Microwave-assisted synthesis of 4-amino-3,5-dihalopyridines

Article abstract of DOI:10.1016/j.tet.2010.01.101

4-Amino-3,5-dihalopyridines have been efficiently prepared via microwave-assisted nucleophilic aromatic substitution of 3,4,5-trihalopyridines using 1-1.1 equiv of primary and secondary amines. The reaction is also applicable to electron rich arylamines.

Full text of DOI:10.1016/j.tet.2010.01.101

Tetrahedron 66 (2010) 2398–2403
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journal homepage: www.elsevier.com/locate/tet
Microwave-assisted synthesis of 4-amino-3,5-dihalopyridines
1
*
Mark Pichowicz , Simon Crumpler, Edward McDonald, Julian Blagg
The Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Belmont, Surrey SM2 5NG, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 August 2009
Received in revised form 14 December 2009
Accepted 27 January 2010
Available online 2 February 2010
4-Amino-3,5-dihalopyridines have been efficiently prepared via microwave-assisted nucleophilic
aromatic substitution of 3,4,5-trihalopyridines using 1–1.1 equiv of primary and secondary amines. The
reaction is also applicable to electron rich arylamines.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Amines
Coupling
Nucleophilic aromatic substitution
Pyridines
Microwave-assisted synthesis
1. Introduction
Recent years have seen the emergence of 4-amino-3,5-diha-
lopyridines as an important structural motif in medicinal
chemistry; for example, as intermediates, which can be further
functionalised through cross-coupling reactions1 and as phar-
maceutically active compounds across a range of disease areas.2
Approaches to these structures often commence with 4-amino-
3,5-dichloropyridine and incorporate further functionality
through functionalisation of the anilino nitrogen.3 As part of an
ongoing medicinal chemistry campaign we required access to
a series of 4-amino-3,5-dihalopyridines. Herein, we report a mi-
crowave-assisted coupling of 3,4,5-trihalopyridines with a range
of amines, allowing rapid access to a diverse range of 4-amino-
3,5-dihalopyridines.
Previously, Spivey et al. demonstrated the substitution of 3,5-
dibromo-4-chloropyridine 1 with diethylamine as a key step in the
preparation of chiral catalysts (Scheme 1).4 This reaction delivered
high overall yield but required heating in a sealed tube to 170 ꢀC
and a long reaction time (20 h). The resulting aminopyridine was
further transformed into the atropisomeric DMAP analogue 3.
Chiral HPLC furnished enantiomerically pure (ꢁ)-3, which was
shown to be an efficient catalyst for kinetic resolution of a series of
secondary alcohols.
Scheme 1. Spivey’s chiral catalyst synthesis.4
Similarly, researchers from AstraZeneca have coupled 3,4,5-tri-
chloropyridine with 1,4-diazepane as a key step in the synthesis of
11-b-hydroxysteroid dehydrogenase inhibitors for the treatment of
metabolic syndrome (Scheme 2).5 Thisreactionwasperformed under
solvent free conditions at 90 ꢀC using 18 equiv of amine. The resultant
diazepane 6 was further functionalised to deliver the sulfonamide 7,
which was shown to have an IC50 value of 0.91
mM versus 11-b-
hydroxysteroid dehydrogenase in a competitive immunoassay.
Neither of the two approaches above was particularly suited to
our needs, either requiring long reaction times and sealed tube
conditions incompatible with sensitive functionality on the amine,
or a large excess of the amine coupling partner, or both. Therefore
we desired alternative conditions.
Metal catalysed amination of halopyridines is well pre-
cedented;6 however, we were concerned about the regioselectivity
of such an approach on our preferred substrates (1) and (4). SNAr
reactions of 2- and 4-halopyridines have been efficiently carried
out under microwave conditions and we chose to follow this
approach for our system. Narayan et al. used the reaction between
2-bromopyridine 8 and pyrrolidine to optimise coupling condi-
tions. Conversion was found to be poor in water with potassium
* Corresponding author. Tel.: þ44 (0)20 8722 4051; fax: þ44 (0)20 8722 4126.
E-mail address: julian.blagg@icr.ac.uk (J. Blagg).
1
Present address: Departement fu¨r Chemie und Biochemie, Universita¨t Bern,
Freiestrasse 3, CH-3012 Bern, Switzerland.
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.101

M. Pichowicz et al. / Tetrahedron 66 (2010) 2398–2403
2399
Table 1
Optimisation of conditions for the reaction between 3,4,5-trichloropyridine 4 and
morpholine
Entry
Temp (ꢀC)
Time (min)
Solvent
Product/SMa
1
2
3
4
5
6
7
120
150
150
180
200
220
220
30
30
30
30
30
30
60
EtOH
EtOH
NMP
NMP
NMP
NMP
NMP
1:21
1:6.8
1.3:1
2.1:1
5.2:1
6.5:1
>99:1
Scheme 2. Synthesis of 11-b-hydroxysteroid dehydrogenase inhibitors.
a
carbonate as base or in toluene with triethylamine. However, the
use of 2.25 equiv of pyrrolidine without added solvent led to the
coupled product 9 in 92% yield (Scheme 3).7
Determined by HPLC trace at 254 nm.
Table 2
Coupling of amines with 3,4,5-trichloropyridine 4
Scheme 3. Microwave-assisted coupling of 2-bromopyridine 8 with amines.7
Similarly, 2-chloropyrimidine was coupled in good yield as was
4-chloropyridine, either as the free base or its hydrochloride salt.
The reaction with piperidine was also successfully demonstrated;
however, in all cases the yields were lower than with pyrrolidine. 3-
Halopyridines gave very little of the desired product (<5%).7
When we attempted the above conditions with 4-halopyridines
bearing additional halo substituents at the 3- and 5-positions as
substrates, no product formation was observed. We were particu-
larly interested in the efficient 4-substitution of 3,4,5-trihalopyr-
idines 1 and 4 in order to maximise the opportunity for subsequent
iterative diversification of the pyridine template.
Compound/Entry
Nucleophile
Product/SMa
Isolated yield (%)
99
10
>99:1
10:1
11
12
13
77
84
67
>99:1
6:1
2. Results and discussion
Initially, we optimised the procedure for the SNAr reaction of
3,4,5-trichloropyridine 4 with morpholine (1.1 equiv) using trie-
thylamine as the base (Table 1). Reaction in ethanol at 120 ꢀC for
30 min led to very low levels of conversion to the desired product
(entry 1). Increasing the reaction temperature to 150 ꢀC led to an
approximately threefold increase in conversion (entry 2), whilst
changing to the polar aprotic solvent N-methylpyrrolidone (NMP)
led to a dramatic improvement (entry 3).8 Further increases in the
reaction temperature led to improvements in conversion (entries
4–6). Finally, heating the mixture at 220 ꢀC for 60 min led to
complete and clean conversion of the starting materials into the
desired product (entry 7).
Having optimised the conditions for the reaction with mor-
pholine (isolated yield 99%), we set about exploring the scope of the
reaction. The coupling reaction proceeded smoothly with 1 equiv of
other cyclic amines including pyrrolidine, piperidine and N-meth-
ylpiperazine to give compounds 11, 12 and 13 in 77%, 84% and 67%
yield, respectively (Table 2). Additionally, the reaction proceeded
smoothly with 1.1 equiv of dimethylamine to furnish product 14 in
67% yield (Table 2).
14
15
Me2NH
>99:1
>99:1
67
75
CH3(CH2)5NH2
16
17
18
>99:1
92
79
71
PhCH2NH2
>99:1 (9.7:1)
>99:1 (102:1)
19
1:3 (1:9.3)
d
20
21
PhCH2OH
PhCH2SH
1:>99
1:>99
d
d
Efficient product formation was also observed with the primary
amines n-hexylamine and benzylamine to give compounds 15 and
Values in parentheses are calculated from integration of the 1H NMR spectra of the
crude product.
a
17, respectively. The introduction of bulky substituents
a
to the
Determined by LCMS trace at 254 nm.

2400
M. Pichowicz et al. / Tetrahedron 66 (2010) 2398–2403
primary amine had no detrimental effect, reaction with cyclohex-
ylamine and racemic -methylbenzylamine both furnishing the
desired products 16 and 18 in good yield. However, reaction with
aniline, a poor nucleophile, led to very low levels of conversion to
compound 19 (Table 2).
We attempted the reaction using benzyl alcohol and benzyl thiol
(Table 2, entries 20 and 21); neither led to formation of the desired
products. These results can be explained by the lower nucleophi-
licity of alcohols and thiols in comparison to amines.9 3,5-Dibromo-
4-chloropyridine 1 was also coupled with piperidine (1.1 equiv) in
68% yield (Scheme 4) demonstrating that the reaction can also be
performed upon this more sterically hindered system, giving rise to
products, which are also versatile partners for further cross-
coupling reactions.
4-methoxyaniline led to excellent conversion to compound 23 as
expected. However, reaction with electron deficient 4-(tri-
fluoromethyl)aniline led to destruction of starting materials and no
indication of formation of the desired product (entry 24). Similarly,
attempts at coupling with the electron poor heterocyclic amines,
2-aminopyridine and 5-amino-3-methylisoxazole, led only to
degradation of starting materials (entries 25 and 26).
a
Table 4
Coupling of anilines with 3,4,5-trichloropyridine 4
Compound/Entry
Amine
Product/SMa
6.1:1
Isolated yield (%)
91
19
Scheme 4. Coupling of 3,5-dibromo-4-chloropyridine 1.
23
24
25
>99:1
1:>99
1:>99
66
d
d
In our hands a number of potentially sensitive functionalities in
the amine coupling partner were tolerated, including amides, al-
cohols, nitriles and Cbz or acetate protected amines.10 Amines
bearing carboxylic acid or ester functionality were not tolerated
due to competing self-condensation of the amine component;
however, this limitation could be overcome via coupling of an
appropriate nitrile followed by hydrolysis.
Following our observation that the reaction with aniline gave
only a low conversion to desired product, further optimisation of
the reaction conditions was performed (Table 3). Increasing the
reaction temperature to 240 ꢀC led to improved conversion (entry
2), this was further improved upon heating to 250 ꢀC (entry 6). The
use of 2 equiv of amine was also found to increase the level of
conversion (entry 4), as did increasing the reaction time to 3 h
(entry 7). Finally we decided upon the use of 2 equiv of aniline at
250 ꢀC for 2 h (entry 8) as our optimal conditions.
26
1:>99
d
Values in parenthesis are calculated from integration of the 1H NMR spectra of the
crude product.
a
Determined by LCMS trace at 254 nm.
Table 3
In summary, we have developed an efficient microwave-assisted
coupling reaction between 3,4,5-trihalopyridines and amines. This
reaction works well for primary amines and for cyclic and acyclic
secondary amines. The procedure offers the significant benefit of
only requiring 1–1.1 equiv of the amine coupling partner and short
reaction times. Coupling with aromatic amines is possible for
electron rich systems. The products of this efficient coupling system
provide versatile intermediates for subsequent iterative elabora-
tion and these results will be published in due course.
Optimisation of conditions for the reaction between 3,4,5-trichloropyridine 4 and
aniline
Entry
Temp (ꢀC)
Time (min)
Aniline (equiv)
Product/SMa
3. General details
1
2
3
4
5
6
7
8
220
240
240
240
250
250
250
250
60
60
120
60
1
1
1
2
1
1
1
2
1:2.8
1:1.6
1.5:1
1.4:1
2.3:1
3.3:1
5.5:1
6.1:1
Microwave experiments were conducted on a Biotage Initiator
SixtyÔ (2.45 GHz) with automatically variable power (watt) for
constant temperature control. All solvents and reagents were used
as received from commercial suppliers unless otherwise stated.
Compounds prepared and used subsequently without further
purification were judged to be of suitable purity by NMR analysis; rt
relates to the temperature range 20–25 ꢀC. Reaction progress was
monitored by thin layer chromatography (TLC) performed on
polgram SIL G/UV254 plastic backed plates or aluminium plates
coated with kieselgel F254. Visualisation was achieved by a combi-
nation of ultraviolet light (254 nm) and staining with anisaldehyde
or acidic potassium permanganate. Flash chromatography was
60
120
180
120
a
Determined by HPLC trace at 254 nm.
Having optimised the conditions for the coupling with aniline to
furnish the desired product in 91% yield we set about further
exploring the scope of coupling with substituted anilines and
heterocyclic amines (Table 4). Coupling with the electron rich

M. Pichowicz et al. / Tetrahedron 66 (2010) 2398–2403
2401
performed using silica gel (Merck 60 (0.015–0.040 mm)), eluted
with the indicated solvent.
2.66 min, m/z 217 (100%, Mþ); m/z (ESI) C9H11Cl2N2 requires
217.0295, found [MþH]þ 217.0294.
Melting points were recorded on a Leica Galen apparatus and are
uncorrected. Infrared spectra were recorded on a Perkin–Elmer
Spectrum RX-I FT-IR spectrometer as dilute solutions in spectro-
3.1.3. Preparation of 3,5-dichloro-4-(piperidin-1-yl)pyridine 12.
General procedure A was followed using 3,4,5-trichloropyridine
scopic grade chloroform within a NaCl cell and are reported in cmꢁ1
.
(50 mg, 0.27 mmol), piperidine (27
mL, 0.27 mmol), triethylamine
Combined HPLC–MS analyses were recorded using a Waters Alliance
2795 Separations Module and Waters/Micromass LCT mass detector
with electrospray ionisation (þve or ꢁve ion mode as indicated). The
UV detector was a Waters 2487 Dual Absorbance (254 nm).
LC–MS (6 min) analyses were performed on a Micromass LCT/
(76 L. 0.54 mmol) and NMP (1.5 mL). The crude product was pu-
m
rified by preparative TLC on silica gel (hexane/EtOAc, 1:1) to furnish
the title compound as a colourless oil (53 mg, 84%); nmax (CHCl3)/
cmꢁ1 2941, 2853, 1558, 1449, 1402, 1246; dH (500 MHz, CDCl3) 1.66–
1.75 (6H, m, CH2CH2), 3.30 (4H, t, J 5.5, NCH2), 8.33 (2H, s, Ar, CH); dC
(125 MHz, CDCl3) 24.1 (CH2), 26.5 (CH2), 51.6 (CH2), 128.3 (Ar, C),
149.1 (Ar, CH), 152.3 (Ar, C); LC–MS (ESI, 6 min) tR 5.49 min, m/z 231
(100%, [MþNa]þ); m/z (ESI) C10H13Cl2N2 requires 231.0450, found
[MþH]þ 231.0451.
Water’s Alliance 2795 HPLC system with a Discovery 5 mm, C18,
50 mmꢂ4.6 mm or 30 mmꢂ4.6 mm i.d. column from Supelco at
a temperature of 22 ꢀC and a flow rate of 1 mL/min using a gradient
elution (10:90 to 90:10 ratio) of methanol and 0.1% formic acid in
water. LC–MS (3.5 min) analyses were performed on a Micromass
LCT/Water’s Alliance 2795 HPLC system with
a
Chromolith
3.1.4. Preparation of 1-(3,5-dichloropyridin-4-yl)-4-methylpiper-
azine 13. General procedure A was followed using N-methyl-
piperazine (27 mg, 0.27 mmol), 3,4,5-trichloropyridine (50 mg,
SpeedROD RP-18e 50ꢂ4.6 mm i.d. column from Merck at a tem-
perature of 30 ꢀC and a flow rate of 2 mL/min using a gradient
elution (10:90 to 90:10 ratio) of methanol and 0.1% formic acid in
water.
HPLC analyses were performed on an Agilent 1200 HPLC system
with a Merck Chromolith SpeedROD RP-18e 50ꢂ4.6 mm i.d.
column from Merck at a temperature of 25 ꢀC and a flow rate of
1 mL/min using a gradient elution (0:100 to 100:0 ratio) of meth-
anol and 0.1% formic acid in water.
NMR spectra were recorded on a Bruker AV500 machine, using
CDCl3 as solvent at 298 K. Chemical shifts are given in parts per
million downfield from tetramethylsilane, using residual protic
solvent as an internal standard. J values are reported in hertz and
rounded to the nearest 0.5 Hz. Where required, assignments were
confirmed by two-dimensional homonuclear (1H–1H) and hetero-
nuclear (1H–13C) correlation spectroscopy.
0.27 mmol), triethylamine (0.76 mL, 0.54 mmol) and NMP (1.5 mL).
The crude product was purified by flash column chromatography
on silica gel (hexane/EtOAc, 1:1) to furnish the title compound as
a colourless oil (44 mg, 65%); nmax (CHCl3)/cmꢁ1 2942, 2849, 2803,
1558, 1449, 1289, 1151; dH (500 MHz, CDCl3) 2.37 (3H, d, J 0.5,
NCH3), 2.56 (4H, br dd, J 5.5, 4.0, CH2), 3.39 (4H, br t, J 5.0, CH2), 8.33
(2H, d, J 0.5, Ar, CH); dC (125 MHz, CDCl3) 46.4 (CH3), 50.0 (CH2), 55.5
(CH2), 128.4 (Ar, C), 149.2 (Ar, CH), 151.3 (Ar, C); LC–MS (ESI, 6 min)
tR 0.92 min, m/z 246 (100%, [MþH]þ); m/z (ESI) C10H14Cl2N3 re-
quires 246.0559, found [MþH]þ 246.0560.
3.1.5. Preparation of 3,5-dichloro-N,N-dimethylpyridin-4-amine
14. General procedure A was followed using 3,4,5-trichloropyridine
(50 mg, 0.27 mmol), a 2 M solution of dimethylamine in THF
(0.15 mL, 0.30 mmol), triethylamine (76 mL, 0.54 mmol) and NMP
(1.5 mL). The crude product was purified by flash column chroma-
tography on silica gel (hexane/EtOAc, 95:5) to furnish the title
compound as a clear colourless oil (35 mg, 67%); nmax (film)/cmꢁ1
2927, 2883, 2800, 1559, 1506, 1424, 957, 810; dH (500 MHz, CDCl3)
3.02 (6H, s, N(CH3)2), 8.30 (2H, s, Ar, CH); dC (125 MHz, CDCl3) 42.6
(CH3),128.2 (Ar, C),149.1 (Ar, CH),152.5 (Ar, C); LC–MS (ESI, 3.5 min)
tR 2.69 min, m/z 191 (100%, [MþH]þ); m/z (ESI) C7H9Cl2N2 requires
191.0137, found [MþH]þ 191.0139.
3.1. General procedure A
3.1.1. Preparation of 4-(3,5-dichloropyridin-4-yl)morpholine 10. To
a
solution of 3,4,5-trichloropyridine (50 mg, 0.27 mmol) in
N-methylpyrrolidone (NMP) (1.5 mL) were added morpholine
(26 L, 0.30 mmol) and triethylamine (76 L, 0.54 mmol). The mix-
m
m
ture was heated in a microwave reactor (Biotage, Initiator) at 220 ꢀC
for 60 min. After cooling to rt the mixture was poured into a satu-
rated solution of sodium hydrogen carbonate (25 mL) and extracted
with EtOAc (2ꢂ25 mL). The combined organic extracts were washed
with water (25 mL) and brine (25 mL), dried (MgSO4) and concen-
trated under reduced pressure. The crude product was purified by
flash column chromatography on silica gel (hexane/EtOAc, 4:1) to
furnish the title compound as a white solid (63 mg, 99%), mp
55–57 ꢀC; nmax (film)/cmꢁ1 2965, 2894, 2862, 1557, 1484, 1471, 1445,
1433, 1270, 1243, 1100, 943, 588; dH (500 MHz, CDCl3) 3.38 (4H, t, J
4.5, NCH2), 3.85 (4H, t, J 4.5, OCH2), 8.37 (2H, s, Ar, CH); dC (125 MHz,
CDCl3) 50.4 (CH2), 67.4 (CH2), 128.4 (Ar, C), 149.0 (Ar, CH), 151.0 (Ar,
C); LC–MS (ESI) tR 2.36 min, m/z 233 (100%, [MþH]þ); m/z (ESI)
C9H11Cl2N2O requires 233.0243, found [MþH]þ 233.0246.
3.1.6. Preparationof3,5-dichloro-N-hexylpyridin-4-amine15. General
procedure A was followed using 3,4,5-trichloropyridine (50 mg,
0.27 mmol), hexylamine (36 mL, 0.27 mmol), triethylamine (76 mL,
0.54 mmol) and NMP (1.5 mL). The crude product was purified by
flash column chromatography on silica gel (CH2Cl2/MeOH, 99:1) to
furnish the title compound as a colourless oil (51 mg, 75%); nmax
(CHCl3)/cmꢁ1 2960, 2859, 1571, 1507, 1089; dH (500 MHz, CDCl3)
0.90 (3H, t, J 7.0, CH3), 1.30–1.62 (6H, m, CH2), 1.62 (2H, tt, J 7.5, 7.0,
CH2), 3.68 (2H, dt, J 7.5, 6.0, CH2), 4.73 (1H, br s, NH), 8.16 (2H, s, Ar,
CH); dC (125 MHz, CDCl3) 13.9 (CH3), 22.5 (CH2), 26.2 (CH2), 31.0
(CH2), 31.4 (CH2), 45.9 (CH2), 117.9 (Ar, C), 146.8 (Ar, C), 148.1 (Ar,
CH); LC–MS (ESI, 6 min) tR 5.24 min, m/z 247 (100%, [MþH]þ); m/z
(ESI) C11H17Cl2N2requires 247.0763, found [MþH]þ 247.0762.
3.1.2. Preparation of 3,5-dichloro-4-(pyrrolidin-1-yl)pyridine 11.
General procedure A was followed using 3,4,5-trichloropyridine
3.1.7. Preparation of 3,5-dichloro-N-cyclohexylpyridin-4-amine 16.
(50 mg, 0.27 mmol), pyrrolidine (25
mL, 0.30 mmol), triethylamine
General procedure A was followed using 3,4,5-trichloropyridine
(76 L, 0.54 mmol) and NMP (1.5 mL). The crude product was
m
(50 mg, 0.27 mmol), cyclohexylamine (35
mL, 0.30 mmol), triethyl-
purified by flash column chromatography on silica gel (hexane/
EtOAc, 20:1) to furnish the title compound as colourless oil (46 mg,
77%); nmax (film)/cmꢁ1 3287, 2959, 2929, 2869, 1561, 1472, 1451,
1402, 1088, 800; dH (500 MHz, CDCl3) 1.97 (4H, m, NCH2CH2), 3.62
(4H, m, NCH2), 8.27 (2H, s, Ar, CH); dC (125 MHz, CDCl3) 25.9 (CH2),
50.6 (CH2), 126.7 (Ar, C), 149.1 (Ar, CH), 149.9 (Ar, C); LC–MS (ESI) tR
amine (76 L, 0.54 mmol) and NMP (1.5 mL). The crude product was
m
purified by flash column chromatography on silica gel (hexane/
EtOAc, 19:1) to furnish the title compound as white solid (62 mg,
92%), mp 38–39.5 ꢀC; nmax (film)/cmꢁ1 3385, 2931, 2854,1565,1496,
1451, 1402, 1079; dH (500 MHz, CDCl3) 1.26 (2H, m, CHH), 1.41 (2H,
dddd, J 23.0, 11.5, 5.5, 3.5, CHH), 1.66 (2H, ddd, J 17.0, 7.5, 3.0, CHH),

2402
M. Pichowicz et al. / Tetrahedron 66 (2010) 2398–2403
1.78 (2H, ddd, J 17.0, 7.0, 4.0, CHH), 2.04 (2H, app dd, J 12.5, 3.5, CHH),
4.16 (1H, dddd, J 17.5, 10.0, 8.0, 4.0, NCH), 4.65 (1H, d, J 8.0, NH), 8.19
(2H, s, Ar, CH); dC (125 MHz, CDCl3) 24.5 (CH2), 25.5 (CH2), 34.6
(CH2), 53.2 (CH), 118.7 (Ar, C), 146.3 (Ar, C), 148.1 (Ar, CH); LC–MS
(ESI, 3.5 min) tR 3.03 min, m/z 245 (100%, [MþH]þ); m/z (ESI)
C11H15Cl2N requires 245.0607, found [MþH]þ 245.0609.
319 (100%, [MþH]þ); m/z (ESI) C10H13Br2ClN2 requires 318.9440,
found [MþH]þ 318.9443.
3.2. General procedure B
3.2.1. Preparation of 3,5-dichloro-N-phenylpyridin-4-amine 19. To
a solution of 3,4,5-trichloropyridine (50 mg, 0.27 mmol) in NMP
(1.5 mL) were added aniline (52 mg, 0.55 mmol) and triethylamine
3.1.8. Preparation of N-benzyl-3,5-dichloropyridin-4-amine 17.
General procedure A was followed using 3,4,5-trichloropyridine
(76 mL, 0.54 mmol). The mixture was heated in a microwave reactor
(Biotage, Initiator) at 250 ꢀC for 60 min. After cooling to rt the
mixture was poured into a saturated solution of sodium hydrogen
carbonate (25 mL) and extracted with EtOAc (2ꢂ25 mL). The
combined organic extracts were washed with water (25 mL) and
brine (25 mL), dried (MgSO4) and concentrated under reduced
pressure. The crude product was purified by flash column chro-
matography on silica gel (hexane/EtOAc, gradient 9:1 to 6:1) to
furnish the title compound as a colourless oil (60 mg, 91%); nmax
(film)/cmꢁ1 3178, 3133, 3028, 2969, 1597, 1561, 1496, 1468, 1458,
1323, 1101; dH (500 MHz, CDCl3) 6.46 (1H, s, NH), 6.95 (2H, dd, J 6.5,
0.5, Ar, CH), 7.14 (1H, app t, J 7.5, Ar, CH), 7.32 (2H, m, Ar, CH), 8.37
(2H, s, Ar, NCH); dC (125 MHz, CDCl3) 121.3 (Ar, CH), 122.5 (Ar, C),
124.3 (Ar, CH), 128.9 (Ar, CH), 139.8 (Ar, C), 143.7 (Ar, C), 148.2 (Ar,
CH); LC–MS (ESI) tR 2.25 min; m/z (ESI) C11H9Cl2N2 requires
239.0143, found [MþH]þ 239.0127.
(50 mg, 0.27 mmol), benzylamine (33
mL, 0.30 mmol), triethylamine
(76 L, 0.54 mmol) and NMP (1.5 mL). The crude product was
m
purified by flash column chromatography on silica gel (hexane/
EtOAc, 95:5) tofurnish the title compound as white oilysolid (55 mg,
79%); nmax (film)/cmꢁ1 3394, 3278, 3030, 2925, 1568, 1496, 1453,
1403,1083,1062, 697; dH (500 MHz, CDCl3) 4.89 (2H, d, J 6.0, CH2Ph),
5.04 (1H, br t, J 6.0, NH), 7.33 (2H, m, Ar, CH), 7.36 (2H, m, Ar, CH), 7.39
(1H, dt, J 7.5,1.5, Ar, CH), 8.59 (2H, s, Ar, CH); dC (125 MHz, CDCl3) 49.9
(CH2),118.5 (Ar, C),127.5 (Ar, CH),127.9 (Ar, CH),128.9 (Ar, CH),138.6
(Ar, C),146.7 (Ar, C),148.2 (Ar, CH); LC–MS (ESI, 3.5 min) tR 2.57 min;
m/z (ESI) C12H11Cl2N2 requires 253.0294, found [MþH]þ 253.0297.
3.1.9. Preparation of 3,5-dichloro-N-(1-phenylethyl)pyridin-4-amine
18. General procedure A was followed using 3,4,5-trichloropyr-
idine (50 mg, 0.27 mmol), (þ/ꢁ)-
a-methylbenzylamine (0.39 mL,
0.30 mmol), triethylamine (76 L, 0.54 mmol) and NMP (1.5 mL). The
m
crude product was purified by flash column chromatography on silica
gel (hexane/EtOAc, 95:5) to furnish the title compound as a clear
colourless oil (52 mg, 71%); nmax (film)/cmꢁ1 3383, 3028, 2976, 1565,
1493, 1449, 1401, 1084, 699; dH (500 MHz, CDCl3) 1.59 (3H, d, J 6.5,
CH3), 5.01(1H, d, J9.0, NH), 5.54(1H, dq, J 9.0, 6.5,CH), 7.26 (1H, tt, J 7.0,
2.0, Ar, CH), 7.28 (2H, dd, J 7.5, 1.5, Ar, CH), 7.29(2H, dd, J 7.5, 7.0, Ar, CH),
8.17(2H, s,Ar, CH);dC (125 MHz,CDCl3)24.8(CH3), 54.4(CH),119.2(Ar,
C),125.7 (Ar, CH),127.5 (Ar, CH),128.8 (Ar, CH),144.0 (Ar, C),146.3 (Ar,
C), 148.1 (Ar, CH); LC–MS (ESI, 3.5 min) tR 2.83 min; m/z (ESI)
C13H13Cl2N2 requires 267.0451, found [MþH]þ 267.0451.
3.2.2. Preparation of 3,5-dichloro-N-(4-methoxyphenyl)pyridin-4-
amine 23. General procedure B was followed using 3,4,5-tri-
chloropyridine
(50 mg,
0.27 mmol),
p-anisidine
(75 mg,
0.55 mmol), triethylamine (76
mL, 0.54 mmol) and NMP (1.5 mL).
The crude product was purified by flash column chromatography
on silica gel (hexane/EtOAc, gradient 9:1 to 6:1) to furnish the title
compound as a colourless oil (49 mg, 66%); nmax (film)/cmꢁ1 3381,
3220, 2920, 2834,1562,1509,1246; dH (500 MHz, CDCl3) 3.83 (3H, s,
OCH3), 6.39 (1H, s, NH), 6.87 (2H, d, J 9.0, Ar, CH), 6.98 (2H, d, J 9.0,
Ar, CH), 8.32 (2H, s, Ar, CH); dC (125 MHz, CDCl3) 55.5 (CH3), 114.1
(Ar, CH), 124.5 (Ar, CH), 132.8 (Ar, C), 144.4 (Ar, C), 148.3 (Ar, CH),
151.6 (Ar, C), 157.2 (Ar, C); LC–MS (ESI) tR 2.33 min, m/z 269 (100%,
Mþ); m/z (ESI) C12H11Cl2N2O requires 269.0243, found [MþH]þ
269.0247.
3.1.10. Preparation of 3,5-dibromo-4-chloropyridine 1. To a solution
of 4-(1H)-pyridone (0.95 g, 10 mmol) and potassium hydroxide
(1.12 g, 20 mmol) in water (20 mL) cooled to 0 ꢀC was added bro-
mine (3.19 g, 20 mmmol). After stirring at this temperature for
75 min, the mixture was filtered, washed with cold water
(3ꢂ50 mL) and hexane (3ꢂ20 mL) to furnish 3,5-dibromo-4-(1H)-
pyridone as a white solid (2.09 g, 83%). This compound was used
directly without further purification.
To 3,5-dibromo-4-(1H)-pyridone (252 mg, 1.0 mmol) was added
POCl3 (2 mL) and the mixture was heated at 100 ꢀC for 2 h.
The mixture was poured into ice/water (25 g) and basified by the
addition of a saturated solution of sodium hydrogen carbonate. The
mixture was extracted with CH2Cl2 (2ꢂ20 mL), the combined or-
ganic extracts were washed with brine (25 mL), dried (MgSO4) and
concentrated under reduced pressure to furnish the title compound
as a white solid (275 mg, 100%), mp 101–103 ꢀC (lit.4 95–96.5 ꢀC);
dH (500 MHz, CDCl3) 8.67 (2H, s, Ar, CH); dC (125 MHz, CDCl3) 121.9
(Ar, C), 144.2 (Ar, C), 150.8 (Ar, CH).
Acknowledgements
This work was supported by Cancer Research UK grant numbers
C309/A8274 and C601/A8198. We acknowledge NHS funding to the
NIHR Biomedical Research Centre. We also thank Dr. Amin Mirza,
Dr. Maggie Liu and Mr. Meirion Richards for their assistance with
NMR and mass spectrometry.
References and notes
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Tetrahedron 2004, 60, 4513.
2. For recent examples see: (a) Geneste, H.; Oost, T.; Netz, A.; Hutchins, C. W.;
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2008025735, 2008; Chem. Abstr. 2008, 148, 306179; (b) Caulkett, P. W. R.;
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US2,007,027,163, 2007; Chem. Abstr. 2007, 146, 206339; (e) Balestra, M.;
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3.1.11. Preparation of 3,5-dibromo-4-(piperidin-1-yl)pyridine 22.
General procedure A was followed using 3,5-dibromo-4-chlor-
opyridine (74 mg, 0.27 mmol), piperidine (30
mL, 0.30 mmol), trie-
thylamine (76 L, 0.54 mmol) and NMP (1.5 mL). The crude product
m
was purified by flash column chromatography on silica gel (hexane/
EtOAc, 95:5) to furnish the title compound as a clear colourless oil
(60 mg, 68%); nmax (film)/cmꢁ1 2934, 2848, 1554, 1457, 1446, 931,
761; dH (500 MHz, CDCl3) 1.65 (2H, dddd, J 9.0, 7.0, 5.5,1.5, CH2),1.73
(4H, m, CHH), 3.26 (4H, app dd, J 5.5, 5.0, NCHH), 8.50 (2H, s, Ar, CH);
dC (125 MHz, CDCl3) 24.1 (CH2), 26.4 (CH2), 51.5 (CH2), 119.7 (Ar, C),
152.2 (Ar, CH), 154.9 (Ar, C); LC–MS (ESI, 3.5 min) tR 3.26 min, m/z
6. For leading references see: (a) Shen, Q.; Ogata, T.; Hartwig, J. F. J. Am. Chem. Soc.
2008, 130, 6586; (b) Buchwald, S. L.; Mauger, C.; Mignani, G.; Scholz, U. Adv.

M. Pichowicz et al. / Tetrahedron 66 (2010) 2398–2403
Synth. Catal. 2006, 348, 23; (c) Jiang, L.; Buchwald, S. L. In Metal-Catalyzed Cross- of reaction. For
2403
a
review see: Reichardt, C. Solvent and Solvent Effects
coupling Reactions, 2nd ed.; de Meijere, A., Diederich, F., Eds.; Wiley-VCH:
Weinheim, 2004.
in Organic Chemistry, 3rd ed.; Wiley-Interscience: New York, NY, 2003,
Chapter 5.
7. Narayan, S.; Seelhammer, T.; Gawley, R. E. Tetrahedron Lett. 2004, 45, 757.
8. The change from protic to dipolar non-hydrogen bond donating solvents
in SNAr reactions has been demonstrated to dramatically increase the rate
9. Bunnett, J. F. Quarterly Rev. Chem. Soc. 1958, 12, 1.
10. These results are part of an ongoing medicinal chemistry campaign and will be
published in due course.