Highly regioselective palladium-catalyzed C2-amination of 2,4-dichloropyridines: Scope and limitations

Article abstract of DOI:10.1055/s-0030-1260080

The use of palladium(0) enables a highly regioselective C-2 amination of 4,6-dichloronicotinonitrile. Coupling with aminoarenes that are N-acetyl-masked to limit cross-coupling overreaction, leads to 4-chloro-6-anilino nicotinonitrile compounds after depr

Full text of DOI:10.1055/s-0030-1260080

PAPER
2431
Highly Regioselective Palladium-Catalyzed C2-Amination of
2,4-Dichloropyridines: Scope and Limitations
C2-Amination of
h
2,4-Dichloro
r
pyridine
i
s
stian Delvare, Patrice Koza, Rémy Morgentin*
AstraZeneca, Centre de Recherches, Parc industriel Pompelle B.P.1050, 51689 Reims cedex 2, France
Fax +33(3)26616842; E-mail: remy.morgentin@astrazeneca.com
Received 17 March 2011; revised 19 May 2011
proach B) can give low yields due to imperfect levels of
C2/C4 regioselectivity. A third method (approach C) to
make 4-chloro-2-aminoarene pyridines A (see Figure 1
below) could involve a reversal of reactivity by carrying
Abstract: The use of palladium(0) enables a highly regioselective
C-2 amination of 4,6-dichloronicotinonitrile. Coupling with ami-
noarenes that are N-acetyl-masked to limit cross-coupling overreac-
tion, leads to 4-chloro-6-anilino nicotinonitrile compounds after
deprotection in situ. The scope of these original conditions was out an SNAr reaction on activated haloheteroarenes
evaluated.
through the anion of 2-amino-4-chloropyridine, however,
this approach is limited to activated haloheteroarenes
(e.g., 2-chlorothioazole).2 For our SAR studies, access to
2-anilino-4-chloropyridines was required so that we could
then create diversity at the C4-position of the pyridine
ring. To the best of our knowledge, there are very few lit-
erature examples where a 2,4-dichloropyridine is first
functionalized at the C2-position.3 Herein, we report a
highly regioselective palladium-catalyzed C2-amination
of 2,4-dichloropyridine derivatives using Buchwald–
Hartwig conditions and N-acetyl-masked aminoarenes.
Key words: regioselectivity, palladium, amination, pyridines,
cross-coupling
Several examples of 2,4-bis-anilino pyridines have been
developed as very potent kinase inhibitors. Due to the
broad range of substituents required to enable extensive
exploration of structure–activity relationships, flexible
synthetic routes to these compounds are required. Litera-
ture methods for accessing 2,4-bis-anilinopyridyl com-
pounds usually start with functionalization at the C4-
position of a 2,4-dihalopyridine ring. Some examples
have involved direct functionalization at the C2-position
either by differentiating two halogen atoms of the starting
material (i.e., 4-iodo-2-fluoro/chloropyridine derivatives)
or by introducing groups by anionic displacement on 2,4-
dichloropyridines derivatives (Scheme 1).1
Firstly, 4-chloro-6-anilino nicotinonitrile derivatives (A)
were required as intermediates in our research, therefore,
4,6-dichloronicotinonitrile (1) was subjected to different
reaction conditions in the presence of an aniline. Palladi-
um-mediated conditions have previously been used,3
however, for substrate 1, overreaction occurred under
these conditions leading to the formation of product B.
C4-Substitution was predominant under basic conditions
(e.g., sodium hydride) to give product C and other by-
products (Figure 1).
I
I
R
R
approach A
H+
N
F/Cl
N
NHAr
N
N
Cl
N
N
N
Cl
N
NHAr
Cl
N
R
+
R
R
Cl
N
Cl
Ar
approach B
B–
N
N
Ar
B
H
NHAr
N
Cl
Cl
A
NHAr
N
Cl
Cl
R
R
approach C
B–
Het
+
X
N
Cl
N
NHHet
N
NH2
C
Scheme 1 Different approaches reported in the literature
Figure 1 Target products A and the main by-products formed under
palladium-catalyzed (B) and basic conditions (C)
Nevertheless, the first method (approach A) can be less
convenient because not all the possible starting materials From previous observations made within our group,4 the
are commercially available. The second method (ap- use of an N-acetyl aniline derivative instead of the aniline
derivative itself could lead to displacement of the C2-
chlorine atom from 2-chloro-4-iodo-5-(trifluorometh-
yl)pyridine under basic conditions in moderate to good
yields. Deacetylation then afforded the desired product.
SYNTHESIS 2011, No. 15, pp 2431–2436
Advanced online publication: 21.06.2011
DOI: 10.1055/s-0030-1260080; Art ID: Z30111SS
x
x.
x
x
.
2
0
1
1
© Georg Thieme Verlag Stuttgart · New York

2432
C. Delvare et al.
PAPER
Thus, the reaction between the 4,6-dichloronicotinonitrile The C2-regioselective palladium-catalyzed cross-cou-
(1) and N-(1,3-dimethyl-1H-pyrazol-4-yl)acetamide (2) pling reaction between 2-chloropyridine and ureas has al-
was explored as a model. Basic conditions (sodium 2- ready been reported,6 but, to the best of our knowledge,
methylbutan-2-olate, dioxane, tetrahydrofuran, or sodium acetamides have never been used in this kind of chemistry
hydride in N,N-dimethylformamide) gave the desired ma- with the aim of using the N-acetyl group as a protecting
jor product 3 but with moderate C2/C4 regioselectivity group, coupled with palladium-catalyzed chemistry to
and were formed together with polymeric products (A/B/ enhance regioselectivity and limit overreaction. In an at-
C = 65:15:20). The acetyl group was cleaved during the tempt to improve conditions for this reaction, several
reaction, probably due to the harsh conditions. Palladium- parameters were explored. Initially, the influence of the
catalyzed conditions were then tried using 3 mol% palla- acetyl group was evaluated; Boc, trifluoroacetyl and
dium(II) acetate, 6 mol% Xantphos, and 1.5 equivalents formyl groups were tried in place of the acetyl group, but
of cesium carbonate in dioxane at 90 °C for four hours. none gave the expected product A and use of the acetyl re-
This furnished the expected product 3 in acceptable yield, mained the preferred choice. Various palladium-catalyzed
with very little by-product B being formed. Total regiose- coupling conditions were then screened. A range of differ-
lectivity occurred and none of the C4 product type C was ent bases, palladium sources, ligands and solvents were
observed.5 Acetyl deprotection was carried out by addi- explored, but these alternative conditions did not lead to
tion of 1 M aqueous lithium hydroxide (Scheme 2).
an improvement over the first results (detailed in
Scheme 2), therefore, our preferred reagent mixture re-
mained as palladium(II) acetate, Xantphos, and cesium
carbonate in dioxane. The palladium was a key compo-
nent in this coupling. Indeed, treating pyridine 1 and
acetyl 4-amino-pyrazole 2 with no palladium source, in
the presence of Xantphos and cesium carbonate in diox-
ane, led to less regioselectivity and the formation of more
by-products.
Me
Cl
Cl
N
Me
N
N
N
a, b
N
N
+
50%
N
N
AcHN
N
Cl
H
3
2
1
Scheme 2 Reagents and conditions (0.58 mmol of 1 and 2): (a)
Pd(OAc)2 (3 mol%), Xantphos (6 mol%), Cs2CO3 (1.5 equiv), di-
oxane (0.3 M), 90 °C, 4 h; (b) 1 M aq LiOH (3 equiv), r.t., 30 min.
To evaluate the scope of this reaction, pyridine 1 was re-
acted with a range of N-acetyl anilines; the results are
summarized in Table 1.
Table 1 Scope of the Reactiona
H
Cl
N
H
Cl
N
N
R4
R3
R2
R4
R3
a) Pd(0)
b) LiOH
+
R2
AcHN
N
H
N
Cl
R1
R1
1
4a–j
5a–j
Entry
R1
R2
R3
R4
H
Product
5a
Yield (%)b
75
1
2
H
H
H
H
H
H
H
H
NO2
OMe
H
H
Me
H
5b
5c
31c
3
H
69
4
CN
Ac
OMe
H
H
5d
5e
31c
5
H
H
32c
6
Me
H
5f
85
7
CH2N(Me)CH2
H
5g
45
8
H
H
H
Cl
H
H
H
5h
5i
54d
66
9
Br
NO2
H
10
H
H
5j
27c
a Reaction conditions: 1 (0.58 mmol) and 4 (0.58 mmol), Pd(OAc)2 (3 mol%), Xantphos (6 mol%), Cs2CO3 (1.5 equiv), dioxane (0.3 M), 90 °C,
4 h, then 1 M aq LiOH (3 equiv), r.t., 30 min.
b Isolated yield after preparative HPLC/MS purification.7
c Required overnight heating for the coupling reaction and overreaction by-product type B was formed.
d Some hydrolysis product of starting pyridine 1 was formed.
Synthesis 2011, No. 15, 2431–2436 © Thieme Stuttgart · New York

PAPER
C2-Amination of 2,4-Dichloropyridines
2433
Table 2 Extending the Scope of the Reactiona
Anilines bearing electron-donating groups gave the high-
est yields (Table 1, entries 3 and 6), comparable to the
standard aniline (entry 1), whereas electron-withdrawing
groups such as nitro (entries 2 and 10), cyano (entry 4),
and 4-acetyl (entry 5) led to lower yields. For these latter
cases, longer reaction times were required, presumably
due to their weak nucleophilicity, compared to the use of
electron-rich N-acetyl anilines (e.g., 4c and 4f). Further-
more, the N-acetyl group on the formed C6 aniline inter-
mediate is probably more labile and is partially cleaved
during the first step (amination reaction), which might ex-
plain the more extensive formation of by-products B. Our
conditions may not be optimal for electron-deficient
anilines and further investigation would be necessary to
achieve improved yields.
Cl
Cl
R
R
a) Pd(0)
b) LiOH
Het
+
AcHN
Het
N
N
N
Cl
H
4k–u
5k–u
1 R = CN
6 R = H
Entry
1
Substrate
4
Product Yield (%)b
AcHN
1
5k
5l
38
N
N
N
Me
AcHN
2
3
4
1
1
1
72c
n/a
n/a
Hindrance of the amino group seemed to have little effect
on the rate of the reaction (Table 1, entries 2, 3 and 6).
Weakly basic aliphatic amine side-chains seemed to give
good conversion in the cross-coupling reaction (entry 7);
however, this substrate was also not very stable under in
situ acetyl deprotection conditions. Complete chemose-
lectivity was observed for halogen-bearing anilines (en-
tries 8 and 9).
N
5m
5n
AcHN
N
H
N
AcHN
AcHN
S
N
5
6
1
1
5o
5p
n/a
n/a
O
Because the versatility of these conditions looked useful
for parallel synthesis, the standard protocol developed in
Table 1 was applied with a wider range of N-acetyl amino
heterocycles; the results are summarized in Table 2.
N
O
N
AcHN
AcHN
7
8
6
6
5q
5r
65d
45
Me
Cl
For these examples, the cross-coupling reaction required
a higher temperature (110 vs. 90 °C) and longer reaction
time (15 vs. 4 h) when 2,4-dichloropyridine (6) was used
instead of pyridine 1 (Table 2, entries 8, 10 and 11 vs.
Table 1, entries 8, 3 and 1, respectively). Some C4-regio-
isomer (type C) could be formed with increasing nucleo-
philicity of the N-acetyl aminoarene 4 when pyridine 6
was employed as starting material. This may be due to the
higher temperature and longer reaction time required (en-
tries 7, 9 and 11), although no C4-regioisomer (type C)
was observed in the case of aniline 4t, bearing an ortho-
methoxy group (entry 10). Additionally, an ortho-cyano
group may hinder the 4-chloro substituent of pyridine 1.
Its absence in pyridine 6 may explain the reduced regiose-
lectivity. An encouraging result also came from the use of
2-amino-6-methylpyridine (4l; entry 2) and acetyl 5-ami-
nopyrazole (4k; entry 1), giving the desired products in 72
and 38% yields, respectively. On the other hand, results
obtained with a number of other heterocycles (entries 3–
6) under these reaction conditions led to the formation of
complex product mixtures, which were not purified.
N
AcHN
AcHN
OMe
OMe
9
6
5s
51e
MeO
AcHN
10
11
6
6
5t
44
MeO
AcHN
5u
42f
a Reaction conditions: 1 (0.58 mmol) or 6 (0.68 mmol), 4 (1 equiv),
Pd(OAc)2 (3 mol%), Xantphos (6 mol%), Cs2CO3 (1.5 equiv), diox-
ane (0.3 M), 90 °C (110 °C for 6), overnight, then 1 M aq LiOH (3
equiv), r.t., 30 min.
b Yield (where purified) after preparative HPLC/MS.7
c Obtained as a mixture with 5 mol% 4,6-bis(6-methylpyridin-2-
ylamino)nicotinonitrile.
d A 95:5 ratio of 5q/B was observed during the coupling reaction.
e A 8:2 ratio 5s/B was observed during the coupling reaction.
f A 9:1 ratio of 5u/B was observed during the coupling reaction.
On a larger scale (55 mmol), the reaction was quite repro-
ducible, and the desired product 3 was obtained in an ac-
ceptable 44% yield (Scheme 1).
In summary, we have shown that the palladium-catalyzed
amination of 4,6-dichloronicotinonitrile (1) can be regio-
selectively performed in acceptable yields with N-acetyl
electron-rich anilines and some aminoheterocycles (e.g.,
3-aminopyrazole and 2-aminopyridine), using Xantphos,
palladium(II) acetate, and cesium carbonate in dioxane at
90 °C. A high preference for coupling at C2 was observed,
but fine-tuning of the reaction conditions is required to
achieve better yields with 2,4-dichloropyridine (6) or with
electron-poor N-acetyl aminoarenes, which was beyond
the scope of this study. The strategy was based on mask-
ing the amine group as an acetamide to avoid arylation
Synthesis 2011, No. 15, 2431–2436 © Thieme Stuttgart · New York

2434
C. Delvare et al.
PAPER
Yield: 13.7 g (44%); pale-yellow solid.
1H NMR (500 MHz, CDCl3): d = 2.15 (s, 1 H), 3.87 (s, 3 H), 6.45
side-reactions that lead to the formation of product B. The
good stability of the N-acetyl group under the reaction
conditions minimizes the formation of products of type B. (br s, 1 H), 6.49 (br s, 1 H), 7.44 (br s, 1 H), 8.35 (s, 1 H).
13C NMR (125 MHz, CDCl3): d = 11.0, 39.3, 100.0, 106.3, 115.43,
117.2, 127.4, 144.7, 146.7, 154.1, 160.6.
MS (ESI): m/z = 248 and 250 [M + H]+.
All starting N-acetyl aminoarenes 4 were purchased from commer-
cial sources or synthesized by known procedures.8 All other re-
agents were purchased from commercial sources and used without
further purification. All reactions were performed in sealed micro-
wave vials under an inert atmosphere of argon, except for the
55 mmol-scale reaction, which was performed in standard glass-
ware. Preparative HPLC/MS was carried out with a Waters auto-
purification system (injector/collector 2767; pump 2525; MS detec-
tor ZQ) using a Waters XBridge 5 mm, reverse-phase column
(19 × 100 mm or 30 × 150 mm) and decreasingly polar mixtures of
H2O (containing 0.2% ammonium carbonate) and MeCN as eluent.
Elemental analyses were performed with a Carlo Erba CHNS EA
1108. High-resolution mass spectra were performed with a Thermo
FT-ICR instrument. NMR spectra were recorded with a Bruker
Avance 500 spectrometer (500 MHz for 1H and 125 MHz for 13C)
relative to TMS as an internal standard. Chemical shifts are ex-
pressed in d units (ppm). Mass spectrometry and purity assessment
at two wavelengths (254 and 310 nm) were carried out with an an-
alytical Waters HPLC/MS system, with positive and negative ion
data collected automatically.
Anal. Calcd for C11H10ClN5: C, 53.34; H, 4.07; N, 28.27. Found: C,
53.11; H, 3.95; N, 27.83.
HRMS (ESI): m/z [M + H]+ calcd for C11H11ClN5: 248.06976;
found: 248.06975.
Palladium-Mediated Amination of Pyridine 1; Typical Proce-
dure
4,6-Dichloronicotinonitrile (1; 100 mg, 0.58 mmol), N-acetyl ami-
noarene 4 (0.58 mmol), Xantphos (20 mg, 0.06 mmol), diacetoxy-
palladium (3.9 mg, 0.02 mmol) and Cs2CO3 (283 mg, 0.87 mmol)
were weighed out and sealed in a microwave vial. Argon-degassed
dioxane (2 mL) was added and the resulting mixture was stirred at
90 °C for 2–6 h. The reaction mixture was allowed to cool to r.t., di-
luted with 1 M aq LiOH (1.8 mL) and stirred at r.t. for 30 min. The
reaction mixture was concentrated, diluted with DMF (1.5 mL),
centrifuged, and the filtrate was purified by preparative HPLC/MS.
The fractions were evaporated to dryness and, depending on the sol-
ubility of the final compound, the residue was triturated in either
EtOAc, pentane, Et2O or a 1:1 mixture of pentane and Et2O. The re-
sulting solid was collected by filtration and dried to afford the title
compound as a solid. Yields are summarized in Table 1.
N-(1,3-Dimethyl-1H-pyrazol-4-yl)acetamide (2)
Acetyl chloride (4.2 mL, 60 mmol) was added dropwise to a suspen-
sion of 1,3-dimethyl-1H-pyrazol-4-amine dihydrochloride salt (10
g, 54 mmol) and Et3N (18.9 mL, 136 mmol) in CH2Cl2 (120 mL)
over a period of 15 min at 25 °C. The resulting suspension was
stirred at 25 °C for 3 h, then the mixture was concentrated and the
residue was taken up in a minimum of CH2Cl2 (ca. 35 mL), the tri-
ethylammonium chloride was removed by filtration and washed
with CH2Cl2 (2 × 15 mL). The filtrate was concentrated in the pres-
ence of silica gel and purified by flash chromatography on silica gel
(MeOH–EtOAc, 2→7%). The solvent was evaporated to dryness to
afford 2.
4-Chloro-6-(phenylamino)nicotinonitrile (5a)
1H NMR (500 MHz, CDCl3): d = 6.82 (s, 1 H, H5), 7.04 (br s, 1 H),
7.25 (t, J = 7.8 Hz, 1 H), 7.32 (dd, J = 7.6, 7.8 Hz, 2 H), 7.43 (t,
J = 7.8 Hz, 2 H), 8.40 (s, 1 H, H2).
13C NMR (125 MHz, CDCl3): d = 100.6, 107.0, 115.3, 123.0, 126.0,
129.9, 137.3, 146.7, 154.0, 158.8.
MS (ESI): m/z = 230 and 232 [M + H]+.
Anal. Calcd for C12H8ClN3: C, 62.76; H, 3.51; N, 18.30. Found: C,
62.99; H, 3.59; N, 18.26.
Yield: 6.2 g (74.5%); pink solid.
1H NMR (700 MHz, DMSO-d6): d = 2.00 (s, 3 H), 2.10 (s, 3 H),
3.70 (s, 3 H), 7.80 (s, 1 H), 9.26 (br s, 1 H).
13C NMR (176 MHz, DMSO-d6): d = 11.58, 23.19, 38.74, 119.08,
124.07, 138.29, 167.50.
HRMS-ESI: m/z [M + H]+ calcd for C7H12N3O: 154.09749; found:
154.09741.
4-Chloro-6-(2-methyl-6-nitrophenylamino)nicotinonitrile (5b)
1H NMR (500 MHz, CDCl3): d = 2.27 (s, 3 H), 6.55 (s, 1 H, H5),
7.38 (dd, J = 7.8, 8.0 Hz, 1 H), 7.60 (d, J = 7.8 Hz, 1 H), 7.85 (br s,
1 H), 7.93 (d, J = 8.0 Hz, 1 H), 8.38 (s, 1 H, H2).
13C NMR (125 MHz, CDCl3): d = 19.0, 102.1, 108.9, 114.8, 123.5,
126.9, 130.4, 136.5, 138.3, 143.8, 146.9, 153.9, 158.0.
MS (ESI): m/z = 330 and 332 [MH + CH3CN]+.
MS (ESI): m/z = 287 and 289 [M – H]–.
4-Chloro-6-(1,3-dimethyl-1H-pyrazol-4-ylamino)nicotinoni-
trile (3)
4,6-Dichloronicotinonitrile (1; 9.6 g, 55 mmol), N-(1,3-dimethyl-
1H-pyrazol-4-yl)acetamide (2; 8.5 g, 55 mmol), diacetoxypalladi-
um (0.374 g, 1.7 mmol), Xantphos (1.9 g, 3.3 mol) and Cs2CO3
(27.1 g, 83 mmol) were weighed out in a flask. Dioxane (110 mL)
was added and argon was allowed to bubble through the reaction
mixture for 5 min at r.t. The resulting suspension was stirred at
90 °C for 2 h, then the reaction mixture was allowed to cool to r.t.
under stirring. H2O (275 mL) was added, followed by portionwise
addition of LiOH·H2O (7 g, 0.17 mol). The resulting solution was
stirred at r.t. for 30 min and the resulting precipitate was collected
by filtration, washed with H2O (2 × 30 mL) and dried to give the
crude product (24 g), which was purified by flash chromatography
on silica gel (0→5% MeOH in EtOAc–CH2Cl2, 1:1). The solvent
was evaporated to dryness and the residue was triturated in Et2O.
The resulting precipitate was collected by filtration, washed with
Et2O and dried to a constant weight to afford 4-chloro-6-(1,3-di-
methyl-1H-pyrazol-4-ylamino)nicotinonitrile.
4-Chloro-6-(2-methoxyphenylamino)nicotinonitrile (5c)
1H NMR (500 MHz, CDCl3): d = 3.90 (s, 3 H), 6.84 (s, 1 H, H5),
6.96 (dd, J = 8.2, 0.9 Hz, 1 H), 7.01 (ddd, J = 8.2, 7.6, 0.9 Hz, 1 H),
7.14 (ddd, J = 7.6, 7.8, 0.9 Hz, 1 H), 7.28 (br s, 1 H), 7.89 (d,
J = 7.8 Hz, 1 H), 8.44 (s, 1 H, H2).
13C NMR (125 MHz, CDCl3): d = 55.7, 100.5, 108.5, 110.9, 115.4,
121.0, 121.3, 125.0, 127.2, 145.9, 150.1, 153.9, 158.1.
MS (ESI): m/z = 260 and 262 [M + H]+.
Anal. Calcd for C13H10ClN3O (10 mol% Et2O): C, 60.26; H, 4.15;
N, 15.73. Found: C, 60.64; H, 3.99; N, 15.88.
4-Chloro-6-(4-cyanophenylamino)nicotinonitrile (5d)
1H NMR (500 MHz, DMSO-d6): d = 6.94 (s, 1 H, H5), 7.11 (br s,
1 H), 7.80 (d, J = 8.9 Hz, 2 H), 7.87 (d, J = 8.9 Hz, 2 H), 8.75 (s,
1 H, H2).
Synthesis 2011, No. 15, 2431–2436 © Thieme Stuttgart · New York

PAPER
C2-Amination of 2,4-Dichloropyridines
2435
13C NMR (125 MHz, DMSO-d6): d = 100.0, 103.9, 111.2, 115.3,
119.1, 119.2, 133.2, 143.6, 143.8, 154.1, 157.3.
13C NMR (125 MHz, DMSO-d6): d = 100.6, 111.6, 115.2, 118.6,
125.1, 141.3, 144.0, 145.7, 154.1, 157.1.
MS (ESI): m/z = 253 and 255 [M – H]–.
MS (ESI): m/z = 273 and 275 [M – H]–.
Anal. Calcd for C13H7ClN4 (30 mol% H2O): C, 60.67; H, 2.86; N,
21.72. Found: C, 60.46; H, 2.59; N, 21.49.
Anal. Calcd for C12H7ClN4O2 (5 mol% pentane): C, 52.87; H, 2.75;
N, 20.13. Found: C, 53.26; H, 2.73; N, 20.34.
6-(4-Acetylphenylamino)-4-chloronicotinonitrile (5e)
1H NMR (500 MHz, CDCl3): d = 2.60 (s, 3 H), 6.95 (s, 1 H, H5),
7.10 (br s, 1 H), 7.51 (d, J = 8.6 Hz, 2 H), 8.01 (d, J = 8.6 Hz, 2 H),
8.50 (s, 1 H, H2).
13C NMR (125 MHz, CDCl3): d = 26.5, 102.1, 109.0, 114.9, 120.0,
130.2, 133.2, 142.3, 146.7, 154.0, 157.3, 196.6.
Palladium-Mediated Amination with Pyridine 6; Typical Pro-
cedure
2,4-Dichloropyridine (6; 100 mg, 0.68 mmol), N-acetyl aminoarene
4 (0.68 mmol), Xantphos (23.5 mg, 0.06 mmol), diacetoxypalladi-
um (4.5 mg, 0.02 mmol) and Cs2CO3 (330 mg, 1.01 mmol) were
weighed out and sealed in a microwave vial. Argon-degassed diox-
ane (2 mL) was added and the resulting mixture was stirred at
110 °C overnight. The reaction mixture was allowed to cool to r.t.,
diluted with a 1 M aq LiOH (2 mL) and stirred at r.t. for 30 min. The
reaction mixture was concentrated, diluted with DMF (1.5 mL),
centrifuged, and the filtrate was purified by preparative HPLC/MS.
The fractions were evaporated to dryness and, depending on the sol-
ubility of the final compound, the residue was triturated in either
EtOAc, pentane, Et2O or a 1:1 mixture of pentane and Et2O. The re-
sulting solid was collected by filtration and dried to afford the title
compound as a solid. Yields are summarized in Table 2.
HRMS-ESI: m/z = 272 and 274 [M + H]+ calcd for C14H11ClN3O:
272.05852; found: 272.05865.
4-Chloro-6-(4-methoxy-2-methylphenylamino)nicotinonitrile
(5f)
1H NMR (500 MHz, CDCl3): d = 2.22 (s, 3 H), 3.83 (s, 3 H), 6.32
(s, 1 H, H5), 6.73 (br s, 1 H), 6.81 (dd, J = 2.6, 8.6 Hz, 1 H), 6.86
(d, J = 2.6 Hz, 1 H), 7.16 (d, J = 8.6 Hz, 1 H), 8.35 (s, 1 H, H2).
13C NMR (125 MHz, CDCl3): d = 18.2, 55.5, 99.7, 105.9, 112.6,
115.5, 116.6, 127.9, 128.3, 136.7, 146.7, 154.1, 159.0, 160.6.
MS (ESI) m/z = 274 and 276 [M + H] +.
4-Chloro-6-(1,3-dimethyl-1H-pyrazol-5-ylamino)nicotinoni-
trile (5k)
1H NMR (500 MHz, CDCl3): d = 2.29 (s, 3 H), 3.69 (s, 3 H), 6.01
(s, 1 H), 6.58 (s, 1 H, H5), 6.68 (br s, 1 H), 8.41 (s, 1 H, H2).
Anal. Calcd for C14H12ClN3O (70 mol% H2O): C, 58.72; H, 4.72; N,
14.67. Found: C, 58.54; H, 4.39; N, 14.42.
13C NMR (125 MHz, CDCl3): d = 14.0, 35.0, 101.3, 102.1, 107.0,
4-Chloro-6-(2-methylisoindolin-4-ylamino)nicotinonitrile (5g)
1H NMR (500 MHz, CDCl3): d = 2.62 (s, 3 H), 3.80 (s, 2 H), 3.98
(s, 2 H), 6.60 (s, 1 H, H5), 6.98 (br s, 1 H), 7.14 (d, J = 7.8 Hz, 1 H),
7.16 (d, J = 8.2 Hz, 1 H), 7.29 (dd, J = 7.8, 8.2 Hz, 1 H), 8.38 (s,
1 H, H2).
13C NMR (125 MHz, CDCl3): d = 42.2, 59.1, 61.2, 100.4, 106.7,
115.3, 120.8, 122.7, 128.5, 131.6, 136.0, 143.3, 146.7, 154.2, 159.0.
114.8, 135.6, 147.5, 148.2, 154.0, 159.3.
MS (ESI): m/z = 248 and 250 [M + H]+.
Anal. Calcd for C11H10ClN5: C, 53.34; H, 4.07; N, 28.27. Found: C,
53.05; H, 3.94; N, 28.15.
4-Chloro-6-(6-methylpyridin-2-ylamino)nicotinonitrile (5l)
1H NMR (500 MHz, CDCl3): d = 2.54 (s, 3 H), 6.87 (d, J = 7.3 Hz,
1 H), 7.13 (d, J = 7.6 Hz, 1 H), 7.59 (dd, J = 7.6, 7.3 Hz, 1 H), 7.71
(br s, 1 H), 8.16 (s, 1 H), 8.46 (s, 1 H).
HRMS (ESI): m/z 285 and 287 [M + H]+ calcd for C15H14ClN4:
285.09015; found: 285.09018.
13C NMR (125 MHz, CDCl3): d = 24.0, 102.3, 109.8, 111.3, 115.1,
4-Chloro-6-(3-chlorophenylamino)nicotinonitrile (5h)
1H NMR (500 MHz, DMSO-d6): d = 6.83 (s, 1 H), 7.06 (s, 1 H),
7.19 (d, J = 6.9 Hz, 1 H), 7.24 (d, J = 7.6 Hz, 1 H), 7.34 (dd,
J = 7.6, 6.9 Hz, 1 H), 7.45 (s, 1 H), 8.43 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 101.5, 108.1, 115.3, 120.3,
122.4, 125.7, 130.8, 135.5, 139.1, 146.8, 154.2, 158.3.
117.8, 138.8, 146.6, 151.4, 151.5, 153.1, 156.3.
HRMS (ESI): m/z 245 and 247 [M + H]+ calcd for C12H10ClN4:
245.05885; found: 245.05893.
4-Chloro-N-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-2-amine
(5q)
MS (ESI): m/z = 262 and 264 [M – H]–.
1H NMR (500 MHz, CDCl3): d = 2.15 (s, 3 H), 3.85 (s, 3 H), 6.11
(br s, 1 H), 6.38 (s, 1 H), 6.65 (d, J = 4.6 Hz, 1 H), 6.41 (s, 1 H),
8.01 (br s, 1 H).
Anal. Calcd for C12H7Cl2N3 (10 mol% pentane): C, 55.33; H, 3.05;
N, 15.49. Found: C, 55.57; H, 2.73; N, 15.18.
13C NMR (125 MHz, CDCl3): d = 11.0, 39.24, 106.3, 114.5, 119.1,
6-(4-Bromophenylamino)-4-chloronicotinonitrile (5i)
1H NMR (500 MHz, DMSO-d6): d = 7.00 (s, 1 H, H5), 7.52 (d,
J = 8.9 Hz, 2 H), 7.63 (d, J = 8.9 Hz, 2 H), 8.66 (s, 1 H, H2), 10.07
(br s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 98.7, 110.1, 114.5, 115.6,
121.7, 131.5, 138.5, 143.3, 154.2, 157.7.
127.2, 144.8, 145.4, 149.1, 159.3.
MS (ESI): m/z = 223 and 225 [M + H]+.
Anal. Calcd for C10H11ClN4 (10 mol% EtOAc): C, 53.96; H, 5.14;
N, 24.20. Found: C, 54.14; H, 4.95; N, 24.28.
4-Chloro-6-(6-methylpyridin-2-ylamino)nicotinonitrile (5r)
1H NMR (500 MHz, CDCl3): d = 6.66 (br s, 1 H), 6.78 (dd, J = 1.8,
5.4 Hz, 1 H), 6.82 (d, J = 1.6 Hz, 1 H), 7.05 (d, J = 7.8 Hz, 1 H),
7.20 (d, J = 8.0 Hz, 1 H), 7.26 (d, J = 7.8, 8.0 Hz, 1 H), 7.44 (dd,
J = 1.8, 1.6 Hz, 1 H), 8.11 (d, J = 5.4 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 108.9, 116.5, 118.8, 120.7, 123.7,
130.7, 135.4, 141.4, 145.6, 149.7, 156.7.
MS (ESI): m/z = 306, 308 and 310 [M – H]–.
Anal. Calcd for C12H7BrClN3: C, 46.71; H, 2.29; N, 13.62. Found:
C, 46.75; H, 2.08; N, 13.48.
4-Chloro-6-(4-nitrophenylamino)nicotinonitrile (5j)
1H NMR (500 MHz, DMSO-d6): d = 7.16 (s, 1 H, H5), 7.94 (d,
J = 8.9 Hz, 2 H), 8.25 (d, J = 8.9 Hz, 2 H), 8.79 (s, 1 H, H2), 10.60
(br s, 1 H).
MS (ESI): m/z = 239 and 241 [M + H]+.
Synthesis 2011, No. 15, 2431–2436 © Thieme Stuttgart · New York

2436
C. Delvare et al.
PAPER
Anal. Calcd for C11H8Cl2N2 (5 mol% pentane): C, 55.67; H, 3.57;
N, 11.54. Found: C, 56.01; H, 3.16; N, 11.23.
pert), Nadine Gondouin (elemental analyses), Bénédicte Delouvrié
(medicinal chemist), and Andrew Williams (intellectual property
attorney).
4-Chloro-N-(3,4,5-trimethoxyphenyl)pyridin-2-amine (5s)
1H NMR (500 MHz, CDCl3): d = 3.85 (s, 9 H), 7.57 (s, 2 H), 6.63
(s, 1 H), 6.72 (d, J = 4.6 Hz, 1 H), 6.78 (s, 1 H), 8.07 (d, J = 4.6 Hz,
1 H).
13C NMR (125 MHz, CDCl3): d = 56.6, 61.4, 100.3, 108.0, 115.6,
135.3, 135.8, 145.6, 149.7, 154.2, 158.0.
References
(1) (a) Tasler, S.; Mueller, O.; Wieber, T.; Herz, T.; Krauss, R.;
Totzke, F.; Kubbutat, M. H. G.; Schaechtele, C. Bioorg.
Med. Chem. Lett. 2009, 19, 1349. (b) Huang, H.; Hutta, D.
A.; Hu, H.; DesJarlais, R. L.; Schubert, C.; Petrounia, I. P.;
Chaikin, M. A.; Manthey, C. L.; Player, M. R. Bioorg. Med.
Chem. Lett. 2008, 18, 2355. (c) Suzuki, T.; Igari, S.;
Hirasawa, A.; Hata, M.; Ishiguro, M.; Fujieda, H.; Itoh, Y.;
Hirano, T.; Nakagawa, H.; Ogura, M.; Makishima, M.;
Tsujimoto, G.; Miyata, N. J. Med. Chem. 2008, 51, 7640.
(d) Adams, J. L.; Faitg, T. H.; Johnsion, N. W.; Pen, X. Int.
Patent Appl. WO 2009/105498, 2009.
(2) Arrington, K. L.; Dudkin, V. Y.; Fraley, M. E.; Wang, C.;
Hoffman, J. M.; Kreatsoulas, C. Int. Patent Appl.
WO 2006/135604, 2006.
(3) Asaki, T.; Sugiyama, Y.; Segawa, J. Int. Patent Appl.
WO 2005/063709, 2005.
(4) (a) Barlaam, B. C.; Foote, K. M.; Ple, P. Int. Patent Appl.
WO 2009/153589, 2009. (b) Barlaam, B.; Foote, K.;
Hassall, L.; Hawkins, J.; Jones, C.; Le Griffon, A.;
Morgentin, R.; Peru, A.; Plé, P. Synth. Commun. 2011, in
press.
(5) Regioselectivity was confirmed by NMR studies on
intermediates and final compounds made by two different
methods.4
MS (ESI): m/z = 295 and 297 [M + H]+.
Anal. Calcd for C14H15ClN2O3 (10 mol% pentane): C, 57.68; H,
5.41; N, 9.28. Found: C, 58.05; H, 5.05; N, 9.19.
4-Chloro-N-(2-methoxyphenyl)pyridin-2-amine (5t)
1H NMR (500 MHz, CDCl3): d = 3.89 (s, 3 H), 6.73 (dd, J = 1.6,
7.5 Hz, 1 H), 6.85 (d, J = 1.5 Hz, 1 H), 6.91 (dd, J = 1.8, 7.7 Hz,
1 H), 6.95–7.04 (m, 3 H), 7.95 (dd, J = 1.8, 7.5 Hz, 1 H), 8.11 (d,
J = 5.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 55.7, 108.8, 110.5, 115.3, 119.2,
120.9, 122.6, 129.3, 144.7, 149.1, 149.2, 156.7.
MS (ESI): m/z = 235 and 237 [M + H]+.
Anal. Calcd for C12H11ClN2O (5 mol% pentane): C, 61.75; H, 4.91;
N, 11.76. Found: C, 62.04; H, 4.60; N, 11.50.
4-Chloro-N-phenylpyridin-2-amine (5u)
1H NMR (500 MHz, CDCl3): d = 6.72 (dd, J = 1.6, 5.5 Hz, 1 H,
H3), 6.84 (d, J = 1.6 Hz, 1 H, H5), 6.85 (br s, 1 H), 7.13 (t,
J = 7.2 Hz, 1 H), 7.30 (d, J = 7.2 Hz, 2 H), 7.36 (dd, J = 7.2, 7.8 Hz,
2 H), 8.08 (d, J = 5.5 Hz, 1 H, H2).
(6) Abad, A.; Agullo, C.; Cunat, A. C.; Vilanova, C. Synthesis
2005, 915.
13C NMR (125 MHz, CDCl3): d = 107.9, 115.8, 121.7, 124.2, 129.9,
140.0, 145.6, 149.7, 157.6.
MS (ESI): m/z = 205 and 207 [M + H]+.
(7) Patrice Koza developed a robust method (0.2% attrition) for
the rapid purification of a wide range of compounds by
preparative HPLC/MS. Koza, P.; unpublished results.
(8) (a) Challis, B. C.; Challis, J. A. In The Chemistry of Amides;
Zabicky, J., Ed.; Wiley: New York, 1970, 731–857.
(b) Vogel, A. I. Vogel’s Textbook of Practical Organic
Chemistry, 5th ed.; Furniss, B. S.; Hannaford, A. J.; Smith,
P. W.; Tatchell, A. R., Eds.; Wiley: New York, 1989, 1273–
1274.
Anal. Calcd for C11H9ClN2 (7 mol% Et2O): C, 64.62; H, 4.66; N,
13.35. Found: C, 65.01; H, 4.23; N, 12.91.
Acknowledgment
The authors would like to especially acknowledge the assistance of
the following scientists: Madeleine Vickers (mass spectroscopy ex-
Synthesis 2011, No. 15, 2431–2436 © Thieme Stuttgart · New York