Lewis acid activation of pyridines for nucleophilic aromatic substitution and conjugate addition

Article abstract of DOI:10.1002/cssc.201403154

A clean, mild and sustainable method for the functionalization of pyridines and their analogues is reported. A zinc-based Lewis acid is used to activate pyridine and its analogues towards nucleophilic aromatic substitution, conjugate addition, and cyclization reactions by binding to the nitrogen on the pyridine ring and activating the pyridine ring core towards further functionalization.

Full text of DOI:10.1002/cssc.201403154

DOI: 10.1002/cssc.201403154
Full Papers
Lewis Acid Activation of Pyridines for Nucleophilic
Aromatic Substitution and Conjugate Addition
Sarah Abou-Shehada,[a] Matthew C. Teasdale,[b] Steven D. Bull,[b] Charles E. Wade,[c] and
Jonathan M. J. Williams*[b]
A clean, mild and sustainable method for the functionalization
of pyridines and their analogues is reported. A zinc-based
Lewis acid is used to activate pyridine and its analogues to-
wards nucleophilic aromatic substitution, conjugate addition,
and cyclization reactions by binding to the nitrogen on the
pyridine ring and activating the pyridine ring core towards fur-
ther functionalization.
Introduction
Pyridines are an important class of heterocycles that are found
in a wide variety of important molecules ranging from pharma-
ceuticals and agrochemicals to functional materials.[1] Tradition-
al methods for their functionalization include nucleophilic aro-
matic substitutions (SNAr) on substrates that are appropriately
activated. However, the substrate scope is limited and the re-
actions tend to require forcing conditions. The Buchwald–Hart-
wig amination reaction using palladium-catalyzed N-arylation
reactions has facilitated a wide range of aryl functionalization
which can be readily applied to the elaboration of halopyri-
dines and their derivatives.[2] However, the application of these
reactions can have limitations due to the high cost of the cata-
lysts and their associated air and moisture-sensitive ligands.[3]
As a result, Ullmann-type reactions modified for use with
copper catalysts have become the favored alternative on an in-
dustrial scale, in the case of the most successful adaptations, li-
gands are still required.[4] In some cases, the methodology may
require stoichiometric amounts of the copper catalyst and
base as well as high reaction temperatures. A recent notewor-
thy development in Ullmann-type reactions is the work by
Zhang et al., which involves the use of tetraethylenepentamine
in conjunction with the copper catalyst in water; the coupling
is reported to proceed cleanly with good yields for a broad
scope of functional groups.[5]
Avoiding the use of precious-metal catalysts in the function-
alization of pyridines and its analogues has been reported in
the recent work by Hartwig et al. using a nickel-based complex
to achieve a methodology of varied scope in incoming nucleo-
phile, and has been used on a wide variety of aryl and pyridine
analogues. However this methodology still suffers from the
need for an air- and moisture-free environment and use of
a stoichiometric amount of base.[6] Methodologies that use
cheap transition metals include a zinc-catalyzed, base-assisted
amination of chloropyrimidines,[7] or copper-catalyzed amina-
tion of heteroaryl halides which, depending on the nature of
amine, may require microwave assistance.[8] The development
of efficient methodology using cheaper and more abundant
metals as catalysts, is a valuable approach from an environ-
mental standpoint.
In a recent publication by Moody et al., they argue that pyri-
dine analogues which are activated enough to undergo stan-
dard SNAr reactions such as pyrimidinyl halides are still being
subjected to the more costly transformations, although green-
er alternatives that harness the substrate’s innate reactivity
could be developed and used.[9] In this work we wanted to
consider approaches to arene coupling reactions that did not
involve direct metal-catalyzed activation of the aryl halide
bond, and specifically to apply this to the functionalization of
pyridines via remote catalytic activation of the halide.
[a] S. Abou-Shehada
Centre for Doctoral training at the Centre for Sustainable Chemical Tech-
nologies
Department of Chemistry
University of Bath
Bath, BA2 7AY (UK)
With this in mind we considered pyridine N-oxides, which
are orders of magnitude more reactive towards nucleophilic
substitution than pyridines,[10] we anticipated that the use of
a Lewis acid in a similar manner to that of the oxygen in pyri-
dine N-oxides would activate the pyridine ring towards SNAr
catalytically. Equally, Brønsted acids such as HCl are also used
as the standard stoichiometric method for SNAr reactions of
halopyridines; by virtue of the pyridinium salt, which activates
the pyridine ring, however these systems tend to require forc-
ing conditions (1508C) and give mitigated yields due to degra-
[b] M. C. Teasdale, Dr. S. D. Bull, Prof. J. M. J. Williams
Department of Chemistry
University of Bath
Bath, BA2 7AY (UK)
E-mail: j.m.j.williams@bath.ac.uk
[c] Dr. C. E. Wade
GSK, Medicines Research Centre
Gunnels Wood Road,
Stevenage, SG1 2NY (UK)
Supporting Information for this article is available on the WWW under
http://dx.doi.org/10.1002/cssc.201403154.
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dation of the chloropyridine as a result of the acidity of the re-
action conditions.[11]
Table 2. Range of amines used in nucleophilic aromatic substitution in 4-
chloropyridine.
In this work, we report the activation of chloropyridine and
analogues towards nucleophilic aromatic substitutions and vi-
nylpyridines towards conjugate additions and cyclization reac-
tions using a cheap metal based Lewis acid catalyst.
Entry
1
Nucleophile (NucH)
Solvent
MeCN
Conv.[a]
[%]
Yield
[%]
Results and Discussion
100
99
In an initial investigation, we examined the Lewis-acid-cata-
lyzed amination of 4-chloropyridine with N-methylaniline to
give the aminopyridine product 1.
2
3
THF
THF
80
65
91
100
The highest conversions into the amination product were
observed using zirconium acetoacetonate and zinc nitrate as
the Lewis acids (entries 2 and 9 respectively, Table 1). Whilst
4
THF
100
95
5
6
THF
THF
93
89
87
75
Table 1. Lewis acid screen.
7
MeCN
MeCN
MeCN
MeCN
100
80
89
71
56
69
8
9
69
Entry
Lewis acid
Conversion into 1 [%][b]
10
80
1
2
3
4
5
6
7
8
Sc(OTf)3
66
81
65
42
41
52
36
32
71
50
–
11
MeCN
100
89
Zr(acac)4
Zr(Cp)2Cl2
Hf(Cp)2Cl2
Fe(SO4)·7H2O
[Rh(nbd)Cl]2
RhCl3
Pd(acac)2
Zn(NO3)2·6H2O
ZnI2
12
13
14
MeCN
MeCN
MeCN
100
100
69
95
95
56
9
10
11
15
16
MeCN
MeCN
–
–
–
–
control
[a] Details of full screen can be found in the supporting information.
[b] Conversion determined by analysis of the H NMR spectra.
1
17
MeCN
71
–
18[c]
19[c]
20[c]
MeOH
EtOH
nPrOH
MeOH
EtOH
nPrOH
59
66
60
53
57
56
the zirconium catalyst offers the higher conversion, it is also
significantly more expensive than the zinc catalyst. In a drive
towards developing a greener more sustainable methodology
we chose to focus our efforts on the zinc-based catalyst. The
reaction was optimized to achieve the formation of product 1
in 100% conversion (99% yield) using 2.5 mol% catalyst load-
ing in zinc nitrate, 758C and a reaction time of 24 h.
If the benzylamine is indeed binding strongly to the Lewis
acid, it effectively poisons the catalyst towards further binding
to, and activation of, the chloropyridine. We tested this idea by
running the parent reaction with N-methylaniline in the pres-
ence of 0.5 equivalents of benzylamine, and indeed the reac-
tion yielded complete return of starting materials
[a] Conversion determined by analysis of the 1H NMR spectra. [b] Reac-
tions run for 4 h. [c] Reaction run with 2 equiv of K2CO3 for 8 h.
methodology, and gave the product in reasonable yield (56%).
Interestingly, acyclic secondary amines such as diethylamine
were not successful nucleophiles in this methodology; the ar-
gument for higher nucleophilicity of the primary amines poi-
soning the catalyst cannot be applied here, as cyclic amines
tend to be more nucleophilic than their acyclic counterpart. In
a similar vein, we looked to investigate this occurrence by run-
ning the reaction of chloropyridine with piperidine in the pres-
ence of 1 equivalent of diethylamine; the result of which gave
entirely the product of the piperidine substitution. The reason
for the success of the cyclic amines is presumably due to the
beneficial steric effect of having the alkyl groups pinned back
Reactions with cyclic amines gave good-to-excellent yields,
for pyrrolidine (entry 7, Table 2) as well as indoline (entry 12,
Table 2). Piperidine and its analogues also gave good-to-excel-
lent yields (entries 8, 11 and 13, Table 2). Aromatic heterocycles
such as imidazole (entry 14, Table 2) were tolerated in this
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to facilitate nucleophilic addition on the chloropyridine sub-
strate.
Lewis acid to the pyridine nitrogen to activate the ring.
Indeed, the same reaction with 2,4-dichloropyridine (entry 3,
Table 3) was run, for which conversion into the substitution
product at either site was not observed. This result also sug-
gests that the mechanism of the reaction proceeds by activa-
tion of the aromatic ring through the binding of zinc to the
pyridine nitrogen, rather than a more conventional cross cou-
pling, which would have proceeded at either site. To elucidate
the mechanism further and eliminate the possibility of this
transformation being achieved via a cross coupling mecha-
nism, the reactions were run with 3-chloropyridine (entry 1,
Table 3); an unreactive substrate towards substitution reactions
as is also found for its N-oxide analogue.[10] With the chlorine
further from the nitrogen on the pyridine ring, it should not in-
terfere with the approach of the catalyst; and, indeed, if a cou-
pling mechanism was taking place, conversion into the prod-
uct should be observed. However, the reaction gave complete
return of starting materials which further supports the idea of
activation of the pyridine to facilitate a nucleophilic aromatic
substitution mechanism. An alternative explanation for the
lack of activity of the 2-chloropyridine was the reduced elec-
tron density on the nitrogen as the result of such an electron-
withdrawing substitute adjacent to it, thus the reaction was
carried out using 2-chloro-4-methoxy pyridine (entry 4,
Table 3), which also showed no activity towards nucleophilic
substitution. This further confirms the steric hindrance of the
chlorine in the 2-position; even with an electron-enriched pyri-
dine-nitrogen, no reaction had taken place.
Oxygen-based nucleophiles such as alcohols were also
tested and it was found the reaction proceeded well when the
incoming group was used as solvent, in the presence of
a base. The base was required to neutralize the acid generated
during the course of the reaction, which tended to degrade
the chloropyridine starting material at these temperatures. In-
vestigations into the optimization of the methodology to use
the incoming alcohol group in one equivalent were investigat-
ed; however the results were not competitive with the use of
alcohol as the solvent.
The methodology tolerates a variety of anilines (entries 1–6,
Table 2), cyclic amines (entries 7–13, Table 2), phenyl hydrazine
(entry 17, Table 2), and alcohols (entries 18–20). Interestingly
when primary amines other than anilines were screened for
this transformation, no reaction was observed (benzylamine
entry 15, Table 2); this is believed to be as a result of competi-
tive binding with the primary amine to the zinc catalyst.
The scope in substrates for nucleophilic substitution was
also investigated (Table 3), particularly 2-chloropyridine which
Table 3. Scope in pyridine analogues for nucleophilic aromatic substitu-
tion.
Entry
Substrate
Solvent
NucH
t
[h]
Conv.[a]
[%]
Yield
[%]
1
2
MeCN
MeCN
24
24
–
–
–
–
Interestingly 4-bromopyridine exhibited a much higher reac-
tivity than 4-chloropyridine, yielding the aromatic substitution
product in a much shorter reaction time of only 2 h (entry 5,
Table 3). Similarly, 2-chloropyrimidine proceeds to the substitu-
tion product in 8 h under Lewis-acid-catalyzed reaction condi-
tions, from which some of the amines from the nucleophile
screen were also run with good yields in product (entries 7–9,
Table 3).
3
MeCN
MeCN
MeCN
MeCN
24
24
2
–
–
–
–
4
Smaller groups such as the CÀH unit of an adjacent fused
ring in the case of 4-chloroquinline (entry 6, Table 3) are toler-
ated in this methodology and still allow for the approach of
zinc Lewis acid to the nitrogen of the pyridine unit, allowing
the reaction to proceed in high yield (93%).
5
100
100
89
93
6[b]
4
With the success of the zinc catalyst at activating chloropyri-
dine towards nucleophilic substitution, we anticipated that it
may also be able to activate vinylic pyridines to conjugate ad-
dition and Diels–Alder cyclization reactions. We were pleased
to observe that the reaction proceeds with our parent nucleo-
phile in high yields (entries 1 and 7, Table 4) for both the 2-
vinyl and 4-vinyl pyridines. The reaction was tested for toler-
ance of incoming group; the catalytic system tolerates a variety
of N- and S-based nucloephiles (Table 4); however, due to the
higher reactivity of the vinyl pyridines, the reactions in most
cases require less time and heat, especially in the case of the
thiol which only requires a maximum reaction time of 10 min
and room temperature (entry 3, Table 4). As with the substitu-
tion reactions, primary amines poisoned the catalyst and no
addition products were observed, the dialkyl amines also yield-
ed no product due to their diminished reactivity. It should be
7
8
9
MeCN
MeCN
MeCN
8
8
8
80
70
74
71
63
61
1
[a] Conversion determined by analysis of the H NMR spectra. [b] Reaction
run at 608C.
has the same activity towards nucleophilic substitution in pyri-
dine N-oxides as the 4-chloropyridine.[10] However, when the
reaction was run using this substrate, no product was ob-
served (Table 3, entry 2); we assumed that this is due to steric
bulk of the chlorine preventing the approach of the zinc-based
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explanation for this minor product would be the zinc Lewis
acid coordinating to and bringing the thermodynamically unfa-
vored Cp* face in close proximity to the vinyl pyridine thus
producing this minor product.
Table 4. Conjugate addition of nucleophiles to vinylic pyridines through
activation by zinc Lewis acid catalyst.
Entry Substrate NucH
t
[h]
T
Catalyst Conv Yield
[8C] loading [%][a] [%]
Conclusions
[mol%]
In conclusion, a novel catalytic methodology has been devel-
oped for the functionalization of pyridines. The mechanism op-
erates through activation of the pyridine ring, which can lend
itself to nucleophilic aromatic substitution, conjugate addition,
and Diels–Alder reaction subject to the substrate used. This
methodology offers an alternative simple, cheap, and greener
catalytic method for the functionalization of pyridines and
their analogues.
1
24
90 15
89
87
2
3
24
12
25
60
5
5
94
94
95
100
4
5
10 min 25
2.5
2.5
95
79
92
78
4
40
(90:10 dr[b]
)
Diels–Alder
Experimental Section
6
7
24
24
75
75
5
5
–
–
–
–
The appropriate amine (2 mmol, Table 2) and Zn(NO3)2·6H2O
(2.5 mol%) were added to an oven dried Radleys carousel tube, fol-
lowed by acetonitrile (2 mL) and 4-chloropyridine (2 mmol). The
tube was sealed before the reaction mixture was heated to 758C
for the appropriate time (Table 2). After being allowed to cool to
room temperature, the solvent was removed in vacuo on a rotary
evaporator and then analyzed by their H NMR and 13C NMR spec-
troscopy and mass spectrometry data. Purification by column chro-
matography was carried out as necessary.
8
24
90 10
86
85
9
12
4
25
40
5
5
100
90
99
87
1
10
11
12
10 min 25
2.5
5
99
79
96
78
Acknowledgements
8
40
(89:11 dr[b]
)
S.A.-S. is funded by the EPSRC through the Doctoral Training
Center in Sustainable Chemical Technologies (Grant No. EP/
G03768X/1).
Diels–Alder
13
14
24
24
75
75
5
5
–
–
–
–
[a] Conversions determined by 1H NMR spectroscopy. [b] Diastereomeric
ratio.
Keywords: amination · conjugate addition · lewis acid ·
pyridine · SNAr
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Received: October 21, 2014
Revised: November 27, 2014
Published online on && &&, 0000
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S. Abou-Shehada, M. C. Teasdale,
Pyridine gets active: For the first time,
the catalytic activation of the pyridine
ring towards nucleophilic aromatic sub-
stitution, conjugate addition, and Diels–
Alder reactions is reported. The method
utilizes a cheap, non-toxic zinc-based
Lewis acid, which binds to the nitrogen
of the pyridine ring and activates it to-
wards nucleophilic aromatic substitu-
tion. The reaction tolerates a variety of
incoming groups and proceeds cleanly
and under mild reaction conditions.
S. D. Bull, C. E. Wade, J. M. J. Williams*
&& – &&
Lewis Acid Activation of Pyridines for
Nucleophilic Aromatic Substitution
and Conjugate Addition
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