Amination of heteroaryl chlorides: Palladium catalysis or SNAr in green solvents?

Article abstract of DOI:10.1002/cssc.201300239

The reaction of heteroaryl chlorides in the pyrimidine, pyrazine and quinazoline series with amines in water in the presence of KF results in a facile S_NAr reaction and N-arylation. The reaction is less satisfactory with pyridines unless an add

Full text of DOI:10.1002/cssc.201300239

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Substitutions go green: The reaction of
heteroaryl chlorides with amines in
water in the presence of KF results in
a SNAr reaction and N-arylation as
a viable green alternative to palladium-
catalysed amination.
K. Walsh, H. F. Sneddon, C. J. Moody*
&& – &&
Amination of Heteroaryl Chlorides:
Palladium Catalysis or SNAr in Green
Solvents?
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DOI: 10.1002/cssc.201300239
Amination of Heteroaryl Chlorides: Palladium Catalysis or
SNAr in Green Solvents?
Katie Walsh,[a] Helen F. Sneddon,[b] and Christopher J. Moody*[a]
The reaction of heteroaryl chlorides in the pyrimidine, pyrazine
and quinazoline series with amines in water in the presence of
KF results in a facile SNAr reaction and N-arylation. The reaction
is less satisfactory with pyridines unless an additional electron-
withdrawing group is present. The results showed that the
transition-metal-free SNAr reaction not only compares favour-
ably to palladium-catalysed coupling reactions but also oper-
ates under environmentally acceptable (“green”) conditions in
terms of the base and solvent.
Introduction
The formation of aryl CÀN bonds is a fundamental process
within organic chemistry, and the product N-arylamines are
present in various natural products and pharmaceutical mole-
cules.[1] Examples include the well-known clinically used kinase
inhibitors Imatinib and Gefitinib (Figure 1). Recent analyses
tions to this method. Alternatively, the copper-mediated ami-
nation of halobenzenes, discovered by Ullmann in 1903 and
shown to be catalytic by Goldberg three years later, can also
be used for the synthesis of a range of N-aryl compounds, and
although the original methodology had limitations, recent de-
velopments have resulted in substantial improvements.[5]
However, the most significant breakthrough in this area came
in 1994 when Buchwald et al. and Hartwig et al. independently
developed a palladium-catalysed N-arylation reaction.[6,7] With
its improved substrate scope and functional group tolerance,
the Buchwald–Hartwig amination has become a fundamental
part of modern organic chemistry.[8]
However, precious metals are expensive and dwindling re-
sources, and although the success of palladium-catalysed reac-
tions has revolutionised N-arylation chemistry, there is a risk
that they are used without due consideration of alternatives.
For instance, 2-chloropyrimidine is 1014–1016 times more reac-
tive than chlorobenzene in terms of its ability to undergo SNAr
reactions;[9,10] however, an examination of the recent literature
reveals that even such reactive substrates are subjected to pal-
ladium-catalysed amination reactions. Some recent examples
of the palladium-catalysed amination of 2-chloropyrimidine
and chloropyrazine are shown in Scheme 1,[11–16] and although
these reactions, some of which are performed under fairly forc-
ing conditions with non-trivial ligands, proceed in good yield,
it does beg the question as to whether palladium is really
needed for such highly activated substrates. The literature con-
tains many examples of activated heteroaromatic chlorides re-
acting readily under SNAr conditions, so the fact that such pro-
cesses appear to have been side-lined in favour of their palla-
dium-mediated counterparts puzzled us. Thus, we sought to
optimise the coupling of heteroaromatic chlorides with amine
nucleophiles under SNAr conditions with a view to defining pa-
rameters that not only resulted in comparable yields to those
given by the published palladium-catalysed methods but also
operated under environmentally acceptable conditions in
terms of the base and solvent. We now report the results of
this detailed study.
Figure 1. Structures of Imatinib and Gefitinib.
showed heteroatom alkylations and arylations to be the largest
single class of transformations used in medicinal chemistry,
and heteroaryl N-arylations make up a significant subclass of
these transformations.[2,3] Classically, these structures have
been accessed through nucleophilic aromatic substitution
(SNAr) reactions on appropriately activated substrates,[4] al-
though poor substrate scope and reactivity are major limita-
[a] K. Walsh, Prof. Dr. C. J. Moody
School of Chemistry
University of Nottingham
University Park, Nottingham NG7 2RD (UK)
Fax: (+44)1159513564
E-mail: c.j.moody@nottingham.ac.uk
[b] Dr. H. F. Sneddon
Green Chemistry Performance Unit
GlaxoSmithKline R&D Ltd
Medicines Research Centre
Stevenage, Hertfordshire SG1 2NY (UK)
Supporting Information for this article is available on the WWW under
http://dx.doi.org/10.1002/cssc.201300239.
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Table 1. Reaction of 2-chloropyrazine with morpholine with various sol-
vents and bases.[a]
Entry
Base
Solvent
Yield [%]
1
2
3
4
5
6
7
8
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DBU[c]
Et3N
2-Me-THF
2-Me-THF/H2O (1:1)
1-butanol
EtOAc
H2O
H2O
H2O
H2O
3
18
<5
4
33[b]
58
40[b]
38
9
K2CO3
CaCO3
K3PO4
KF
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
63
38
60
70
10
11
12
13
14
15
16
17
KF[d]
30
KF[e]
KF
KF
KF
64[b]
47[b]
63[f]
81[d,g]
H2O
[a] All reactions were performed with chloropyrazine (1 equiv.), morpho-
line (1 equiv.) and base (2 equiv.) in the specified solvent at 808C for 17 h.
Reactions in water were performed at 1008C unless otherwise specified.
[b] The reaction was performed at 808C. [c] DBU=1,8-diazabicycloundec-
7-ene. [d] The reaction used 1 equiv. of base. [e] The reaction used
3 equiv. of base. [f The reaction was performed in a microwave reactor
(300 W) at 1508C for 30 min. [g] The reaction was performed in a micro-
wave reactor (300 W) at 1758C for 30 min.
vents were found to be generally ineffective for chloropyrazine
reactions (Table 1, entries 1–6), although they are better in the
reaction of 2-chloropyrimidine and yield 2-morpholinopyrimi-
dine (2) (data shown in the Supporting Information). However,
for both the chloroheterocycles, the best result was obtained
by using water as a solvent, which gave both the highest yield
and the cleanest reaction mixtures; in most cases, the product
required only a simple extraction with isopropyl acetate.
Because the reaction mixture is not homogeneous, this unex-
pected result could be attributed to an “on-water” effect.[18]
Yields were improved from 33% to 58% (Table 1, entry 6) by
increasing the temperature to 1008C. Water is not automatical-
ly a green solvent. For any given reaction, consideration needs
to be given to how wastewater is to be handled—whether it is
energy intensive to clean or whether contaminated aqueous
streams have to be incinerated in which other waste solvent
streams could be recycled or productively burnt to generate
heat and power. However, if multiple factors are weighed,[17]
water is often one of the more benign choices. Isopropyl ace-
tate was chosen for extractions on the basis that it can be
easier to recover and recycle on a large scale than ethyl
acetate.
Scheme 1. Examples of palladium-catalysed amination of reactive heteroaryl
chlorides.
Results and Discussion
The reaction of chloropyrazine with a secondary amine mor-
pholine to yield morpholinopyrazine (1) was taken as a simple
test reaction to screen a range of solvents and bases, although
from the outset we limited ourselves to solvents that are gen-
erally accepted as “green”.[17] Solvents with environmental or
toxicity alerts were disregarded, and as a result of previous lit-
erature,[11,14] caesium carbonate was chosen initially as the base
for these reactions. Although caesium carbonate sometimes
creates problematic waste streams on large scale, its solubility
made it a good starting point for these studies. Organic sol-
We then investigated the reactions of chloropyrazine with
morpholine in water with respect to the base (Table 1, en-
tries 7–15). Organic bases proved inefficient in water (entries 7
and 8), and moderate yields were obtained with other carbo-
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Table 2. Amination of chloropyrazine and 2-chloropyrimidine.[a]
Entry
Amine
Product (yield [%]) for the reaction with
1
2
3 (28; MW 60[c])
4 (47)
11 (77)
12 (85)
3
5 (58)
13 (85)
4
5
6
6 (33; MW 52[c])
14 (81)
–
15 (78)
–
16 (80) [95][b]
7
8
7 (48)
8 (76)
17 (52)
18 (76)
9
9 (52)
19 (69)
10
11
1 (70) [68, 86][b]
10 (81[d]) [93][b]
2 (84)
20 (93)
12
14
15
no reaction
no reaction
no reaction
21 (86) [75, 83][b]
22 (62)
23 (83)
[a] All reactions were performed with heteroaryl halide (1 equiv.), amine
(1 equiv.) and KF (2 equiv.) in water at 1008C for 17 h. [b] Yields in square
brackets refer to the palladium-catalysed variants shown in Scheme 1.
[c] MW refers to the yield obtained if the reaction was performed in a mi-
crowave reactor (300 W) at 1758C for 60 min with KF (1 equiv.). [d] Yield
reported as an NMR yield calculated from the internal standard using
1,4-dioxane.
nates or potassium phosphate bases (entries 9–11). Potassium
fluoride was found to be the most effective base and was thus
investigated further. Reducing the amount of base to 1 equiv.
dramatically lowered the yield (entry 13); however, only a small
increase in yield was observed by increasing the amount to
3 equiv. (entry 14). However, with 2 equiv. of potassium fluo-
ride in water at reflux (entry 12), the highest yield of 70% of
1 was achieved. Reaction times were reduced dramatically by
performing the reaction in a microwave reactor for 30 min at
150 or 1758C (63% and 81% yield, respectively). Inductively
coupled plasma mass spectrometry (ICP-MS) analysis was per-
formed to determine what levels of other metals were present
in the sample of potassium fluoride. Copper could not be de-
tected at a limit of 24 ppb, and palladium was not detected at
a limit of 10 ppb.
Figure 2. Amination products of chloropyrazine and 2-chloropyrimidine.
These results are favourably comparable to those obtained
with the palladium-catalysed variants that produced 1 in 86%
yield with Pd-PEPPSI, Cs2CO3 in 1,2-dimethoxyethane (DME) at
808C (Scheme 1d)[14] or in 68% yield with [Pd(cinnamyl)Cl]2,
Mor-Dal-Phos, NaOBut, KOH, and H2O at 1108C (Scheme 1e).[16]
However, other researchers have also found that the palladium
catalyst is unnecessary and the reaction of chloropyrazine with
morpholine proceeds at 1308C in DMSO.[19]
With the useful KF-in-water conditions now established,
chloropyrazine and 2-chloropyrimidine were screened against
a wide range of primary and secondary amines as well as ani-
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lines and NH heteroaromatic
compounds; they were selected
because they contain a range of
functional groups that are rele-
vant to contemporary medicinal
chemistry and yielded the corre-
sponding N-arylamines 1–23
(Table 2 and Figure 2). As expect-
ed, reactions with the more reac-
tive 2-chloropyrimidine generally
produced higher yields (2-chlo-
Table 3. Amination of halopyrimidines and 4-chloroquinazoline.[a]
Entry
Amine
Product (yield [%]) for the reaction with
1
2
11 (77)
12 (85)
11 (72)
12 (89)
no reaction
no reaction
27 (78)
28 (71)
ropyrimidine
is
ꢀ100 times
3
4
5
6
14 (81)
18 (76)
2 (84)
14 (68)
18 (59)
2 (85)
no reaction
24 (45)
29 (71)
30 (97)
31 (80)
32 (82)
more reactive than chloropyra-
zine)[9] and reacted in moderate
to excellent yield with primary
and secondary amines (Table 2,
entries 1–11). In the case of
a-methylbenzylamine (entry 5),
HPLC demonstrated that there
was no loss of enantiomeric
excess in the final product (ee>
98). With p-anisidine (entry 12),
the yield of 86% was compara-
25 (49)
20 (93)
20 (91)
26 (80)
7
21 (86)
21 (65)
no reaction
33 (86)
[a] All reactions were performed with aryl halide (1 equiv.), amine (1 equiv.) and KF (2 equiv.) in water at 1008C
for 17 h.
ble with that obtained through the corresponding palladium-
catalysed amination [Pd(OAc)2, Xantphos, dioxane, microwave,
1608C, 83%; Scheme 1a].[11] However, the reaction was poor
with ortho-substituted anilines and 2-aminothiazole not react-
ing. Chloropyrazine gave moderate to excellent yields with
electron-rich primary and secondary amines, but was unreac-
tive with all anilines and NH heterocycles examined. Reaction
times can be reduced again by conducting the reaction in a mi-
crowave reactor for 60 min at 1758C (entries 1 and 4). The
structures of the products 1–23 of amination of chloropyrazine
and 2-chloropyrimidine with the range of amines are shown in
Figure 2.
amination reactions with such highly activated heteroaryl
halides.
From this list of amines, seven examples were chosen to be
tested against other pyrimidines in comparison to 2-chloropyr-
imidine (Table 3). Unsurprisingly, 2-bromopyrimidine showed
similar reactivity; however, the reactions with 4-chloro-2,6-di-
aminopyrimidine resulted in unpredictable yields, possibly as
a result of solubility issues. 4-Chloroquinazoline gave good to
excellent yields in all cases, which is in line with its well-known
reactivity in SNAr reactions, for example in the synthesis of
4-anilinoquinazolines that are used as kinase inhibitors.[23] The
In the case in which direct comparison is possible, our ami-
nation method involving KF in water can be compared with
the palladium-catalysed protocols outlined in Scheme 1
(Table 2, entries 6 and 10–12): 80% vs. 95%, 70% vs. 68 or
86%, 81% vs. 93% and 86% vs. 75 or 83%. In addition, the
coupling of 2-chloropyrimidine with imidazole and benzimida-
zole performed under copper catalysis resulted in 90% and
100% yield, respectively,[20] which are comparable to the slight-
ly poorer yields of 62% and 83% obtained under our condi-
tions (Table 2, entries 14 and 15). In other cases, the transition-
metal catalyst is clearly beneficial. Although chloropyrazine
does not react readily with 4-methoxyaniline under our SNAr
conditions (Table 2, entry 12), palladium catalysis with the
BrettPhos [2-(dicyclohexylphosphino)3,6-dimethoxy-2’,4’,6’-tri-
isopropyl-1,1’-biphenyl] ligand results in a high yield of the
coupled product.[21] Given the high reactivity of 2-chloropyrimi-
dine towards nucleophilic attack, it is not surprising that there
are other examples of the SNAr process involving amine nu-
cleophiles (pyrrolidine,[22] cyclohexylamine and 4-methoxyben-
zylamine),[13] which in combination with our own results rein-
force the idea that precious metal catalysis is not needed for
Figure 3. Amination products of halopyrimidines and 4-chloroquinazoline.
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chemistry, there are examples of
reactions involving activated hal-
ides, in which it could appear
that the use of transition metals
was unnecessary. We have ad-
dressed this issue of over-reli-
ance on palladium catalysis in
organic chemistry in a range of
nucleophilic aromatic substitu-
tion reactions with activated het-
eroaryl halides to synthesise vari-
ous heteroaryl amine substrates.
A set of conditions has been de-
veloped with potassium fluoride
and water at reflux for 17 h that
allow for SNAr chemistry to be
performed, without the use of
palladium catalysis and with vari-
ous heteroaryl halides and
amines. The results showed that
the transition-metal-free SNAr re-
action not only compares fa-
Table 4. Amination of 2-halopyridines.[a]
Entry
Amine
Product (yield [%]) for the reaction with
1
2
(<5)
(<5)
(6)
37 (60)
38 (65)
43 (96)
44 (70)
no reaction
3
4
5
6
(<5)
no reaction
34 (54)
39 (48; MW 59)[b]
40 (53)
45 (73)
46 (74)
47 (87)
48 (76)
34 (<5)
35 (9; MW 25)[b]
36 (21)[c]
35 (16)
41 (36)
36 (46)[c]
42 (85)
7
no reaction
no reaction
no reaction
49 (73)
[a] All reactions were performed with aryl halide (1 equiv.), amine (1 equiv.) and KF (2 equiv.) in water at 1008C
for 17 h. [b] MW refers to the yield if the reaction was performed in a microwave reactor (300 W) at 1758C for
1 h (2 h in the case of furfurylamine) with KF (1 equiv.). [c] Yield reported as an NMR yield calculated from the
internal standard using 1,4-dioxane.
structures of the new products 24–33 obtained are
shown in Figure 3.
The same seven representative amines were also
reacted with halopyridines under the KF/water condi-
tions (Table 4), even though 2-chloropyridine is ap-
proximately 108 times less reactive towards nucleo-
philes than 2-chloropyrimidine under SNAr conditions.
Hence, the reactions of the amines with
2-chloropyridine were generally unsatisfactory, al-
though, as expected for an SNAr reaction, 2-fluoropyr-
idine resulted in better yields. If the pyridine sub-
strate contained an additional electron-withdrawing
group such as trifluoromethyl or nitro, these substi-
tuted pyridines demonstrated reactivities similar to
pyrimidines. 2-Chloro-5-nitropyridine gave good re-
sults with all the amines examined. The structures of
the wide range of N-pyridylamines 34–49 obtained
are shown in Figure 4.
Although 2-bromopyridine is reported to react
with pyrrolidine under microwave irradiation,[22] it is
clear that in the absence of additional activation,
2-halopyridines represent the limit of what will un-
dergo facile amination reactions under our simple
SNAr conditions. In contrast, both 2-bromo- and
Figure 4. Amination products of 2-halopyridines.
2-chloropyridine undergo coupling under a range of
palladium-catalysed conditions with, for example, cy-
clohexylamine and pyrrolidine,[21] with morpholine[12,16] and
with 4-methoxyaniline (63%).[24]
vourably to palladium-catalysed coupling reactions but also
operates under environmentally acceptable conditions in
terms of the base and solvent.
Whilst we believe that this methodology offers an improve-
ment over many Pd-catalysed reactions, the compatibility of
fluoride ions with other reagents and waste streams (on
a large scale) should be considered.
Conclusions
Although palladium-catalysed N-arylation amination reactions
have undoubtedly made a major impact on synthetic organic
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[7] J. Louie, J. F. Hartwig, Tetrahedron Lett. 1995, 36, 3609–3612.
[8] D. S. Surry, S. L. Buchwald, Angew. Chem. 2008, 120, 6438–6461; Angew.
Chem. Int. Ed. 2008, 47, 6338–6361.
[9] T. L. Chan, J. Miller, Aust. J. Chem. 1967, 20, 1595–1600.
[10] J. A. Joule, K. Mills, Heterocyclic Chemistry, 5th ed., Wiley, Hoboken,
2010.
[11] H. Q. Zhang, Z. Xia, A. Vasudevan, S. W. Djuric, Tetrahedron Lett. 2006,
47, 4881–4884.
[12] C. V. Reddy, J. V. Kingston, J. G. Verkade, J. Org. Chem. 2008, 73, 3047–
3062.
[13] D. S. Ermolat’ev, E. V. Van der Eycken, J. Org. Chem. 2008, 73, 6691–
6697.
[14] M. G. Organ, M. Abdel-Hadi, S. Avola, I. Dubovyk, N. Hadei, E. A. B. Kant-
chev, C. J. O’Brien, M. Sayah, C. Valente, Chem. Eur. J. 2008, 14, 2443–
2452.
Experimental Section
General Procedure: To a Reacti-Vial (Thermo Scientific, 5 mL) was
added aryl halide (1.75 mmol), amine (1.75 mmol), potassium fluo-
ride (3.50 mmol) and the solvent (1 mL); the resulting mixture was
heated to 1008C for 17 h on a heating block. Upon cooling, the
mixture was quenched with an aqueous potassium carbonate solu-
tion (40 mL) and extracted into isopropyl acetate (2ꢁ30 mL). The
organic extracts were then combined and washed with brine
before they were dried over sodium sulfate and the solvent evapo-
rated under reduced pressure. If necessary, purification was per-
formed by using column chromatography over silica gel (light pe-
troleum/ethyl acetate 4:1).
[15] D. Michalik, K. Kumar, A. Zapf, A. Tillack, M. Arlt, T. Heinrich, M. Beller,
Tetrahedron Lett. 2004, 45, 2057–2061.
[16] B. J. Tardiff, M. Stradiotto, Eur. J. Org. Chem. 2012, 3972–3977.
[17] R. K. Henderson, C. Jimenez-Gonzalez, D. J. C. Constable, S. R. Alston,
G. G. A. Inglis, G. Fisher, J. Sherwood, S. P. Binks, A. D. Curzons, Green
Chem. 2011, 13, 854–862.
[18] S. Narayan, J. Muldoon, M. G. Finn, V. V. Fokin, H. C. Kolb, K. B. Sharpless,
Angew. Chem. 2005, 117, 3339–3343; Angew. Chem. Int. Ed. 2005, 44,
3275–3279.
[19] A. J. Henderson, M. Hadden, C. Guo, N. Douglas, H. Decornez, M. R. Hell-
berg, A. Rusinko, M. McLaughlin, N. Sharif, C. Drace, R. Patil, Bioorg.
Med. Chem. Lett. 2010, 20, 1137–1140.
Acknowledgements
We thank the Engineering and Physical Sciences Research Council
and GlaxoSmithKline for an Industrial CASE award (to K.W.),
Matthew Campbell-Crawford (GSK, Stevenage) for some addition-
al experiments, and Ian Churcher, Alan Nadin and Channa Hatto-
tuwagama for helpful discussions about the choice of medicinally
relevant amines as coupling partners.
[20] Y.-X. Xie, S.-F. Pi, J. Wang, D.-L. Yin, J.-H. Li, J. Org. Chem. 2006, 71,
8324–8327.
Keywords: amination
·
aromatic substitution
·
green
[21] D. Maiti, B. P. Fors, J. L. Henderson, Y. Nakamura, S. L. Buchwald, Chem.
Sci. 2011, 2, 57–68.
chemistry · nucleophilic substitution
[22] S. Narayan, T. Seelhammer, R. E. Gawley, Tetrahedron Lett. 2004, 45,
757–759.
[23] W. A. Denny, Farmaco 2001, 56, 51–56.
[24] H. Wang, Y. Wang, C. Peng, J. Zhang, Q. Zhu, J. Am. Chem. Soc. 2010,
132, 13217–13219.
[1] L. Ackermann in Modern Arylation Methods (Ed.: L. Ackermann), Wiley-
VCH, Weinheim, 2009.
[2] J. S. Carey, D. Laffan, C. Thomson, M. T. Williams, Org. Biomol. Chem.
2006, 4, 2337–2347.
[3] S. D. Roughley, A. M. Jordan, J. Med. Chem. 2011, 54, 3451–3479.
[4] M. B. Smith, J. March, Advanced Organic Chemistry, 5th ed., Wiley-
Interscience, New York, 2001.
Received: February 6, 2013
Revised: March 26, 2013
[5] G. Evano, N. Blanchard, M. Toumi, Chem. Rev. 2008, 108, 3054–3131.
[6] A. S. Guram, R. A. Rennels, S. L. Buchwald, Angew. Chem. 1995, 107,
1456–1459; Angew. Chem. Int. Ed. Engl. 1995, 34, 1348–1350.
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