Regioselective coupling reactions of 2,4-diaminopyridine derivatives with aryl halides: the synthesis of elaborated pyridines

Article abstract of DOI:10.1016/j.tet.2009.08.056

The development of a synthetically useful, regioselective cross-coupling of 2,4-diaminopyridines with aryl and heteroaryl halides is reported. Selectivity for coupling through either amine is controlled by a simple change in the reaction conditions. Cross

Full text of DOI:10.1016/j.tet.2009.08.056

Tetrahedron 65 (2009) 8950–8955
Contents lists available at ScienceDirect
Tetrahedron
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Regioselective coupling reactions of 2,4-diaminopyridine derivatives
with aryl halides: the synthesis of elaborated pyridines
*
*
Matthew M. Bio , Ed Cleator , Antony J. Davies, Simon E. Hamilton, Andrew Lawrence,
Faye J. Sheen, Gavin W. Stewart, Robert D. Wilson
Department of Process Research, Merck Sharp & Dohme, Hertford Road, Hoddesdon, Hertfordshire, EN11 9BU, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 July 2009
Received in revised form 14 August 2009
Accepted 20 August 2009
Available online 26 August 2009
The development of a synthetically useful, regioselective cross-coupling of 2,4-diaminopyridines with
aryl and heteroaryl halides is reported. Selectivity for coupling through either amine is controlled by
a simple change in the reaction conditions. Cross-coupling through the 2-amino group predominates in
the presence of a palladium catalyst, whilst the 4-amino coupled product predominates in the absence
of palladium.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
through either the 2- or 4-amino group, depending on the reaction
conditions (Scheme 1).
The prevalence of nitrogen containing small molecules among
the ranks of biologically active molecules is well known.1 As a result,
the development of selective carbon–nitrogen bond forming
reactions has been the focus of a number of research groups.2
Specifically, palladium mediated cross-couplingof amines oramides
with aryl or heteroaryl halides is well studied and widely used.3
Relevant tothe study discussed herein, the regioselectivecouplingof
polyhalogenated pyridines with amines has been reported.4 We
now wish to report an orthogonal reaction in which 2,4-diamino-
pyridines are regioselectively coupled to aryl and heteroaryl halides
During the course of a recent project we required an efficient,
scalable synthetic route to compound 1. We anticipated 1 could be
accessed through one of two preferred routes. There was literature
precedent, which suggested that a regioselective reaction of 2,4-
dichloropyridine 2 with 3 (route A) may afford our desired target.5
Whilst an alternative construction resulting from selective coupling
of 2,4-diaminopyridine 4 with 5 (route B) was unprecedented;
however, the possibility of employing readily accessed 4 as an
intermediate to 1, was too attractive to ignore.
In this account we report the successful realisation of a regio-
selective arylation of 2,4-diaminopyridines. This methodology
enables the efficient synthesis of two regioisomeric compounds
from a common intermediate, greatly simplifying such syntheses.
Cl
F3C
NO2
+
A
N
3
NH2
e
t
N
2
Cl
2. Results and discussion
NH2
u
o
r
NO2
NH
2.1. Regioselective amination of 2,4-diamino-3-nitropyridine
N
N
r
o
We initially investigated the selective reaction of 2,4-dichloro-
3-nitropyridine 2 (route A),6 as selective amination reactions at
either the 2- or 4-positions have been previously reported. Of
particular interest was the reaction of 2,4-dichloro-3-nitro-
pyridines with primary amines, which generally display modest to
good selectivity for substitution of the 4-chloride.7 Meanwhile
palladium-catalysed coupling reactions with benzophenone imine
have been shown to be selective towards the 2-isomer.8 Un-
fortunately, in our case the yields observed in both types of reaction
were generally modest, with competing chloride hydrolysis being
a significant problem. This prompted us to pursue the alternative
synthesis from 2,4-diamino-3-nitropyridine 4 (route B), which
u
t
e
B
1
NH2
F3C
NO2
NH2
+
CF3
N
Cl
N
4
5
Scheme 1.
* Corresponding authors. Tel.: þ44 1992 452179; fax: þ44 1992 470437.
E-mail address: edward_cleator@merck.com (E. Cleator).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.08.056

M.M. Bio et al. / Tetrahedron 65 (2009) 8950–8955
8951
could be easily obtained by complete amination of 2 upon treat-
NH2
N
NO2
NH
ment with ammonia at elevated temperatures and pressures
NH2
(Scheme 2).9
NO2
NH2
a
OH
OH
N
NH2
N
4
Cl
NO2
O
1
a
b,c
d
NO2
NH2
NO2
Cl
CF3
N
H
O
N
H
N
4
N
2
6
7
Scheme 3. a) 2-Chloro-5-trifluoromethylpyidine 5, 5 mol % Pd(dba)2, 5 mol % Xant-
phos, 2.2 equiv t-BuOK (1 M in THF), DMPU, 80 ꢀC.
Scheme 2. a) HNO3, H2SO4, 0 ꢀC, 98%; b) oxalyl chloride, DMF, MeCN, 91%; c) POCl3,
LiCl, 37% HCl, 105 ꢀC then MeCN for work up 89%; d) NH3, H2O, 91 ꢀC, 4.09 bar, 94%.
NH2
NH2
2.2. Selective 2-arylation
NO2
NO2
NH
N
Cognisant of the extensive literature on palladium-catalysed
amination reactions, we were now in a position to screen our
desired reaction (Table 1, Scheme 3). A range of typical palladium–
ligand combinations were tested along with a screen of bases. We
were pleased to see that the palladium–Xantphos derived catalyst
was highly selective for the 2-arylation of pyridine 4 (Table 1, entry
2), without the need for protecting groups. Optimisation of this
reaction was performed employing 1,3-dimethyl-3,4,5,6-tetrahydro-
2(1H)-pyrimidinone (DMPU) as a solvent. Potassium tert-butoxide
(t-BuOK) was found to be the base of choice, giving rise to the best
regioisomeric ratio (Table 1, entries 11 and 12). It is noteworthy that
a bidentate ligand must be employed in order for the catalytic cycle
to predominate over the background reaction to generate the 4-
arylated products (Table 1, entries 5 and 6). Using Pd(dba)2 as the
catalyst was favoured over Pd2(dba)3, as the amount of 2,4-
bisarylated by-product obtained was lower and hence the overall
yield of the 2-aryl product could be maximised. The optimised
conditions for the palladium cross-coupling of 2,4-diamino-3-
N
NH
Ar
Ar
Pd
Pd
L
L
L
A
B
L
Figure 1.
These optimised conditions were applied to a range of sub-
strates to produce the corresponding 2-substituted heterocycles
in good to excellent yields, with selectivities for the 2- versus 4-
mono-arylation ranging from 9 to 1 to complete selectivity in
the cases of 4-nitrobenzylbromide (Table 2, entry 3). Another
parameter of importance was the rate of addition of base to the
reaction mixture. It was found that simply charging the base in
one portion at the beginning of the reaction led to formation of
large amount of the 2,4-bis-arylated product. The formation of
this side product could be minimised by addition of the base
over 2 h. This dimeric impurity could be easily rejected by
chromatography.
nitropyridine
4 and 2-chloro-5-trifluoromethylpyridine 5 are
highlighted below (Table 1, entry 11). These optimal conditions
were shown to afford the highest N-2 versus N-4 selectivity (22:1)
whilst minimising the formation of the 2,4-bis product.
2.3. Selective 4-arylation
The regioselectivity of the palladium-catalysed amination can be
rationalised on the ability of the pyridine nitrogen to form com-
plexes with metals.10 Two regioisomeric intermediates can be pro-
posed for the formation of 2-arylaminopyridine and its 4-isomer
(Fig. 1). Intermediate A, leading to the major reaction product, is
stabilised by coordination of the pyridine nitrogen to the metallic
centre, whereas no such stabilisation is possible for intermediate B.
During the screen of palladium catalysts and ligands we noticed
that in the absence of a bidentate ligand the undesired 4-arylated
product 8 predominated in the reaction mixture (Table 1, entry 5;
Scheme 4) and this selectivity was further enhanced when no li-
gand was present (Table 1, entry 6). This led us to study this process
as a potential extension of this methodology, whereby either the 2-
or 4-arylated products could be afforded directly from the same
Table 1
Optimisation of the palladium-catalysed amination reaction
R
R
NH2
NH2
NH
N
5mol % Pd
NH
CF3
NO2
5mol % ligand
CF3
NO2
NH2
NO2
NO2
NH2
+
+
+
base
R
N
R
N
R =
Cl
N
N
80 ºC, DMPU
N
N
N
H
H
2-aryl
4-aryl
2,4-bis
Entry
Metal Source
Ligand
Base
Solvent
2-Coupled/4
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(dppf)Cl2
Pd(OAc)2
Pd(dba)2
Pd2(dba)3
Xantphos
Cs2CO3
DMPU
DMPU
DMPU
DMPU
DMPU
DMPU
DMPU
DMPU
DMPU
2:1
19:1
1:1
Xantphos
rac-Binap
dppb
PPh3
d
1 M t-BuOLi
1 M t-BuOLi
1 M t-BuOLi
1 M t-BuOLi
1 M t-BuOLi
1 M t-BuOK
1 M NaHMDS
1 M t-BuOLi
1 M t-BuOLi
1M t-BuOK
1 M t-BuOK
2:1
1:10
1:24
17:1
5:1
6:1
6:1
Xantphos
Xantphos
d
9
10
11
12
Xantphos
Xantphos
Xantphos
1,4-Dioxane
DMPU
DMPU
22:1
27:1

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M.M. Bio et al. / Tetrahedron 65 (2009) 8950–8955
Table 2
Selective palladium catalysed formation of 2-aryl-4-aminopyridines
R
R
NH2
NH2
NH
N
5mol % Pd(dba)2
NH
NO2
NO2
NH2
5mol % Xantphos
NO2
NO2
NH2
+
+
+
RX
2.2equiv. t-BuOK
80 ºC, DMPU
R
N
R
N
N
N
N
H
H
2-aryl
4-aryl
2,4-bis
Entry
1
Substrate RX
CF3
Yield 2-aryl (%)
76
Yield 4-aryl (%)
4
Yield 2,4-bis (%)
10
Cl
N
2
3
76
71
2a
0
3a
8a
F3C
Br
Br
O2N
4
5
55
70
5
8
10
9
Br
N
I
N
NO2
6
46
4a
4a
Cl
N
Yield established from crude 1H NMR.
a
starting material without the need for N-protection. During opti-
misation we found the regioselective SNAr reaction proceeded best
in polar aprotic solvents such as N,N-dimethylformamide (DMF) or
N,N-dimethylacetamide (DMA). However, a competing N-acylation
reaction was observed with these solvents. This unwanted side
reaction could be eliminated when we again moved to DMPU as the
solvent of choice. The use of 2 equiv of strong base was required to
force the reaction to completion since the more acidic product was
CF3
NH2
HN
N
N
NO2
NO2
a
N
4
NH2
NH2
8
Scheme 4. a) 2-Chloro-5-trifluoromethylpyridine 5, 2.2 equiv t-BuOK, DMPU, 80 ꢀC.
Table 3
Selective formation of 4-aryl product
R
R
NH2
NH2
N
NH
N
NH
NO2
2.2 equiv t-BuOK
NO2
NH2
NO2
NO2
NH2
+
+
+
RX
80 °C, DMPU
R
N
R
N
N
N
H
H
2-aryl
4-aryl
2,4-bis
Entry
1
Substrate RX
CF3
Yield 2-aryl (%)
1
Yield 4-aryl (%)
68
Yield 2,4-bis (%)
2
Cl
N
NO2
2
3
0
0
83
64
0
F
N
N
1a
Cl
F
F
4
0
61
46
0
0
Br
F
O2N
Br
5
14a
N
a
Yield established from crude 1H NMR.

M.M. Bio et al. / Tetrahedron 65 (2009) 8950–8955
8953
preferentially deprotonated under the reaction conditions. Again,
the formation of 2,4-bisarylated by-products was problematic but
could be suppressed by slow addition of the base to the reaction
mixture. Using these optimised conditions, a regioisomeric ratio of
65:1 in favour of the 4-aryl isomer was observed. The minor un-
desired isomer was rejected by crystallisation of the product upon
addition of water, providing an isolated yield of 68% of 8. A range of
substrates were subjected to the 4-selective arylation conditions
and the reaction was found to be generally applicable. Similar levels
of selectivity were observed to that of the optimised lead (Table 3,
Entry 1). In the case of the doubly activated 2-bromo-3-nitro pyr-
idine a less selective amination was observed (Table 3, entry 5). This
is thought to be due to the differences in the N-2 and N-4 amine
reactivities becoming less important on treatment with more re-
active electrophiles.
in both academic and industrial settings, by allowing a rapid entry
into complex heterocyclic structures such as thosewehave described
herein, without the need to resort to protecting group strategies.
4. Experimental
4.1. General information
All reactions were carried out under a nitrogen atmosphere,
unless otherwise stated. All commercially available reagents and
solvents were used as received. Melting points are uncorrected. 1H
NMR spectra were recorded using a Bruker DRX 400 MHz spec-
trometer. Chemical shifts are referenced to residual protons in the
deuterated solvent and are quoted in ppm. Coupling constants are
quoted in Hz. 13C NMR spectra were recorded on a Bruker 400 MHz
(100 MHz) spectrometer with complete proton decoupling. Mass
spectrometry was carried out using a Waters LCTdTime of Flight
Mass Spectrometer running in positive ion electrospray mode.
Flash column chromatography was carried out using 60/silica gel
(DavisilÒ 40–63 micron).
The structure of the 4-substituted compounds was confirmed by
NOE experiments, which showed a correlation between the two
aryl rings (Fig. 2). For example, the p-nitrophenyl adduct (Table 3,
entry 2) showed a 3.9% correlation. No such correlation was ob-
served in the 2-substituted compounds.
4.2. Typical procedure for Pd cross-coupling: method A
NH2
NO2
NO2
2,4-Diamino-3-nitropyridine (0.25 g, 1.62 mmol), the aromatic
halide (1.35 mmol), Pd(dba)2 (0.04 g, 0.07 mmol) and Xantphos
(0.04 g, 0.07 mmol) were dissolved/suspended in DMPU (2 mL) un-
der an atmosphere of nitrogen. The flask was evacuated then purged
with nitrogen three times. The reaction mixture was heated at 80 ꢀC
then treated with a 1.0 M solution of KOtBu inTHF (2.7 mL, 2.7 mmol)
over 2 h. The resulting dark red solutionwas heated at 80 ꢀC until the
aromatic halide had been consumed. The reaction was then cooled
and diluted with EtOAc followed by water. The phases were sepa-
rated and the aqueous layer extracted three times with EtOAc. The
combined organics were washed with brine three times then dried
over MgSO4. The solvent was removed under reduced pressure and
the residue purified by flash column chromatography.
N
NH
H
H
N
N
nOe 3.9 %
H
NO2
NH2
NO2
No nOe observed
Figure 2.
In order to establish whether the observed regioselectivity of
the SNAr and palladium catalysed cross-coupling reactions was
solely a result of the 3-nitro functionality, 2,4-diamino-pyridine 9
was synthesised and subjected to both sets of reaction conditions.11
The product ratio obtained from the base mediated reaction, al-
though lower in magnitude, was of the same sense as those ob-
served for 2,4-diamino-3-nitropyridine. This lowering in product
ratio shows the importance of a suitably positioned electron
withdrawing substituent in differentiating between the two
amines in the SNAr reaction, although there is some inherent se-
lectivity for preferential reaction at N-4 (Scheme 5). Conversely the
pyridine nitrogen directing group for the palladium catalysed N-2
substitution is still present in 9. This allows the reaction to progress
with similar product ratios to those seen in the corresponding
3-nitro activated substrate.
4.3. Typical procedure for SNAr reactions: method B
2,4-Diamino-3-nitropyridine (0.25 g, 1.62 mmol) and the aro-
matic halide (1.35 mmol) were dissolved in DMPU (2 mL) under an
atmosphere of nitrogen. The flask was evacuated then purged with
nitrogen three times. The reaction mixture was heated to 80 ꢀC then
treated with a 1.0 M solution of KOtBu in THF (2.70 mL, 2.70 mmol)
over2 h. The resulting darkred solutionwas heatedat 80 ꢀC until the
aromatic halide had been consumed. The reaction was then cooled
and diluted with EtOAc followed by water. The phases were sepa-
rated and the aqueous layer extracted three times with EtOAc. The
combined organics were washed with brine three times then dried
over MgSO4. The solvent was removed under reduced pressure and
the residue purified by flash column chromatography.
NH2
F3C
NH2
4.3.1. 3-Nitro-N2-[5-(trifluoromethyl)pyridin-2-yl]pyridine-2,4-di-
amine: Table 2 entry 1. Prepared by method A, in a 76% isolated
yield.
b
N
NH
N
a
N
NH
N
N
NH2
10
9
11
Mp 171–173 ꢀC; 1H NMR (DMSO-d6) dH: 11.09 (1H, s), 8.63 (1H, s),
8.53 (1H, d, J¼8.8), 8.22 (2H, s), 8.14 (1H, d, J¼8.8), 7.84 (1H, d, J¼6.3),
6.54 (1H, d, J¼6.3); 13C NMR (DMSO-d6) dC: 149.6,147.3,144.4,143.9,
140.8, 132.2, 123.4, 118.7 (q, JCF¼272.0), 116.9, 112.7, 106.9; HRMS
(ESIþ) calcd for C11H8F3N5O2 300.0708, found 300.0703.
NH2
CF3
Scheme 5. a) 2.2 equiv t-BuOK, DMPU 80 ꢀC, 43% (product ratio 3.1:1; 10/11); b)
Pd(dba)2$Xantphos, t-BuOK, DMPU, 100 ꢀC, 60% (product ratio 1:10; 10/11).
3. Conclusion
4.3.2. 3-Nitro-N,N0-bis[5-(trifluoromethyl)pyridin-2-yl]pyridine-2,4-
diamine: Table 2 entry 1. Prepared by method A, in a 10% isolated
yield.
In conclusion, we have demonstrated that by judicious choice of
reagents, novel and selective arylations of 2,4-diaminopyridines can
be effected to afford high yields on mono-arylated products. We
envisage that this methodology will be useful for synthetic chemists
Mp 194–195 ꢀC; 1H NMR (DMSO-d6) dH: 10.21 (1H, s), 10.20 (1H,
s), 8.60 (1H, s), 8.56 (1H, s), 8.35 (1H, d, J¼5.7), 8.11 (1H, d, J¼9.0),

8954
M.M. Bio et al. / Tetrahedron 65 (2009) 8950–8955
8.10 (1H, d, J¼9.0), 7.95 (1H, d, J¼9.0), 7.75 (1H, d, J¼5.7), 7.33 (1H, d,
J¼9.0); 13C NMR (DMSO-d6) dC: 156.4, 156.3, 151.1, 147.6, 145.5,
145.3, 143.3, 136.1, 135.9, 126.5, 126.0, 123.4 (q, JCF¼272.0), 123.3 (q,
JCF¼272.0), 119.2, 114.0, 112.7, 111.0; HRMS (ESIþ) calcd for
C17H10F6N6O2 445.0848, found 445.0847.
4.3.10. 3-Nitro-N4-(4-nitrophenyl)pyridine-2,4-diamine: Table
entry 2. Prepared by method B, in a 83% isolated yield.
3
Mp 251–253 ꢀC; 1H NMR (DMSO-d6) dH: 10.11 (1H, s), 8.25 (2H, d,
J¼9.0), 7.91 (1H, d, J¼5.8), 7.75 (2H, s), 7.53 (2H, d, J¼9.0), 6.48 (1H, d,
J¼5.8); 13C NMR (DMSO-d6) dC: 156.1,153.9,147.3,146.3,143.3,125.7,
122.7,119.1,100.9; HRMS (ESIþ) calcd for C11H9N5O4 276.0733, found
276.0734.
4.3.3. 3-Nitro-N2-[4-(trifluoromethyl)phenyl]pyridine-2,4-diamine:
Table 2 entry 2. Prepared by method A, in a 76% isolated yield.
Mp 174–176 ꢀC; 1H NMR (DMSO-d6) dH: 10.57 (1H, s), 8.18 (2H, s),
7.93 (2H, d, J¼8.6), 7.76 (1H, d, J¼5.9), 7.65 (2H, d, J¼8.6), 6.41 (1H, d,
J¼5.9); 13C NMR (DMSO-d6) dC: 153.3,151.3,149.9,143.4,126.3,126.1,
123.5 (q, JCF¼272.0), 121.9, 117.7, 105.6; HRMS (ESIþ) calcd for
C12H9F3N4O2 299.0756, found 299.0745.
4.3.11. 3-Nitro-N4-pyrimidin-2-ylpyridine-2,4-diamine: Table 3 entry
3. Prepared by method B, in a 64% isolated yield.
Mp 190–192 ꢀC; 1H NMR (DMSO-d6) dH: 10.99 (1H, s), 8.66 (2H, d,
J¼4.7), 8.08 (1H, d, J¼5.5), 7.86 (1H, d, J¼5.5), 7.83 (2H, s), 7.15 (1H, t,
J¼4.7); 13C NMR (DMSO-d6) dC: 159.0,158.8,156.0,154.6,144.9,118.9,
116.2, 102.9; HRMS (ESIþ) calcd for C9H8N6O2 233.0787, found
233.0792.
4.3.4. 3-Nitro-N2-(4-nitrophenyl)pyridine-2,4-diamine: Table 2 entry
3. Prepared by method A, in a 71% isolated yield.
Mp 244–246 ꢀC; 1H NMR (DMSO-d6) dH: 10.65 (1H, s), 8.19 (2H, d,
J¼9.2), 8.15 (2H, s), 7.98 (2H, d, J¼9.2), 7.81 (1H, d, J¼5.8), 6.49 (1H, d,
J¼5.8); 13C NMR (DMSO-d6) dC: 153.0,150.5,149.4,146.4,141,8,125.1,
120.7,118.4,106.6; HRMS (ESIþ) calcd for C11H9N5O4 276.0733, found
276.0734.
4.3.12. N4-(2-Bromo-3,5-difluorophenyl)-3-nitropyridine-2,4-di-
amine: Table 3 entry 4. Prepared by method B, in a 61% isolated
yield.
Mp 246–248 ꢀC; 1H NMR (DMSO-d6) dH: 10.19 (1H, s), 7.97 (2H, s),
7.80 (1H, d, J¼6.0), 7.49 (1H, m), 7.38 (1H, m), 5.94 (1H, d, J¼6.0); 13C
NMR (DMSO-d6) dC: 156.5, 154.2, 149.1, 140.3 (dd, JCF¼259.1, 12.0),
117.2,111.7 (dd, JCF¼255.1,12.0),110.0,109.6,104.2,103.8, 99.0; HRMS
(ESIþ) calcd for C11H7BrF2N4O2 344.9799, found 344.9789.
4.3.5. 3-Nitro-N2-pyridin-2-ylpyridine-2,4-diamine: Table 2 entry 4
and 5. Prepared by method A, in a 55 & 70% isolated yield,
respectively.
Mp 179–181 ꢀC; 1H NMR (DMSO-d6) dH: 10.97 (1H, s), 8.43 (1H,
d, J¼8.4), 8.30 (1H, m), 8.26 (2H, s), 7.80 (2H, m), 7.09–7.05 (1H, m),
6.45 (1H, d, J¼6.0); 13C NMR (DMSO-d6) dC: 153.4, 152.7, 150.5,
149.8, 148.5, 138.5, 119.2, 117.6, 114.9, 105.8; HRMS (ESIþ) calcd for
C10H9N5O2 232.0834, found 232.0826.
4.3.13. 3-Nitro-N4-(3-nitropyridin-2-yl)pyridine-2,4-diamine: Table
3 entry 5. Prepared by method B, in a 46% isolated yield.
Mp240–242 ꢀC;1HNMR(DMSO-d6)dH:12.26(1H,s), 8.68(2H, m),
8.12 (1H, d, J¼5.8), 7.86 (1H, d, J¼5.8), 7.81 (2H, s), 7.32 (1H, dd, J¼8.4,
4.5); 13C NMR (DMSO-d6) dC: 155.9, 154.5, 154.1, 147.5, 144.0, 136.4,
133.1, 119.6, 118.7, 104.5; HRMS (ESIþ) calcd for C10H8N6O4 277.0685,
found 277.0687.
4.3.6. 3-Nitro-N4-(pyridin-2-yl)pyridine-2,4-diamine: Table 2 entry
4 and 5. Prepared by method A, in a 5 & 8% isolated yield,
respectively.
4.3.14. N4-[5-(Trifluoromethyl)pyridin-2-yl]pyridine-2,4-diamine:
10. Prepared by method B, in a 43% isolated yield as a mixture of
isomers. An analytically pure sample was provided by preparative
HPLC.
Mp 181–183 ꢀC; 1H NMR (DMSO-d6) dH: 10.49 (1H, s), 8.34 (1H,
m), 7.94 (1H, d, J¼5.9), 7.79 (1H, m), 7.71 (2H, s), 7.51 (1H, d, J¼5.9),
7.23 (1H, d, J¼8.2), 7.10 (1H, m); 13C NMR (DMSO-d6) dC: 156.0,
153.9, 153.2, 148.1, 146.2, 139.0, 119.3, 118.5, 115.7, 101.8; HRMS
(ESIþ) calcd for C10H9N5O2 232.0834, found 232.0836.
1H NMR (CD3OD) dH: 8.65 (1H, s), 8.09 (1H, dd, J¼9.6, 4.4), 7.81
(1H, d, J¼7.2), 7.16 (1H, d, J¼8.8), 6.55 (1H, dd, J¼6.8, 1.6), 6.32 (1H,
d, J¼1.8); 13C NMR (CD3OD) dC: 160.2, 149.1, 143.9, 143.8, 136.0,
135.9, 135.6, 120.5, 112.2, 105.5, 92.0; HRMS (ESIþ) calcd for
C11H9F3N4 255.0858, found 255.0851.
4.3.7. 3-Nitro-N,N0-di(pyridin-2-yl)pyridine-2,4-diamine: Table
2
entry 4 and 5. Prepared by method A, in a 10 & 9% isolated yield,
respectively.
Mp 113–115 ꢀC; 1H NMR (DMSO-d6) dH: 10.20 (2H, s), 8.30 (2H,
m), 8.19 (1H, d, J¼5.9), 8.11 (1H, d, J¼8.4), 7.81 (2H, m), 7.70 (1H, d,
J¼5.9), 7.25 (1H, d, J¼8.4), 7.14–7.05 (2H, m); 13C NMR (DMSO-d6)
dC: 152.9, 152.7, 151.1, 149.1, 148.0, 145.6, 139.1, 138.8, 122.3, 119.5,
119.0, 117.5, 115.6, 114.5, 107.1; HRMS (ESIþ) calcd for C15H12N6O2
309.1100, found 309.1104.
4.3.15. N2-[5-(Trifluoromethyl)pyridin-2-yl]pyridine-2,4-diamine:
11. Prepared by method A, in a 61% isolated yield as a mixture of
isomers. An analytically pure sample was provided by preparative
HPLC.
1H NMR (CD3OD) dH: 8.61 (1H, s), 8.01 (1H, s,), 7.96 (1H, dd,
J¼9.0, 1.9), 7.66 (1H, d, J¼8.0), 7.10 (1H, d, J¼8.4), 6.86 (1H, dd, J¼7.2,
2.0); dC: 157.0, 145.08, 144.7, 143.91, 136.0, 134.7, 131.0, 125.44, 116.7,
112.3, 95.2; HRMS (ESIþ) calcd for C11H9F3N4 255.0858, found
255.0850.
4.3.8. 3-Nitro-N2-(5-nitropyridin-2-yl)pyridine-2,4-diamine: Table 2
entry 6. Prepared by method A, in a 46% isolated yield.
Mp 250–252 ꢀC; 1H NMR (DMSO-d6) dH: 11.21 (1H, s), 9.09 (1H, s),
8.59 (1H, d, J¼2.7), 8.45 (1H, J¼2.7), 8.17 (2H, s), 7.88 (1H, d, J¼5.9),
6.60 (1H, d, J¼5.9); 13C NMR (DMSO-d6) dC: 156.9,152.8,149.1,149.0,
145.4, 139.3, 134.4, 119.5, 112.8, 108.1; HRMS (ESIþ) calcd for
C10H8N6O4 277.0685, found 277.0684.
References and notes
1. (a) Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Eds.;
Elsevier: Oxford, 1996; (b) Craig, P. N. In Comprehensive Medicinal Chemistry;
Drayton, C. J., Ed.; Pergamon: New York, NY, 1991; Vol. 8; (c) Southon, I. W.;
Buckingham, J. In Dictionary of Alkaloids; Saxton, J. E., Ed.; Chapman and Hall:
London, 1989; (d) Negwer, M. Organic-Chemical Drugs and their Synonyms, 8th
ed.; VCH-Wiley: Berlin, 2002.
2. Rossi, R.; de Rossi, R. H. Aromatic Substitution by the SRN1 Mechanism; American
Chemical Society: Washington, DC, 1983; Vol. 178; For reviews on copper
mediated C–N bond formation see: (a) Beletskaya, I. P.; Cheprakov, A. V. Coord.
Chem. Rev. 2004, 2337–2364; (b) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed.
2003, 42, 5400–5449; (c) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428–
2439.
4.3.9. 3-Nitro-N4-[5-(trifluoromethyl)pyridin-2-yl]pyridine-2,4-di-
amine: Table 3 entry 1. Prepared by method B, in a 68% isolated
yield.
Mp250–252 ꢀC; 1H NMR(DMSO-d6)dH: 10.48 (1H, s), 8.80(1H, s),
8.07 (1H, dd, J¼8.8 & 2.4), 8.04 (1H, d, J¼5.9), 7.53 (2H, s), 7.39 (1H, d,
J¼5.9), 7.30 (1H, d, J¼8.8).13C NMR (DMSO-d6) dC: 156.5,155.3,153.6,
145.4,144.3,135.9,120.3,119.3,113.0,114.3,114.1; HRMS (ESIþ) calcd
for C11H8F3N5O2 300.0708, found 300.0709.
3. (a) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534–1544; (b) Janey, J. M. Name
Reactions for Functional Group Transformations; VCH-Wiley: NJ, 2007; (c) Zeni,

M.M. Bio et al. / Tetrahedron 65 (2009) 8950–8955
8955
G.; Larock, R. C. Chem. Rev. 2006, 106, 4644–4680; (d) Buchwald, S. L.; Mauger,
C.; Mignani, G.; Scholz, U. Adv. Synth. Catal. 2006, 348, 23–39; (e) Schlummer,
N. B.; Scholz, U. Adv. Synth. Catal. 2004, 346, 1599–1626; (f) Jiang, L.; Buchwald,
S. L. In Metal-Catalyzed Cross-Coupling, 2nd ed.; de Meijere, A., Diederich, F.,
Eds.; Wiley-VCH: Weinheim, 2004; (g) Hartwig, J. F. In Modern Arene Chemistry;
Astruc, D., Ed.; Wiley-VCH: Weinheim, Germany, 2002; (h) Hartwig, J. F. In
Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.;
Wiley-Interscience: New York, NY, 2002; (i) Muci, A. R.; Buchwald, S. L. Top.
Curr. Chem. 2002, 219, 131–209.
7. Forexamplesee:(a)Kumar, J.S.;Dileep, M.;Vattoly, J.;Sullivan,G. M.;Prabhakaran,
J.; Simpson, N. R.; Van Heertum, R. L.; Mann, J. J.; Parsey, R. V. Bioorg. Med. Chem.
2006, 4, 4029–4034; (b) Guo, Z. J. Med. Chem. 2005, 48, 5104–5107; (c) Lindstrom,
K. J.; Dressel, L. T.; Bonk, J. D. US Patent Application, US 2004/0248929 A1.
8. Similar selectivity has been observed, see for example: (a) Ji, J.; Li, T.; Brunnelle,
W. H. Org. Lett. 2003, 5, 4611–4614; (b) Jonckers, T. H. M.; Maes, B. U. W.;
´
Lemiere, G. L. F.; Dommisse, R. Tetrahedron 2001, 57, 7027–7034.
9. Compounds 2 and 4, 6 and 7 were prepared by modification of a literature
procedure see: Kogl, F.; Van der Want, G. M.; Salemink, C. A. Recueil des Travaux
Chimiques des Pays-Bas et de la Belgique 1948, 67, 29–44.
4. Stroup, B. W.; Szklennik, P. V.; Forster, C. J.; Serrano-Wu, M. H. Org. Lett. 2007, 9,
2039–2042.
10. Hartley, F. R. Coord. Chem. Rev. 1981, 35, 143–209.
5. Abad, A.; Agullo´ , C.; Cun˜at, A. C.; Vilanova, C. Synthesis 2005, 915–924.
6. Caution should be taken when handling compound 2 which we found to be
a powerful sensitiser.
11. Whilst Compound 9 is commercially available it was prepared in this instance
following the literature procedure see: Horn, A. S.; and Agoston, S. US Patent
Application, US 84-597732 19840406.