Microwave-promoted piperidination of halopyridines: A comparison between Ullmann, Buchwald-Hartwig and uncatalysed SNAr reactions

Article abstract of DOI:10.1002/aoc.2853

A comparative study between the most used methodologies for the preparation of piperidinyl pyridines (Buchwald-Hartwig reaction, Ullmann reaction and nucleophilic aromatic substitution (S_NAr)) by microwave-assisted piperidination of halopyridines is reported. Our results suggest that the Ullmann reaction is most effective for less reactive halopyridines, while uncatalysed S_NAr is sufficient for more reactive ones. Copyright

Full text of DOI:10.1002/aoc.2853

Full Paper
Received: 17 October 2011
Revised: 30 January 2012
Accepted: 2 March 2012
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI 10.1002/aoc.2853
Microwave-promoted piperidination of
halopyridines: a comparison between Ullmann,
Buchwald–Hartwig and uncatalysed
SNAr reactions
Ricardo S. Yaunner, José C. Barros and Joaquim F. M. da Silva*
A comparative study between the most used methodologies for the preparation of piperidinyl pyridines (Buchwald–Hartwig
reaction, Ullmann reaction and nucleophilic aromatic substitution (SNAr)) by microwave-assisted piperidination of halopyridines
is reported. Our results suggest that the Ullmann reaction is most effective for less reactive halopyridines, while uncatalysed SNAr
is sufficient for more reactive ones. Copyright © 2012 John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this article.
Keywords: C-N coupling; Buchwald–Hartwig; Ullmann; nucleophilic aromatic susbtitution; microwave irradiation
piperidine should act both as nucleophile and as base,[19] an
excess of this reagent was employed. Having all conditions well
Introduction
Heteroaromatic amines are present in several biologically active
compounds in addition to being versatile building blocks.[1,2]
We are particularly interested in the synthesis of aminopyridines
analogous to prazosin for a study on the mechanism of action of
Transport-P ligands.[3–5] Aminopyridines are usually prepared
from halopyridines and amines by nucleophilic aromatic substitu-
tion (SNAr)[6] or by transition metal-mediated protocols like the
Ullmann[7] or Buchwald–Hartwig[8] reaction, but some drawbacks
such as high temperature, phosphine ligands, toxic solvents and
long reaction times limit the application of these methodologies.[9–14]
Our group has been working on the development of microwave
(MW)-promoted synthetic methods, such as the preparation of
biologically relevant nitriles and oximes from aldehydes.[15] Here,
we wish to disclose our results concerning the application of MW
irradiation for the piperidination of halopyridines by the three
methods cited above; as far as we know, no comparative study
between the three methodologies under microwave irradiation has
been reported.
established, a series of coupling reactions between different
halopyridines and piperidine was performed and the results
obtained are shown in Table 1.
When 2-bromopyridine was used as substrate (entries 1–7), no
differences in terms of reactivity in the three methodologies were
detected. However, in the presence of palladium catalysts, 2,2′-
bipyridine is formed and the amount of this homocoupling
product is higher when a Pd+2 species was used, probably due
to its higher electronegativity, which favours complexation with
2-bromopyridine.
The absence of triphenylphosphine had no effect on the
conversion and selectivity of the Buchwald–Hartwig reaction.
Entry 4 shows that lowering the temperature of the Buchwald–
Hartwig reaction decreases the conversion but increases selectivity
towards the heterocoupling product.
In general, we were not able to say whether the Ullmann or the
uncatalysed SNAr reaction occurred, but the use of copper iodide
did not alter the course of the reaction, while palladium catalysts
decreased the reaction selectivity.
Next, we evaluated the behaviour of 3-bromopyridine (entries
8–13) towards these different methodologies, since this com-
pound is less susceptible to a nucleophilic attack.[20] While SNAr
(entries 11 and 13) and the Buchwald–Hartwig reaction employ-
ing Pd/C (entry 9) resulted in the recovery of the initial reagents,
Results and Discussion
We started our study by selecting initial experimental conditions.
In previous reports, ethylene glycol was already being used for
promoting C-N coupling either as solvent[16] or as a ligand in
presence of an alcoholic solvent (i-PrOH).[17] Among these two
potential solvents, we chose ethylene glycol due to its higher
absorbing MW property when compared to i-PrOH, as indicated
by loss tangent (tan d 2.350 vs. 0.799 respectively).[18] We first
attempted to optimize the reaction time and temperature for
the three methods and the initial results indicated that in
30 min at 150ꢀC and with an initial power of 100 W the reaction
between 2-bromopyridine and piperidine occurred almost
completely with CuI, or Pd/C or in the absence of catalysts. Since
*
Correspondence to: Joaquim F. M. da Silva, Laboratório de Química Medicinal
do Polo de Xistoquímica (PXQMed), Instituto de Química, Universidade Federal
do Rio de Janeiro, Rua Hélio de Almeida, Lab A-107, Cidade Universitária, Rio
de Janeiro, RJ 21941-614, Brazil. E-mail: joaquim@iq.ufrj.br
Laboratório de Química Medicinal do Polo de Xistoquímica (PXQMed), Instituto
de Química, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio
de Janeiro, RJ 21941-614, Brazil
Appl. Organometal. Chem. (2012)
Copyright © 2012 John Wiley & Sons, Ltd.

R. S. Yaunner et al.
Table 1. Reaction between halopyridines and piperidines
Entry
Conditions
Conversiona (%)
Selectivitya A:B
2-Bromopyridine
1
CuI (5 mol%)
100 (70)e
100
100:0
62:38
62:38
71:29
40:60
62:38
100:0
2
Pd/C (5 mol%), PPh3 (10 mol%)
Pd/C (5 mol %)
3
4b
100
Pd/C (5 mol %), PPh3 (10 mol%)
Pd(OAc)2 (5 mol%), PPh3 (10 mol%)
Pd(PPh3)4 (5 mol%), PPH3(10 mol%)
—
81
5
100
6
100
7
100
3-Bromopyridine
8
CuI (5 mol%)
3
100:0
0
9
Pd/C (5 mol%) PPh3 (10 mol%)
0
10
11
12c
13c
Pd(OAc)2 PPh3 (10 mol%)
100
0:100
0
—
0
CuI (5 mol%)
58 (12)e
100:0
0
—
0
2-Chloropyridine
4-Bromopyridine
14c
15c
16c
17c
CuI (5 mol%)
98
100:0
100:0
23:77
100:0
Pd/C (5 mol%) PPh3 (10 mol%)
Pd(OAc)2 (5 mol%) PPh3 (10 mol%)
—
86
100
91
18
19
20
21
CuI (5 mol%)
100 (69)e
100
100:0
100:0
100:0
100:0
Pd/C (5 mol%) PPh3 (10 mol%)
Pd(OAc)2 (5 mol%) PPh3 (10 mol%)
—
100
100
aConversions and selectivities were determined by GC/MS; conversions were based on halide consumption.
bReaction temperature 100ꢀC.
cReaction time 120 min.
dt-BuOK (12 mmol) was added as base.
eisolated yield.
the use of Pd(OAc)2 led to a quantitative conversion to the homo-
coupling product (entry 10), and the Ullmann reaction furnished
exclusively the heterocoupling product at very low conversion
rates (entry 8). Increasing the Ullmann reaction time up to 2 h
led to 12% conversion (data not shown).
At this point we decided to use a stronger base such as t-BuOK
in an attempt to improve the yields. Since Pd-promoted reactions
showed drawbacks with product selectivity, we changed the
base only in the Ullmann and uncatalysed SNAr reactions. To
our delight the formation of the desired product in the copper-
catalysed reaction increased substantially, while under SNAr
conditions no conversion could still be observed.
These results not only show that the Ullmann reaction should
be applied to a less reactive system, but also that, at least in this
case, Ullmann and SNAr reactions are not taking place
simultaneously.
Inspired by the results obtained with 3-bromopyridine, we
decided to test these methodologies using 2-chloropyridine
(entries 14–17) – another less reactive system. After 30 min the
Ullmann reaction showed the highest conversion among the
three methods evaluated, but no methodology was able to
promote the complete conversion of the starting material (data
not shown). Increasing the reaction time to 2 h (entries 14–17)
led to a higher conversion to the heterocoupling product
through SNAr and Buchwald–Hartwig protocols and to an almost
complete conversion under Ullmann conditions, with the possi-
bility of a synergic contribution of SNAr and Ullmann reaction that
could explain its higher conversion. Another striking observation
comes in terms of the selectivity of the palladium catalysis. Unlike
the reactions with 2-bromopyridine, where there was formation
of the homocoupling product, 2-chloropyridine furnished only
the heterocoupling product, which may be due to the lower
nucleophilicity and the higher dissociation energy of 2-chloropyridine,
making the processes of addition or complexation with palladium less
favoured. In Fig. 1 are outlined the proposed mechanisms for the
Buchwald–Hartwig (A) and Ullmann (B) reactions of 2-halopyridines,
based on previous studies by Zhang and Ding[21] and Schlummer
and Scholz.[22]
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Appl. Organometal. Chem. (2012)

Microwave-promoted piperidination of halopyridines
Figure 1. Proposed mechanisms for the Buchwald–Hartwig (A) and Ullmann (B) reactions of 2-halopyridines
Finally, we evaluated the methodologies with 4-bromopyridine
as a substrate and all of them resulted in a 100% heterocoupling
conversion. The most plausible explanation for these results is
that SNAr on 4-bromopyridine is so favourable that this reaction
occurred promptly.
over Na2SO4, followed by evaporation of solvent under reduced
pressure. The compounds were purified by flash chromatography
(AcOEt/hexanes) in moderate yields (Table 1, entries 1, 12, and
18) besides the high conversion observed. For analytical data
see supporting information.
In comparison with Nolan’s work,[23] in which several examples
of piperidination of the same kind of halopyridines are described,
our conditions when applied to 2-chloro and 2-bromopyridine
improved the yield of the Buchwald heterocoupling product
versus the homocoupling one without adding any catalyst;
nonetheless the 3-bromopyridine presents better results under
Nolan’s conditions: 1 mmol aryl halide, 1 mol% (IPr)Pd(acac)Cl
(acac = acetylacetone; IPr= N,N′-bis(diisopropylphenyl)imidazol-2-
ylidene), 1.1mmol KOtBu, 1 ml dimethoxyethane, 50ꢀC, 0.2h.
Conclusion
Our original idea was to establish a comparison between the
most used methodologies for the preparation of piperidinyl
pyridines in order to choose the most suitable one, not only in
terms of yield and selectivity but also in terms of cost, time
consumption and simplicity. For this particular case our results
allow us to make the following conclusions:
•
The SNAr reaction is sufficient for the coupling of piperidine
with 2- and 4-halopyridines, where the nucleophilic attack is
favourable.
Experimental
General Procedure for Piperidination of Halopyridines
•
The Ullmann reaction is required for less reactive systems,
such as 3-halopyridine, instead of Buchwald–Hartwig or
uncatalysed SNAr reactions. For all other tested substrates
we could not confirm that the Ullmann reaction occurred,
but the presence of copper had a small positive effect in terms
of conversion and did not affect the reaction selectivity.
The Buchwald–Hartwig reaction is the most sensitive method-
ology as yields and selectivities depend on the structure of the
substrate, the source of palladium and temperature. The
Buchwald–Hartwig conditions used in this study should be
avoided for the preparation of piperidinyl pyridines.
A 25 mL round-bottomed flask with a magnetic stirring bar was
charged with halopyridine (1 mL, 10 mmol), piperidine (3 mL,
30 mmol), ethylene glycol (3 mL), and 5 mol% of catalyst (except
for the SNAr reactions). Additionally, for palladium-catalysed
reaction triphenylphosphine (262 mg, 1 mmol) was added. The
reaction mixture was placed in a CEM DiscoverW microwave
reactor, stirred and refluxed under argon atmosphere for 30 min
at 150ꢀC (initial power at 100 W). The reaction mixture was then
cooled to room temperature, followed by the withdrawal of a
0.05 mL aliquot that was diluted with dichloromethane (3 mL),
filtered through a C18 sep-packW SPE cartridge and analysed by
gas chromatography/mass spectrometry. The product isolation
for NMR characterization was achieved by diluting the reaction
mixture with dichloromethane (20 mL) and filtrating over a
Büchner filter to remove the catalyst. The filter was washed with
dichloromethane (3 Â 5 mL) and 3 mL of water. The filtrate was
extracted with brine (3 Â 10 mL) and the organic phase was dried
•
Our efforts are now focused on expanding the scope of these
methodologies, especially with the least favoured substrates.
Acknowledgements
The authors acknowledge the Brazilian governmental financing
agencies CAPES, CNPq and FAPERJ.
Appl. Organometal. Chem. (2012)
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R. S. Yaunner et al.
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