acetylphenyl)-2-(phenethylamino)acetonitrile (5): Employing 4-

acetylbenzaldehyde (4) and 2-phenylethylamine (7) as precursors,

the micro reaction was performed at a total flow rate of 20 µLmin^–1

to afford 5 as a pale yellow oil (0.0333 g, 99.8%). C₁₈H₁₈N₂O

(278.35): calcd. C 77.67, H 6.52, N 10.06; found C 77.62, H 6.53,

[17] W. Ehrfeld, V. Hessel, H. Lowe, in Microreactors: New Technol-

ogy for Modern Chemistry, Wiley-VCH, 2000 and references

cited therein.

[18] K. Mikami, M. Yamanaka, M. N. Islam, K. Kudo, N. Seino,

M. Shinoda, Tetrahedron Lett. 2003, 44, 7545–7548.

[19] B. M. Fetterly, N. K. Jana, J. G. Verkade, Tetrahedron 2006, 62,

440–456.

N 10.10]. IR: ν

= 610.5, 721.2, 842.6, 1001.3, 1246.1, 1561.3,

˜

max

1600.2, 1690.3, 2245.3, 2880.5, 2890.6, 2961.2, 3031.2 and

[20] C. Wiles, P. Watts, S. J. Haswell, Tetrahedron 2005, 61, 5209–

1

3461.2 cm^–1. H NMR (400 MHz, CDCl₃/TMS): δ = 2.63 (s, 3 H,

5217.

CH₃), 2.84–2.93 (m, 2 H, CH₂), 3.04–3.12 (m, 2 H, CH₂N), 4.89

(s, 1 H, CH), 7.22–7.35 (m, 5 H, 5ϫ ArH), 7.63 (d, J = 8.7 Hz, 2

H, 2ϫ ArH), 8.00 (d, J = 8.7 Hz, 2 H, 2ϫ ArH) ppm and NH not

observed. ¹³C NMR (100 MHz, CDCl₃/TMS): δ = 26.7 (CH₃), 35.8

(CH₂), 48.0 (CH₂), 54.0 (CH), 118.1 (CN), 126.5 (CH), 127.5 (2ϫ

CH), 128.6 (2ϫ CH), 128.7 (2ϫ CH), 128.9 (2ϫ CH), 137.5 (C₀),

138.8 (C₀), 139.4 (C₀) and 197.3 (CO) ppm. MS (EI): m/z = 279

(5), 278 (20), 264 (5), 252 (10), 235 (25), 159 (45), 145 (20), 131

(15), 120 (10), 105 (100), 91 (45) and 76 (5).

[21] C. Wiles, P. Watts, S. J. Haswell, Tetrahedron Lett. 2006, 47,

5261–5264.

[22] a) C. Wiles, P. Watts, S. J. Haswell, Tetrahedron 2004, 60, 8421–

8427; b) C. Wiles, P. Watts, S. J. Haswell, Chem. Commun. 2007,

966–968.

[23] E. Comer, M. G. Organ, J. Am. Chem. Soc. 2005, 127, 8160–

8167.

[24] I. R. Baxendale, J. Deeley, C. M. Griffiths-Jones, S. V. Ley, S.

Saaby, G. K. Tranmer, Chem. Commun. 2006, 2566–2568.

[25] I. R. Baxendale, C. M. Griffiths-Jones, S. V. Ley, G. K.

Tranmer, Synlett 2005, 427–430.

Supporting Information (see also the footnote on the first page of

this article): Additional experimental details such as the spectro-

scopic data obtained for known compounds (NMR and MS).

[26] C. Wiles, P. Watts, Org. Proc. Res. Dev. 2008, in press, op-2008–

00025p.

[27] The hydrolytic instability of TMSCN 2 makes it an ideal candi-

date for use within a sealed reaction unit such as a micro reac-

tor.

Acknowledgments

[28] Personal communication with Dr Michael Singer, Sigma–Ald-

rich (Natick, MA).

The authors would like to acknowledge the Engineering and Physi-

cal Sciences Research Council (EPSRC) and The University of Hull

for funding (to C. W.) in the form of a RAIS award. In addition,

the authors would like to acknowledge Dr Steve Clark for assist-

ance with device fabrication and Mr Bob Knight for performing

ICP-MS analysis of reaction products. The authors would also like

to thank Dr Michael Singer (Sigma–Aldrich, USA) for useful dis-

cussions with regard to the polymer-supported ruthenium catalyst.

[29]

A starting concentration of 0.4  was selected as this afforded

an imine concentration of 0.2  which was found to be soluble

within MeCN, any attempts to increase this concentration were

met with precipitation, and with time blockages, within the

central reaction channel. Consequently, for completeness, all

investigations were conducted at a total concentration of 0.1 ,

however, for specific aldimines, it may be possible to increase

this concentration further.

5612

www.eurjoc.org

Eur. J. Org. Chem. 2008, 5597–5613

Catalyzed Strecker Reaction Conducted Under Continuous Flow

[30] No residual amine or aldehyde was detected, and as such the

percent conversion was calculated based on residual imine,

with the cyanation being the rate-limiting step.

[31] This also shows that if necessary, the catalyst can be removed

and the reactor re-packed with an alternative supported mate-

rial, enabling the same reactor to be used for all investigations.

[32] S. Kobayashi, R. Akiyama, Chem. Commun. 2003, 449–460

and references cited therein.

[33] Unless otherwise stated, where the total flow rate equals 20 to

30 µLmin^–1, a run time of 1 h was employed and in cases where

an optimal flow rate of 40 µLmin^–1was employed, reaction

products were collected over 0.5 h.

Received: July 29, 2008

Published Online: October 15, 2008

Eur. J. Org. Chem. 2008, 5597–5613

www.eurjoc.org

5613

Article Doi

Evaluation of the heterogeneously catalyzed strecker reaction conducted under continuous flow

DOI: 10.1002/ejoc.200800751

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Article abstract of DOI:10.1002/ejoc.200800751

Full text of DOI:10.1002/ejoc.200800751

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