Multistep reactions using microreactor chemistry
Batoul Ahmed-Omer,a,b David A. Barrow,a* and Thomas Wirth b*
a Laboratory for Applied Microsystems, Cardiff School of Engineering, Cardiff University,
Cardiff CF24 3AA, United Kingdom
b School of Chemistry, Cardiff University, Park Place, Cardiff CF10 3AT, United Kingdom
E-mails: barrow@cf.ac.uk, wirth@cf.ac.uk
Dedicated to Professor Siegfried Blechert on the occasion of his 65th birthday Abstract
A microflow system for the investigation of multistep synthes involving Pd-catalyd Heck reactions and Ru-catalyd ring-closing metathesis is described. A successful provision of reagent and catalyst delivery in a concutive fashion allowed control over reaction parameters leading to fast optimisation. The performance of Heck reactions in multistep procedures was not as successful as in the single step coupling, whereas the ring-closing metathesis proved to be successful in the production of the desired compounds for further functionalisation.goldmine
Keywords: Catalysis, Heck reaction, metathesis, microreactors, multistep synthesis
Introduction
Concutive multistep synthesis using microflow techniques offer advantages over conventional methods. In addition to a better control over reaction parameters and fast optimisation, multistep reactions in flow enable an improved and more controlled addition of reagents in a concutive fashion which can be accomplished without delays. It is indeed the continuous nature of the system that allows efficient reaction optimisation: small aliquots of product can be collected as they are produced, and analyd in order to decide how to change reaction conditions and parameters without stopping the process. The efficiency and speed of optimisation could be further improved by introducing automation in addition to fast online analysis into the systems allowing the chemist to obtain faster feedback. There is a growing interest in the literature in carrying out concutive multistep synthes using microflow technique by exploiting the above mentioned advantages.1
Results and Discussion
The typical multistep microflow tup ud in this investigation consisted of two or more parate microflow ctions connected to each other. In a two-step microflow tup, the first reaction step tak
es place in ction 1 where the compounds A and B mix and react to form intermediate C as illustrated in Figure 1. Once the intermediate is formed, the cond reaction step takes place after introducing the required reagent D before entering ction 2 to form product E. Product E is then collected at the output of ction 2. A coiled polytetrafluoroethylene (PTFE) microtubing was ud along with multi-way connectors enabling an easy variation of different ctions, or introduce reagents as required, with good flexibility. A limitation with the multistep tup is that once the required residence time for ction 1 has been t, the total flow rate in ction 2 becomes fixed and the residence time in ction 2 can only be changed by varying the length of the ction.
A + B
E ction 1
reaction
conditions 1
ction 2
reaction
conditions 2
Figure 1. Multistep reactions using flow chemistry.
We already have reported on simple Heck reactions using flow chemistry.2 Also other rearch groups have been investigated Heck reactions in flow using supported palladium catalysts. Kirschning et al.3 ud a monolith containing nanoparticular palladium while Garcia-Verdugo and Luis et al.4investigated an imidazolium-functionalized polystyrene monolith successfully for such cross-coupling reactions. Palladium-containing monoliths were also ud by Ley et al. for Heck reactions carried out in superheated ethanol.5 Seeberger and co-workers ud palladium on charcoal as a catalyst for Heck reactions.6 Jenn and Buchwald demonstrated an acceleration of such reactions when performed at elevated temperatures and pressures facilitated by microreactors7 and ud a similar reaction for automated optimisation.8 A review on the u of transition metal-catalyzed Heck reactions using microwave and microreactor technologies has appeared recently.9 Our interest focud on carrying out a multistep microflow synthesis consisting
of a combination of a ruthenium-catalyd ring closing metathesis (RCM) followed by a Heck coupling reaction. Precursor 1was prepared by allylation of o-iodoaniline and then subjected to a quence of metathesis and Heck reaction. In the first step of the reaction quence, product 2 was prepared by metathesis of N,N-diallyl-2-iodoaniline1 and isolated in 98% yield, with only traces of the side product 1-(2-iodophenyl)-1H-pyrrole3.
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Scheme 1. Metathesis and Heck reaction of diallylaniline 1.
A combination of the metathesis reaction with a Heck reaction as the cond step was carried
out using methyl acrylate. After a ries of optimisation experiments, (E)-methyl 3-(2-(2H-pyrrol-
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1(5H)-yl) phenyl) acrylate 4 was obtained in yields between 38% and 64%. When the Heck reaction was carried out using less activated substrates such as styrene, p-fluorostyrene, p-trifluoromethylstyrene and m-nitrostyrene, no coupling product was obrved.
A similar example of a concutive RCM and Heck reaction was carried out using the metathesis precursor N,N’-diallylaniline 5, prepared in 89% yield from aniline. The RCM of compound 5 was carried out in the prence of Grubbs II catalyst using the reaction tup shown in Figure 1 to afford the intermediate1-phenyl-2,5-dihydro-1H-pyrrole6 in 96% yield. Compound 6 was then reacted with iodobenzene and 1,3-diphenyl-1H-pyrrole 8 was obtained in yields between 53% and 60% (Scheme 2). In addition to the Heck reaction, an aromatisation of the heterocyclic ring system is occuring under the reaction conditions and the pyrrole derivative 8 is the only reaction product obrved in this reaction quence.
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Scheme 2. Metathesis and Heck reaction quence.
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In this reaction quence, the solvent flow was parated into a gmented flow. In such
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multipha flow mass transfer is accelerated by alternating immiscible fluid packets benefiting
from having both (i) a continually refreshing interface between adjacent fluid packets, and (ii) a
rapid vortex flow within a fluid packet.10 One early study of the Heck reaction under biphasic conditions was reported using toluene/ethylene glycol as a biphasic solvent system.11 Keeping the catalyst parated from the reactants and product pha is a typical strategy ud in biphasic catalysis giving the advantage of product/catalyst paration and recycling. Such a strategy has also been adopted by dissolving the palladium catalyst in an ionic liquid. This allowed Heck reactions with an easy continuous recycling of the catalyst.12
Particularly in the metathesis reaction it is very important to avoid the u of nucleophilic solvents such as acetonitrile or dimethylformamide, as they would affect the catalyst’s performance. The need of carrying out the Heck reaction at high temperature ems to make toluene an ideal solvent for the
two-step synthesis. However, there are very few solvents which are immiscible with toluene in order to create gmentation, and are compatible with the catalytic reactions. Water and ethylene glycol are incompatible with the reaction conditions, therefore a perfluorocarbon solvent (perfluorononane) was chon as the inert pha to form gmentation, due to its compatibility with toluene as well as with a wide range of organic solvents in terms of immiscibility.
Scheme 3. Concutive reactions in gmented flow.
A third substrate was investigated in a similar multistep quence. t -Butyl-2-
(diallylamino)phenylcarbamate 9 was prepared in a conventional flask synthesis by N -allylation of benzene-1,2-diamine with allyl bromide producing a mixture of five N -allylated derivatives with the desired N,N -diallyl-1,2-phenylenediamine being the major product. After BOC protection the compound 9 was employed in a metathesis reaction using Grubbs catalyst 13 as the first step of the microflow synthesis. The metathesis reaction was initially conducted with compound 9 using 5
mol% of Grubbs I catalyst in a PTFE microtube at 40 °C, obtaining product 10 in a modest 63% yield, along with the side product t -butyl-2-(1H -pyrrol-1-yl)-phenylcarbamate 11 in 32% yield . In order to improve the yield of product 10, we carried out a brief optimisation study of the metathesis reaction by investigating the effect of the four main factors affecting the reaction, i.e. choice of cataly
st, load of catalyst, heating method and temperature. The most significant results are summarid in Table 1. N N N Grubbs catalyst toluene
40ºC 91011+NH
O t Bu
O NH O t Bu O NH
O t Bu O
Scheme 4. Metathesis reaction of compound 9.
able 1. Optimisation of RCM of t -butyl-2-(diallylamino)phenylcarbamate 9 in PTFE microtubing
Catalyst Heating method
T Amount of catalyst Yield of 10 Yield of 11 [mol%] [%] [%] Grubbs I
Oil bath 1 31 23 Grubbs I
5 Oil bath 63 32 Grubbs I
5 MW (150 W) 73 21 Grubbs II
1 Oil bath 48 19 Grubbs II
5 Oil bath 87 1
6 Grubbs II 5 MW (150 W) 91 4
Reaction conditions: Grubbs catalyst, compound 9, solvent system (toluene /
In general it was obrved that by changing the RCM catalyst type from Grubbs I to Grubbs II the perfluorononane), residence time 10 minutes, reaction temperature 40 °C.
yield of the desired product 10 improved significantly with a decrea of the yields of side product 11. Further studies showed that catalyst loadings larger than 5 mol% and an increa in
