Successful application of microstructured continuous reactor in the palladium catalysed aromatic amination

Article abstract of DOI:10.1016/j.jorganchem.2005.03.071

Micro reactor technology was successfully applied in the palladium catalysed C-N cross-coupling reaction between 4-bromotoluene and piperidine. Excellent conversions and selectivities were obtained without any by-product formation in continuous reactor.

Full text of DOI:10.1016/j.jorganchem.2005.03.071

Journal of Organometallic Chemistry 690 (2005) 3627–3629
www.elsevier.com/locate/jorganchem
Successful application of microstructured continuous reactor
in the palladium catalysed aromatic amination
*
Christelle Mauger, Olivier Buisine, Sylvain Caravieilhes , G e´ rard Mignani
Rhodia Recherches, Centre de Recherches de Lyon, 85 Avenue des Fr e` res Perret BP 62, 69192 Saint-Fons Cedex, France
Received 7 December 2004; received in revised form 15 March 2005; accepted 15 March 2005
Available online 15 June 2005
Abstract
Micro reactor technology was successfully applied in the palladium catalysed C–N cross-coupling reaction between 4-bromotol-
uene and piperidine. Excellent conversions and selectivities were obtained without any by-product formation in continuous reactor.
Ó 2005 Elsevier B.V. All rights reserved.
Keywords: Amination; Palladium; Organic chemistry; Catalysis micro reactor and continuous reactor
Micro reactors have proven to be highly valuable tools
in organic chemistry [1]. Among further advantages of
this technology are a large flexibility of operating condi-
tions with efficient heat transfer, optimized mixing and
high reaction control. Micro reactors are available in sev-
eral designs and models, but only few examples of pilot
plant implementation are reported [2]. Cellular Process
Chemistry GmbH Company has recently developed a
continuous bench top micro reactor, with pumping and
heating systems fully integrated, appropriate to process
optimization and production (gram to kilogram). During
the course of our studies, we focussed on the palladium
catalyzed cross-coupling reaction between 4-bromotolu-
ene and piperidine. We were particularly interested in
applying this micro reactor technology to palladium cat-
alyzed amination developed by Hartwig and Buchwald
tions, as well as the elevated temperature often required,
have prompted research groups to search for new more
active catalysts. Thus catalysts based on bulky electron-
rich diarylphosphanes discovered by Buchwald have
proven to be particularly mild and versatile [4]. Many
compounds in the drug development pipelines have bond
connections, carbon–nitrogen or others, that can be made
with a palladium-catalyzed coupling reaction.
In this paper we wish to report our preliminary
results concerning the usefulness and advantages of a
micro reactor towards a classical batch reactor for our
synthesis application.
Initially we focussed on the direct coupling between
4-bromotoluene and piperidine in a standard batch reac-
tor (Scheme 1). The reaction was carried out in xylene at
110 ° C using 1.4 equiv of base and 0.2% molar of cat-
[
3]. Interest in palladium-catalyzed C–N coupling reac-
alyst (Pd(OAc) + 3 DavePhos [5]) and 1.05 equiv of
2
tion has grown constantly during the last few years [3].
Since 1998, major advances have been described by a
number of research groups. However the lack of a general
palladium-based catalyst for aryl halide substitution reac-
piperidine versus 4-bromotoluene. A common industrial
base, sodium tert-amylate, was chosen because of its
high solubility in non polar organic solvents. The reac-
tion reached completion in less than 20 min and allowed
the selective formation of N-(4-tolyl)-piperidine without
any side-product formation.
*
Corresponding author. Tel: +33 472 896 617; fax: +33 472 896 894.
E-mail address: sylvain.caravieilhes@eu.rhodia.com (S. Cara-
We have then turned out our attention to transferring
the reaction to continuous micro reactors. Reactions
vieilhes).
0
022-328X/$ - see front matter Ó 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2005.03.071

3628
C. Mauger et al. / Journal of Organometallic Chemistry 690 (2005) 3627–3629
1
0.8
0.6
0.4
0.2
0
Scheme 1. Amination reaction of p-bromotoluene with piperidine
using Pd/L catalyst.
0
10
20
30
40
eluted volume (ml)
were performed in a CPC-GmbH micro reactor made up
e
a 2 mL mixing area (CYTOS ) and a 17 mL reaction
Fig. 2. Inlet (n) and outlet (h) signal; Q = 1 mL/min, V = 17 mL,
inert tracer: dodecane and solvent: xylene.
e
plate (RESIDOS ). In this configuration, the addition
e
of other RESIDOS could improve the productivity
(
Fig. 1). Indeed the choice of volume and flow rate has
e
CYTOS reaction area and mixed together in the heated
e
RESIDOS . Samplings from the outlet solution were
a crucial impact on the residence time thus increasing
from seconds to several hours.
regularly collected, immediately cooled at room temper-
ature and analyzed by gas chromatography. Sodium
bromide being formed during the reaction process, the
outlet solution consisted in a slurry solution. However
no clogging could be noticed during all our studies. This
confirmed the compatibility of these continuous micro
reactors with heterogeneous reactions.
We have first investigated the influence of the temper-
ature. An experiment was realized at room temperature
using 1 mL of each solution. Nevertheless, after 3 days
of residence time, no coupling reaction could occur
The micro reactor hydrodynamic properties were first
determined with a residence time distribution analysis
(
(
RTD). A positive injection step of the inert tracer
dodecane) displayed a typical RTD profile from which
the P e´ clet dimension number (Pe) was calculated.
2
s
u ꢀ L 2 ꢀ V
ax
Pe ¼
ꢁ
.
ð1Þ
2
D
r
This number is defined by the product of linear velocity
u) and length (L) per axial dispersion (D ). It is also an
approximation of the reactor volume (V ) per signal out-
(
ax
s
(
Table 1, entry 6). We have then conducted a set of
2
let variance (r ) and is related to flow (convection) ver-
experiments at 110 °C using two operating conditions
described as follow:
sus dispersion (conduction). We found a high P e´ clet
number (300) which denotes a low axial dispersion dur-
ing elution and then reasonably allows to consider the
micro reactor as a plug flow reactor (Fig. 2).
First of all, reservoir A was filled with reagents solu-
tion (4-bromotoluene, piperidine, base in xylene and
dodecane as an internal standard for gas chromatogra-
phy analysis) and reservoir B with catalytic solution
1. Reagent and catalyst solution 1 mL/min, residence
time 7.5 min and molar concentrations: [4-bromotolu-
ene] = 0.298 mol/L, [piperidine] = 0.30 mol/L, [base] =
0
[
.417 mol/L, [internal standard] = 0.05 mol/L and
Pd] = 0.545 mmol/L (0.18% molar).
. Reagent solution 1 mL/min and catalyst solution
.5 mL/min, residence time 11.3 min and molar con-
2
0
(palladium acetate and ligand in xylene). Both of the
solutions were then simultaneously injected in the
centrations: [4-bromotoluene] = 0.397 mol/L, [piperi-
dine] = 0.404 mol/L, [base] = 0.556 mol/L, [internal
Table 1
Selected results using continuous micro reactor
Entry Eluted volume
(
Residence time Conversion Selectivity
b
test time, min) (min)
(%)
(%)
c
1
2
3
4
5
6
24 (12)
35 (29)
22.5 (44)
27 (1 h)
No
7.5
7.5
100
99
>99
>99
>99
>99
>99
0
c
d
d
a
11.3
11.3
17
100
100
100
0
3 days
a
Batch test experimental condition [4-bromotoluene] and [piperi-
dine] = 0.69 mol/L, [Base] = 0.92 mol/L and [Pd] = 1.4 mmol/L
(
0.2%molar), temperature = 110 °C.
GC analysis.
b
Fig. 1. A and B reagentÕs reservoir: (i) CYTOSÒ and (ii) RESIDOSÒ
modules.
c
Operating conditions 1.
Operating conditions 2.
d

C. Mauger et al. / Journal of Organometallic Chemistry 690 (2005) 3627–3629
3629
standard] = 0.05 mol/L and [Pd] = 0.36 mmol/L (0.09%
molar).
(d) K. Jahnisch, V. Hessel, H. Lowe, M. Baerns, Angew. Chem.
Int. Ed. 43 (2004) 407, and references cited;
(
e) P.D.I. Fletcher, S.J. Haswell, E. Pombo-Villar, B.H. Warring-
ton, P. Watts, S.Y.F. Wong, X. Zhang, Tetrahedron 58 (2002)
735;
Whatever the conditions were, in terms of conversion
and selectivity, the micro reactor performances were clo-
sely identical to those obtained in the batch reactor (Ta-
ble 1, entries 1–4 and 5). Reactions reached completion
with low residence time and no by-product resulting of a
reduction C–Br to C–H and an aryne processes was de-
tected. Due to short residence time, no catalyst decom-
position was observed (no Pd colloids) and slightly
orange-yellow final solution was obtained.
4
(f) C. de Bellefon, N. Tanchoux, S. Caravieilhes, P. Grenouillet, V.
Hessel, Angew. Chem. Int. Ed. 39 (9) (2000) 3442–3445;
(
g) T. Schwalbe, V. Autze, G. Wille, Chimia 56 (2002) 634–646.
2] (a) O. Work, K.P. Jackel, Th. Richter, A. Wolf, Chem. Eng. Sci.
6 (2001) 1029;
b) Th. Richter, W. Ehrfeld, V. Hessel, H. Lowe, M. Storz, A.
[
5
(
Wolf, in: Proceedings of the 3rd International Conference On
Microreaction Technology, 1999, p. 636.;
(
c) S. Kiesewaleter, K. Russov, C. Balsalobre, P. Boulon, E.
Mounier, M. Provence, Mst News 3/02 (2002) 10;
d) S. Taghavi-Moghadam, A. Kleeman, K.G. Golbig, Org.
Process Res. Dev. 5 (2001) 652.
This micro reactor allowed a high productivity in N-
4-tolyl)-piperidine (150 g per day). Moreover the addi-
(
tion of two RESIDOS modules can increase volume
(
Ò
(
47 mL) and thus productivity to 400 g per day.
In conclusion, we have demonstrated that it is possible
[3] (a) M. Beller, Angew. Chem. Int. Ed. 34 (1995) 1316;
(b) J.F. Hartwig, Synlett (1997) 329;
(c) J.P. Wolfe, S. Wagaw, J.F. Marcoux, S.L. Buchwald, Acc.
Chem. Res. 31 (1998) 805;
to carry out palladium-catalyzed cross-coupling amina-
tion reaction in a continuous plug-flow reactor. This
technology presents many advantages: an easy increase
of productivity by additional reactors, easy extrapola-
tion, low reactor volume, low time to get a stationary
mode. Otherwise, numbering up micro reactor advanta-
geously replaces scale up, for example a micro structured
(
(
d) J.F. Hartwig, Angew. Chem. Int. Ed. 37 (1998) 2046;
e) B.H. Yang, S.L. Buchwald, J. Organomet. Chem. 576 (1999)
125;
(f) S. Wagaw, B.H. Yang, S. Buchwald, J. Am. Chem. Soc. 120
(
(
(
(
1998) 6621;
g) S. Wagaw, B.H. Yang, S. Buchwald, J. Am. Chem. Soc. 121
1999) 1251;
h) J.F. Hartwig, Angew. Chem. Int. Ed. 37 (1998) 2090;
Ò
reactor obtained by addition of 10 CYTOS and RESI-
Ò
DOS in parallel was enough for a production of 1.3 ton
3
per year (0.36 t/h/m ). Further applications of this micro
(i) C. Mauger, G. Mignani, Org. Process Res. Dev. 6 (2004) 1065.
[4] (a) For reviews on biarylphosphanes see: A.F. Littke, G.C. Fu,
Angew. Chem. Int. Ed. 41 (2002) 4176;
reactor technology to a wide range of other catalytic
reactions are currently in progress in our laboratories.
(
b) S.L. Buchwald, D.W. Old, J.P. Wolfe, M. Palucki, K.
Kamikawa, US Patent US 6,307,087B1, 2001.;
c) D. Prim, J.-M. Campagne, D. Joseph, B. Andrioletti, Tetrahe-
(
dron 58 (2002) 2041;
(d) A. Ehrentraut, A. Zapf, M.J. Beller, Mol. Catal. A: Chemical
References
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82–183 (2002) 515;
(
(
(
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1] (a) S. Taghavi-Moghadam, A. Kleemann, K. Golbig, Org. Process
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(
(
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0
[
5] DavePhos: 2-dicyclohexylphosphino-2 -(N,N-dimethylamino)bi-
phenyl [213697-53-1].
Trans. IchemE 80 (Part A) (2002) 3–30;