Synthesis of analogs of the phenylamino-pyrimidine type protein kinase C inhibitor CGP 60474 utilizing a Negishi cross-coupling strategy

Article abstract of DOI:10.1016/j.tet.2005.11.067

Analogs of 3-{4-[2-(3-chlorophenylamino)-pyrimidin-4-yl]-pyridin-2-yl- amino}-propanol (CGP 60474) were synthesized as useful models for the evaluation of structure-activity relationships of phenylamino-pyrimidine-type protein kinase C inhibitors. The app

Full text of DOI:10.1016/j.tet.2005.11.067

Tetrahedron 62 (2006) 2380–2387
Synthesis of analogs of the phenylamino-pyrimidine type protein
kinase C inhibitor CGP 60474 utilizing a Negishi
cross-coupling strategy
*
¨
Peter Stanetty, Ju¨rgen Rohrling, Michael Schnurch and Marko D. Mihovilovic
¨
Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/163-OC, A-1060 Vienna, Austria
Received 5 October 2005; revised 25 November 2005; accepted 28 November 2005
Available online 20 December 2005
Abstract—Analogs of 3-{4-[2-(3-chlorophenylamino)-pyrimidin-4-yl]-pyridin-2-yl-amino}-propanol (CGP 60474) were synthesized as
useful models for the evaluation of structure–activity relationships of phenylamino-pyrimidine-type protein kinase C inhibitors. The
approach involved Pd-assisted cross-coupling as the key step. Negishi-type coupling was performed both with free amino functionalities and
Boc-protected amines present and showed that the protection–cross-coupling–deprotection sequence leads to significantly higher yields.
q 2005 Elsevier Ltd. All rights reserved.
CH3
1. Introduction
N
CH3
Protein kinase C (PKC) plays a crucial role in signal
transductions, cellular proliferation, and differentiation.1
PKC is the term for a whole family of cytosolic serine/
threonine kinases. The individual PKC subtypes show
differences in the mode of activation and in the specificity
with respect to protein substrates.2,3 It has already been
shown in animal tumor models, that different inhibitors of
PKC show cytostatic activity.4,5 Therefore, the discovery
and the development of specific protein kinase inhibitors
will have the potential to define more clearly the respective
functional roles of every protein kinase in cells.
H
N
H
Cl
N
N
N
N
N
N
N
N
HN
O
. CH3SO3H
N
H
OH
CGP 60474
Imatinib, GlivecTM
Figure 1. Significant Phenylamino-pyrimidines.
and its isomer I were prepared in that course via Negishi
cross-coupling from the organozinc 1a as key intermediate
(Scheme 1). This method was now extended to the
preparation of a series of other analogs. With respect to
CGP 60474 one or both of the present heterocycles
(pyrimidine and pyridine) were substituted by other ring
systems (phenyl or pyridine).
Phenylamino-pyrimidines like 3-{4-[2-(3-chlorophenyl-
amino)-pyrimidin-4-yl]-pyridin-2-yl-amino}-propanol
(CGP 60474)6 represent a promising class of inhibitors of
PKC with a high degree of selectivity versus other serine/
threonine and tyrosine kinases and show competitive
kinetics relative to ATP. Imatinib (Glivece),7 a tyrosine
kinase inhibitor with high activity against chronic myeloid
leukemia (CML), was introduced as the first commercial
product of this type to the pharmaceutical market recently
by Novartis (Fig. 1).8,9
2. Results and discussion
The preparation of the title compounds was based on a
recently published strategy.10 The scaffold of CGP 60474
The envisioned target compounds are presented in Figure 2.
From the original pyridinyl-pyrimidine motif in CGP 60474
variations of the pyrimidine and pyridine ring were
undertaken. The target compounds contain therefore a
pyridine–phenyl (2), a pyridine–pyridine (3), and a
pyrimidine–phenyl (4) connection.
Keywords: Negishi cross-coupling; Protein kinase inhibitors; Nucleophilic
displacement; Phenylamino-pyrimidines.
*
Corresponding
e-mail: peter.stanetty@tuwien.ac.at
author.
Fax:
C43
1
58801
15499;
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.11.067

P. Stanetty et al. / Tetrahedron 62 (2006) 2380–2387
2381
I
1
N
F
H
N
H
N
Cl
Cl
N
N
N
N
Met
N
N
ii
i
N
F
OH
N
H
OH
N
H
I
1a
CGP 60474
Scheme 1. (i) Three steps, 70% overall yield. (ii) three steps, 33% overall yield.
H
N
H
N
H
N
Cl
Cl
Cl
N
N
N
N
OH
OH
OH
N
H
N
N
H
N
H
2
3
4
Figure 2. Target compounds 2, 3, and 4.
Compounds 2 and 3 should again be prepared from key
intermediate 1a via a Negishi cross-coupling reaction.11 For
preparation of compound 2, 1a was initially reacted with
3-bromoaniline (5a) under Pd(PPh3)4 catalysis. Since in this
reaction only 37% of the desired cross-coupling product 6a
were obtained (besides 5% of homo-coupling by-product 7),
suitable protection of the amine function was required.
Substrate 5a was Boc-protected via a standard method12 in
88% yield to give 5b. Cross-coupling reaction of this
compound yielded again only 40% of the desired product.
A possible hydrolysis of 1a by the NH proton of carbamate
5b was excluded by initial deprotonation with NaH at room
temperature. This led to no improvement in the cross-
coupling process but N-alkylation of the cross-coupling
product by iodobutane was observed to some extent.
Consequently, the cross-coupling strategy was ‘inverted’
utilizing the organozinc species derived from the Boc-
protected aniline 5b (Scheme 2). The NH-proton of 5b was
removed with MeLi at 15 8C before the metal–halogen
N
F
N
F
I
ZnCl
i
ii
+
5a/b
N
F
N
F
N
F
NHR
1
1a
6a: R = H (37% from 5a)
6b: R = BOC (40% from 5b)
7 (5%)
N
F
Br
ZnCl
iv
v
vi
6a
96%
quant.
NHR
NLiR
NHR
iii
5a: R = H
5c: R = BOC
6b
88%
5b: R = BOC
Scheme 2. (i) n-BuLi, ZnCl2, THF, K75 8C to rt; (ii) Pd(PPh3)4, 5a/b, THF, reflux; (iii) (Boc)2O, THF, reflux; (iv) MeLi, t-BuLi, ZnCl2, THF; (v) Pd(PPh3)4, 1,
THF, reflux; (vi) TFA, CH2Cl2, rt.

2382
P. Stanetty et al. / Tetrahedron 62 (2006) 2380–2387
H
N
N
F
N
F
N
F
Cl
N
i
ii
iii
75%
64%
84%
O
O
O
OH
N
H
N
H
NH2
OH
N
H
6a
8
9
2
Scheme 3. (i) ClCOCH2COOMe, NEt3, THF, 0 8C; (ii) BH3–THF, THF, 0 8C; (iii) HCl, 3-chloroaniline, water/dioxane 4:1, reflux.
exchange was performed at K75 8C with n-BuLi. Sub-
sequent addition of an excess of ZnCl2 gave the desired
organozinc derivative, which was then submitted to the
cross-coupling reaction. Again, some N-alkylated coupling
product was detected. This could be avoided by replacing
n-BuLi with t-BuLi. With these modifications the yield of
6b was optimized to 96%. Subsequent deprotection with
TFA gave 6a quantitatively.
The aminopropanol side chain was introduced by refluxing
13a in 3-aminopropanol10 to give 84% of 3. We found that 3
can be accessed directly from 13b under the conditions of
the nucleophilic displacement in 92% yield due to the
thermal instability of the Boc group.
2.2. Synthesis of target compound 4
The synthesis of 4 is very similar to the route finally applied
to the preparation of target compound 2. In this case, 2,4-
dichloropyrimidine was cross-coupled with 5c under
Negishi conditions to give 75% of desired product 14 and
9% of by-product 15, which is formed in a follow-up
reaction of 14. In contrast to aromatic organozinc
species,16,17 aliphatic organozinc compounds can undergo
a cross-coupling reaction in the 2-position of the pyrimidine
system under thermal conditions. The formation of 15 can
therefore be explained by a cross-coupling reaction of
methylzinc chloride (from excess of MeLi and ZnCl2) with
14. The structure of 14 was confirmed via 2D NMR
experiments (NOE, NOESY). Recently, we have demon-
strated that the 2-position is accessible for cross-coupling
also with aromatic organozincs under microwave
conditions.18
The aminopropanol side chain was introduced via acylation
of 6a in the presence of NEt3 with methyl chlorocarbonyl-
acetate in dry THF to yield 75% of 8. Subsequent reduction
with BH3–THF gave 9 in 64% yield (Scheme 3).
The nucleophilic displacement of the fluorine moiety was
initially performed by heating 9 in an excess of 3-chloro-
aniline to 210–230 8C for 17 h to give 2 in 51% yield.
Optimized yields were obtained performing the reaction
with equimolar amounts of HCl under reflux in a water–
dioxane (4/1) mixture for 48 h providing 2 in 84% yield.
2.1. Synthesis of target compound 3
In the case of the target bipyridinyl 3, a different strategy
had to be employed since an immediate cross-coupling
reaction of intermediate 1a with 1 would lead to the
symmetric compound 7 with no selectivity for the
nucleophilic displacements of the two fluoro atoms.
Hence, one nucleophilic displacement had to be performed
before the cross-coupling step. The challenge of this
approach lies in the similar reactivity of positions 2 and 4
in the halogenated pyridine substrate. Indeed, when the
reaction was carried out under standard reaction con-
ditions13 we did not observe selectivity between these two
positions. Instead of the desired mono substituted 10,
di-substituted compound 11 was obtained as the major
product only accompanied by starting material. Milder
reaction conditions did not give any conversion. An option
to overcome this problem is proton catalyzed activation of
the pyridine system, which activates the 2-position.14,15 In
an optimization approach aqueous reaction conditions
proved to be crucial and compound 10 was obtained in
66% yield only accompanied by small amounts of by-
product 11 (9%).
The Boc group was then cleaved to give 16 (97%), followed
by introduction of the side chain as already described for
the synthesis of 2. Acylation of the amine function gave
75% of 17. Reduction of 17 with BH3–THF failed to give
the desired compound even under very mild reaction
conditions (ice cooling) only leading to decomposition of
the heterocyclic system. In order to decrease the high
reactivity of the 2-position in the pyrimidine part
3-chloroaniline was introduced prior to the reduction of
the side chain in this series. The nucleophilic displacement
was performed in dry dioxane under p-TSA-catalysis at
reflux and yielded 18 in 90%. The reduction with BH3–THF
at this stage finally gave 4 in a satisfactory 58% yield
(Scheme 5).
3. Conclusion
Based on the synthesis of CGP 60474 we developed
suitable reaction sequences for the formation of all three
target compounds (2, 3, and 4). Compound 2 was
synthesized starting from 3-bromoaniline and 2-fluoro-4-
iodopyridine (1, prepared from commercially available
2-fluoropyridine in two steps and improved 88% yield
compared to the literature19,20) in six steps with 34%
overall yield, compound 4 was obtained in five steps from
The Negishi reaction was performed with coupling partner
10 and gave an optimized 37% of 13a besides starting
material 10. Boc-protection of the amine (12, 80%)
improved substantially the yield in the cross-coupling step
giving 13b in 73%. Cleavage of the Boc group via a
standard protocol yielded 13a quantitatively (Scheme 4).

P. Stanetty et al. / Tetrahedron 62 (2006) 2380–2387
2383
H
H
I
Cl
N
I
N
N
N
i
+
N
F
Cl
10 (66%)
HN
Cl
1
11 (9%)
ii
iii
37%
80%
BOC
BOC
H
N
N
N
N
N
N
N
v
iv
100%
73%
Cl
Cl
Cl
I
N
F
12
F
13b
13a
vi 92%
vi
84%
H
N
N
N
3
Cl
OH
N
H
Scheme 4. (i) HCl, 3-chloroaniline, water/dioxane 4:1, reflux; (ii) (1) n-BuLi, ZnCl2, THF, K75 8C to rt; than Pd(PPh3)4, 10, THF, reflux; (iii) NaH, (Boc)2O,
THF, reflux; (iv) 1, n-BuLi, ZnCl2, THF, K75 8C to rt; (2) Pd(PPh3)4, 12, THF, reflux; (v) TFA, CH2Cl2, rt; (vi) 3-aminopropanol, reflux.
N
Cl
N
N
Cl
I
N
N
N
i
ii
+
97%
NHBOC
NH2
NHBOC
NHBOC
5b
15 (9%)
14 (75%)
16
iii 75%
H
N
H
N
N
Cl
Cl
Cl
N
N
N
N
N
v
iv
90%
58%
O
O
O
O
O
N
OH
O
N
H
N
H
H
4
18
17
Scheme 5. (i) (1) n-BuLi, ZnCl2, THF, K75 8C to rt; (2) 2,4-dichloropyrimidine, Pd(PPh3)4, THF, reflux; (ii) TFA, CH2Cl2, rt; (iii) ClCOCH2COOMe, NEt3,
THF, 0 8C; (iv) 3-chloroaniline, p-TSA$H2O, dioxane, reflux; (v) BH3–THF, THF, 0 8C.
3-bromoaniline and 2,4-dichloropyrimidine with 26% over-
all yield, and compound 3 was formed starting from 1 in
four steps and 35% overall yield. The results of the
biological screening of the title compounds showed no
improved fungicidal activity compared to CGP 60474 and
will be published elsewhere.
4. Experimental
4.1. General
Melting points were determined using a Kofler-type Leica
Galen III micro hot stage microscope and are uncorrected.

2384
P. Stanetty et al. / Tetrahedron 62 (2006) 2380–2387
Combustion analysis was carried out in the Microanalytical
Laboratory, Institute of Physical Chemistry, University of
Vienna. Flash column chromatography was performed on
silica gel 60 from Merck 40–63 mm). NMR-spectra were
recorded from CDCl3 or d6-DMSO solutions on a Bruker
AC 200 (200 MHz) or Bruker Avance UltraShield 400
(400 MHz) spectrometer and chemical shifts are reported in
ppm using TMS as internal standard.
was boiled for 5 min. After cooling to room temperature,
water was added and the solution was adjusted to basic
pH with saturated aqueous Na2CO3 solution. The mixture
was extracted with ethyl acetate, the combined organic
layers were dried over Na2SO4, and the solvent was
removed under reduced pressure. The crude material was
purified by column chromatography (LP/EtOAc 1:1/1:2)
to give 4 as yellow crystals (0.52 g, 1.47 mmol, 58%); mp
100–102 8C (DIPE); 1H NMR (d6-DMSO, 200 MHz): d
3
3
1.78 (quin, JZ6.6 Hz, 2H), 3.18 (m, 2H), 3.59 (t, JZ
4.1.1. 3-{3-[2-(3-Chlorophenylamino)-pyridin-4-yl]-phenyl-
amino}-propanol (2). Substrate 9 (0.50 g, 2.03 mmol,
1 equiv), 1.6 N HCl (1.3 mL, 2.03 mmol, 1 equiv) and
3-chloroaniline (1.5 mL, 14.2 mmol, 7 equiv) were dis-
solved in 20 mL of a water–dioxane mixture (4/1) and
refluxed for 48 h. The solution was poured onto water,
adjusted to basic pH with saturated aqueous Na2CO3
solution, and extracted with ethyl acetate. The combined
organic layers were dried over Na2SO4 and the solvent was
removed under reduced pressure. The crude product was
purified by column chromatography (LP/EtOAc 2:1/1:2)
to give 2 as a brown oil (0.60 g, 1.70 mmol, 84%); 1H NMR
(d6-DMSO, 200 MHz): d 1.79 (quin, 3JZ6.6 Hz, 2H), 3.14
(m, 2H), 3.55 (m, 2H), 4.58 (br s, 1H), 5.73 (br s, 1H), 6.68
(d, 3JZ7.6 Hz, 1H), 6.75–6.95 (m, 3H), 7.02 (d, 3JZ
3
6.6 Hz, 2H), 4.52 (br s, 1H), 5.73 (t, JZ6.6 Hz, 1H), 6.78
(m, 1H), 6.99 (m, 1H), 7.15–7.45 (m, 5H), 7.78 (m, 1H),
3
8.11 (m, 1H), 8.56 (d, JZ5.6 Hz, 1H), 9.84 (s, 1H); 13C
NMR (d6-DMSO, 50 MHz): dZ31.9 (t), 40.0 (t), 58.7 (t),
108.6 (d), 109.2 (d), 114.3 (d), 115.3 (d), 117.0 (d), 117.8
(d), 120.6 (d), 129.2 (d), 130.0 (d), 133.0 (s), 137.2 (s),
142.7 (s), 149.5 (s), 158.7 (d), 159.8 (s), 164.6 (s). Anal.
Calcd for C19H19ClN4O (354.84): C, 64.31; H, 5.40; N,
15.79. Found: C, 64.06; H, 5.60; N, 15.66.
4.1.4. N-(3-Bromophenyl)-carbamic acid 1,1-dimethyl-
ethyl ester (5b). 3-Bromoaniline (7.00 g, 40.7 mmol,
1 equiv) and (Boc)2O (9.16 g, 40.7 mmol, 1 equiv) were
refluxed in dry THF (120 mL) for 65 h. The solvent was
evaporated in vacuo and the crude product was washed
twice with cold LP to afford 8 as colorless crystals (9.72 g,
3
5.5 Hz, 1H), 7.08 (s, 1H), 7.20 (t, JZ7.6 Hz, 1H), 7.27 (t,
3JZ8.5 Hz, 1H,), 7.56 (d, 1H), 8.09 (s, 1H), 8.24 (d, 1H),
9.37 (s, 1H); 13C NMR (d6-DMSO, 50 MHz): d 32.0 (t),
40.0 (t), 58.8 (t), 108.3 (d), 109.6 (d), 112.9 (d), 113.2 (d),
113.8 (d), 116.2 (d), 117.0 (d), 119.7 (d), 129.7 (d), 130.1
(d), 133.2 (s), 138.6 (s), 143.4 (s), 147.7 (d), 149.7 (s, 2C),
156.1 (s).
1
35.7 mmol, 88%); mp 85–86 8C (LP); H NMR (CDCl3,
200 MHz): d 2.51 (s, 9H), 6.54 (br s, 1H), 7.06–7.26 (m,
3H), 7.66 (m, 1H); 13C NMR (CDCl3, 50 MHz): d 28.2 (q),
80.9 (s), 116.9 (d), 121.3 (d), 122.6 (s), 125.8 (d), 130.1 (d),
139.7 (s), 152.4 (s).
4.1.2. 3-{[20-(3-Chlorophenylamino)-[4,40]-bipyridinyl-
2-yl]-amino}-propanol (3). Substrate 13b (0.50 g,
1.25 mmol) or 13a (0.20 g, 0.67 mmol) were refluxed in
an excess of 3-aminopropanol (20 mL) for 3 h. The mixture
was cooled with ice and water was added (80 mL). The
crude product, precipitated as sticky oil, was dissolved in
ethyl acetate and subsequently washed with water (2!) and
brine. The organic solution was dried over Na2SO4 and the
solvent removed in vacuo to afford 3 as yellow crystals
(0.41 g, 1.16 mmol, 92% in the case of starting material
13b; 0.20 g, 0.56 mmol, 84% in the case of starting material
13a); mp 138–140 8C (EtOAc); 1H NMR (d6-DMSO,
4.1.5. 3-(2-Fluoropyridin-4-yl)-phenylamine (6a).
Method A. Compound 6b (6.17 g, 21.4 mmol, 1 equiv)
was suspended in dry dichloromethane (80 mL) and
trifluoroacetic acid (25 mL, 15.7 equiv) was added. The
mixture was stirred for 2 h at room temperature. The
solution was poured onto water, adjusted to basic pH with
saturated aqueous Na2CO3 solution, and extracted with
ethyl acetate. The combined organic layers were dried over
Na2SO4 and concentrated in vacuo to afford 6a as yellow
crystals (4.02 g, 21.4 mmol, 100%);
Method B. 2-Fluoro-4-iodo-pyridine 1 (0.97 g, 4.36 mmol,
1.5 equiv) was dissolved in dry THF (30 mL) and n-BuLi in
hexane (2.1 mL, 2.29 M, 4.80 mmol, 1.65 equiv) was added
at K75 8C. After stirring for 30 min, freshly dried ZnCl2
(0.59 g, 4.36 mmol, 1.5 equiv) in dry THF (5 mL) was
added. The mixture was allowed to warm to room
temperature. Pd(PPh3)4 (0.03 g, 0.03 mmol, 0.01 equiv)
and 3-bromoaniline (0.50 g, 2.91 mmol, 1 equiv) in dry
THF (10 mL) were added and the mixture was refluxed for
4 h. The mixture was poured onto water, adjusted to basic
pH with 2 N NaOH solution, and extracted with diethyl
ether. The combined organic layers were dried over Na2SO4
and concentrated in vacuo. The residue was subjected to
column chromatography (LP/EtOAc 7:1) to afford 6a as
yellow crystals (0.20 g, 1.06 mmol, 37%); mp 110–112 8C
3
200 MHz): d 1.70 (quin, JZ6.6 Hz, 2H), 3.35 (m, 2H),
3
3
3.50 (q, JZ6.6 Hz, 1H), 4.53 (t, JZ6.6 Hz, 1H), 6.63–
3
4
6.80 (m, 3H), 6.91 (m, 1H), 7.02 (dd, JZ5.3 Hz, JZ
1.1 Hz, 1H), 7.09 (s, 1H), 7.27 (t, 3JZ8.0 Hz, 1H), 7.52 (m,
3
1H), 8.00–8.13 (m, 2H), 8.28 (d, JZ5.5 Hz, 1H), 9.40 (s,
1H); 13C NMR (d6-DMSO, 50 MHz): d 32.4 (t), 38.1 (t),
58.7 (t), 104.9 (d), 108.3 (d), 109.0 (d), 112.6 (d), 116.3 (d),
117.1 (d), 119.9 (d), 130.1 (d), 133.2 (s), 143.2 (s), 145.8 (s),
147.2 (s), 148.1 (d), 148.7 (d), 156.1 (s), 159.8 (s). Anal.
Calcd for C19H19ClN4O (354.84): C, 64.31; H, 5.40; N,
15.79. Found: C, 64.18; H, 5.30; N, 15.53.
4.1.3. 3-{3-[2-(3-Chlorophenylamino)-pyrimidin-4-yl]-
phenylamino}-propanol (4). BH3–THF complex
(23.5 mL, 1 M in THF, 23.5 mmol, 10.7 equiv) was cooled
to 0 8C and 18 (1.00 g, 2.52 mmol, 1 equiv) in dry THF
(20 mL) was added dropwise within 15 min. The mixture
was stirred for 15 min at 0 8C and for 5 h at room
temperature. 6 N HCl (20 mL) was added and the mixture
1
(methanol); H NMR (d6-DMSO, 200 MHz): d 5.32 (br s,
4
2H), 6.68–6.75 (m, 1H), 6.88–6.93 (m, 1H), 6.98 (t, JZ
3
1.8 Hz, 1H), 7.17 (t, JZ8.0 Hz, 1H), 7.32 (s, 1H), 7.47–
7.52 (m, 1H), 8.25 (d, 3JZ5.6 Hz 1H); 13C NMR
2
(d6-DMSO, 50 MHz): d 106.2 (d, JCFZ38 Hz), 112.0 (d),

P. Stanetty et al. / Tetrahedron 62 (2006) 2380–2387
2385
3
1
114.5 (d), 115.5 (d), 119.4 (d, 4JCFZ4 Hz), 129.8 (d), 136.7
(s, 4JCFZ3 Hz), 147.9 (d, 3JCFZ16 Hz), 149.4 (s), 154.2 (s,
(s, JCFZ8 Hz), 164.0 (s, JCFZ235 Hz), 164.4 (s), 168.1
(s). Anal. Calcd for C15H13FN2O3 (288.28): C, 62.50; H,
4.55; N, 9.72. Found: C, 62.27; H, 4.64; N, 9.64.
1
3JCFZ8 Hz), 164.0 (s, JCFZ234 Hz). Anal. Calcd for
C11H9FN2 (188.20): C, 70.20; H, 4.82; N, 14.88. Found: C,
69.91; H, 4.74; N, 14.81.
4.1.9. 3-[3-(2-Fluoropyridin-4-yl)-phenylamino]-propanol
(9). BH3–THF complex (25.5 mL, 1 M in THF, 25.5 mmol,
3.67 equiv) was cooled to 0 8C and 8 (2.00 g, 6.94 mmol,
1 equiv) in dry THF (30 mL) was added dropwise within
15 min. After additional stirring for 15 min at 0 8C, the
mixture was refluxed for 2 h. After cooling to room
temperature water was added and the mixture was stirred
for 1 h. The solution was adjusted to basic pH with saturated
aqueous Na2CO3 solution. The mixture was extracted with
diethyl ether, the combined organic layers were dried over
Na2SO4, and the solvent was removed under reduced
pressure. The crude product was purified by column
chromatography (LP/EtOAc 1:1/1:2) to give 9 as yellow
crystals (1.10 g, 4.47 mmol, 64%); mp 88–90 8C (DIPE); 1H
NMR (d6-DMSO, 200 MHz): d 1.75 (quin, 3JZ6.6 Hz, 2H),
3.18 (q, 3JZ6.6 Hz, 2H), 3.58 (q, 3JZ6.6 Hz, 2H), 4.52 (t,
4.1.6. N-[3-(2-Fluoropyridin-4-yl)-phenyl]-carbamic
acid 1,1-dimethylethyl ester (6b). Substrate 5b (6.10 g,
22.4 mmol, 1 equiv) was dissolved in dry THF (200 mL)
and MeLi in diethyl ether (17.1 mL, 1.44 M, 24.7 mmol,
1.1 equiv) was added at room temperature. After 30 min the
mixture was cooled to K85 8C and t-BuLi in pentane
(37.1 mL, 1.33 M, 49.3 mmol, 2.2 equiv) was added. The
solution was stirred at K85 8C for 30 min. Then freshly
dried ZnCl2 (10.1 g, 74.0 mmol, 3.3 equiv) in dry THF
(80 mL) was added. After 30 min the reaction mixture was
allowed to warm to room temperature. Pd(PPh3)4 (0.25 g,
0.22 mmol) and 1 (5.00 g, 22.4 mmol, 1 equiv) in dry THF
(25 mL) were added and the mixture was refluxed for 1 h.
The cooled solution was poured onto a solution of EDTA
(22 g) in water (300 mL), and adjusted to basic pH with
saturated aqueous Na2CO3 solution. The mixture was
extracted with diethyl ether, the combined organic layers
were dried over Na2SO4, and the solvent was removed under
reduced pressure to give 9 as yellow crystals (6.18 g,
3JZ6.6 Hz, 1H), 5.76 (t, JZ6.6 Hz, 1H), 6.70 (d, JZ
8.2 Hz, 1H), 6.90–7.00 (m, 2H), 7.22 (t, JZ8.2 Hz, 1H),
3
3
3
3
5
7.38 (s, 1H), 7.55–7.60 (m, JZ5.1 Hz, JZ1.5 Hz, 1H),
8.25 (d, JZ5.1 Hz, 1H); 13C NMR (d6-DMSO, 50 MHz): d
32.0 (t), 39.8 (t), 58.7 (t), 106.3 (d, 2JCFZ38 Hz), 109.7 (d),
113.7 (d), 114.1 (d), 119.6 (d, 4JCFZ4 Hz), 129.7 (d), 136.8
(s, 4JCFZ3 Hz), 147.9 (d, 3JCFZ16 Hz), 149.8 (s), 154.3 (s,
1
21.4 mmol, 96%); mp 181–184 8C (DIPE); H NMR (d6-
DMSO, 200 MHz): d 1.52 (s, 9H), 7.30–7.65 (m, 3H), 7.48–
7.65 (m, 2H), 7.92 (s, 1H), 8.30 (d, 3JZ5.3 Hz, 1H), 9.52 (s,
1H); 13C NMR (d6-DMSO, 50 MHz): d 28.1 (q), 79.3 (s),
3JCFZ8.4 Hz), 164.0 (s, JCFZ234 Hz). Anal. Calcd for
1
C14H15FN2O (246.28): C, 68.28; H, 6.14; N, 11.37. Found:
C, 68.08; H, 6.24; N, 11.26.
2
106.4 (d, JCFZ39 Hz), 116.4 (d), 119.5 (d), 119.6 (d,
4
4JCFZ4 Hz), 120.7 (d), 129.6 (d), 136.5 (s, JCFZ4 Hz),
140.4 (s), 148.1 (d, 3JCFZ16 Hz), 152.8 (s), 153.4 (s, 3JCF
8 Hz), 164.0 (s, JCFZ235 Hz). Anal. Calcd for
C16H17FN2O2 (288.32): C, 66.65; H, 5.94; N, 9.72.
Found: C, 66.52; H, 5.78; N, 9.56.
Z
4.1.10. N-(3-Chlorophenyl)-4-iodo-2-pyridinamine (10).
Substrate 1 (4.00 g, 17.9 mmol, 1.2 equiv), 3-chloroaniline
(1.91 g, 14.9 mmol, 1 equiv) and 1.6 N HCl (9.3 mL,
14.9 mmol, 1 equiv) were dissolved in a water–dioxane
mixture (9/1, 250 mL) and refluxed for 22 h. Dioxane
(30 mL) was added and the mixture was refluxed for further
24 h. The solvents were evaporated and the residue was
suspended in a saturated aqueous Na2CO3 solution
(150 mL). After extraction with diethyl ether, the combined
organic layers were dried over Na2SO4 and concentrated.
The crude material was triturated with LP–EtOAc (4/1) to
give crystalline 10 (2.85 g), which was dried in vacuo. The
mother liquor was concentrated and the residue was purified
by column chromatography (LP/EtOAc 4:1/1:1) to obtain
a second fraction of 10 (0.40 g). Total yield: 3.25 g
(9.83 mmol, 66%) of 10 as colorless crystals; mp
127–129 8C (LP); Rf 0.40 (LP/EtOAc 4:1); 1H NMR
(d6-DMSO, 400 MHz): d 6.94 (ddd, JZ8.1 Hz, JZ1.8,
1.2 Hz, 1H), 7.16 (dd, 3JZ5.5 Hz, 4JZ1.5 Hz, 1H),
7.23–7.34 (m, 2H), 7.45 (ddd, 3JZ8.1 Hz, 4JZ1.8,
1.2 Hz, 1H), 7.91 (d, JZ5.5 Hz, 1H), 7.96 (t, JZ1.8 Hz,
1H), 9.32 (s, 1H); 13C NMR (d6-DMSO, 100 MHz): d 106.3
(s), 116.5 (d), 117.3 (d), 119.5 (d), 120.3 (d), 123.2 (d),
130.1 (d), 133.1 (s), 142.5 (s), 147.8 (d), 155.7 (s). Anal.
Calcd for C11H8ClIN2 (330.56): C, 39.97; H, 2.44; N, 8.47.
Found: C, 40.25; H, 2.61; N, 8.31.
1
4.1.7. 2,20-Difluoro-[4,40]-bipyridinyl (7).21 Compound 7
was formed as by-product during the formation of 6a
according to method B. Colorless crystals (20 mg,
0.10 mmol, 5%); Rf 0.60 (LP/EtOAc 2:1). Anal. Calcd for
C10H6F2N2 (192.17): C, 62.50; H, 3.15; N, 14.58. Found: C,
62.21; H, 3.29; N, 14.33.
4.1.8. 3-{[3-(2-Fluoropyridin-4-yl)-phenyl]-amino}-3-
oxopropanoic acid methyl ester (8). Substrate 6a (2.00 g,
10.6 mmol, 1 equiv) and triethylamine (1.18 g, 11.7 mmol,
1.1 equiv) were dissolved in dry THF (30 mL) and cooled to
0 8C. 3-Chloro-3-oxopropanoic acid methyl ester (1.60 g,
11.7 mmol, 1.1 equiv) in dry THF (3 mL) was added
dropwise within 10 min. After stirring for 2 h at 0 8C the
mixture was poured onto water and extracted with ethyl
acetate. The combined organic layers were washed with
saturated aqueous NaCl solution, dried over Na2SO4, and
the solvent was removed in vacuo. The crude product was
purified by column chromatography (LP/EtOAc 1:1) to
yield 8 as orange crystals (2.31 g, 8.01 mmol, 75%); mp
72–75 8C (EtOAc); 1H NMR (d6-DMSO, 200 MHz): d 3.55
(s, 2H), 3.68 (s, 3H), 7.40 (s, 1H), 7.47–7.56 (m, 2H), 7.56–
7.63 (m, 1H), 7.64–7.72 (m, 1H), 8.03 (s, 1H), 8.32 (d, 3JZ
5.1 Hz, 1H), 10.4 (s, 1H); 13C NMR (d6-DMSO, 50 MHz): d
3
4
4.1.11. N2,N4-Bis-(3-chlorophenyl)-pyridine-2,4-
diamine (11). Formed as by-product during the formation
2
43.5 (t), 52.0 (q), 106.6 (d, JCFZ39 Hz), 117.5 (d), 119.6
of 10. 0.22 g (0.60 mmol, 9%); 1H NMR (d6-DMSO,
4
3
4
(d, JCFZ4 Hz), 120.5 (d), 122.3 (d), 129.8 (d), 136.7
400 MHz): d 6.43 (dd, 1H, JZ6.0 Hz, JZ1.8 Hz), 6.51
(d, JZ1.8 Hz, 1H), 6.85 (ddd, 1H, JZ8.2 Hz, JZ2.4,
4
3
3 4
(s, JCFZ3 Hz), 139.6 (s), 148.2 (d, JCFZ16 Hz), 153.1

2386
P. Stanetty et al. / Tetrahedron 62 (2006) 2380–2387
2
1.4 Hz), 7.03 (ddd, 1H, 3JZ8.2 Hz, 4JZ2.4, 1.4 Hz), 7.13–
13C NMR (d6-DMSO, 50 MHz): d 107.0 (d, JCFZ39 Hz),
3
4
108.8 (d), 112.6 (d), 116.4 (d), 117.2 (d), 119.6 (d, JCF
7.28 (m, 3H), 7.35 (t, 1H, JZ8.2 Hz), 7.40–1.48 (m, 1H),
Z
4 Hz), 120.1 (d), 130.1 (d), 133.1 (s), 142.9 (s), 144.6 (s,
3
4
7.95 (d, JZ6.0 Hz, 1H), 8.02 (t, JZ2.4 Hz, 1H), 8.82 (s,
1H), 9.02 (s, 1H); 13C NMR (d6-DMSO, 100 MHz): d 94.3
(d), 104.5 (d), 116.0 (d), 116.9 (d), 117.8 (d), 118.8 (d),
119.2 (d), 119.9 (d), 129.8 (d), 130.7 (d), 133.1 (s), 133.7
(s), 142.6 (s), 143.6 (s), 147.9 (s), 150.3 (s), 156.6 (d). Anal.
Calcd for C17H13Cl2N3$HCl (366.68): C, 55.69; H, 3.85; N,
11.46. Found: C, 55.83; H, 3.87; N, 11.17.
4JCFZ3 Hz), 148.4 (d), 148.5 (d, JCFZ15 Hz), 151.1 (s,
3
3JCFZ8 Hz), 156.2 (s), 164.0 (s, JCFZ235 Hz). Anal.
Calcd for C16H11ClFN3 (299.74): C, 64.12; H, 3.70; N,
14.02. Found: C, 63.97; H, 3.68; N, 13.84.
1
4.1.14. N-(3-Chlorophenyl)-N-(20-fluoro-[4,40]-bipyridinyl-2-
yl)-carbamic acid 1,1-dimethylethyl ester (13b). n-BuLi
in hexane (4.2 mL, 2.29 M, 9.54 mmol, 1.48 equiv) was
added to 2-fluoro-4-iodo-pyridine (1.93 g, 8.67 mmol,
1.33 equiv) in dry THF (100 mL) at K75 8C within
10 min. After 30 min freshly dried ZnCl2 (1.18 g,
9.54 mmol, 1.48 equiv) in dry THF (10 mL) was added.
The reaction mixture was warmed to room temperature and
Pd(PPh3)4 (0.04 g, 0.003 mmol, 0.0005 equiv) and 12
(2.80 g, 6.50 mmol, 1 equiv) in dry THF (15 mL) were
added. After refluxing for 1.5 h the solution was poured onto
water, adjusted to basic pH with saturated aqueous Na2CO3
solution, and extracted with diethyl ether. The combined
organic layers were dried over Na2SO4 and concentrated in
vacuo. The residue was recrystallized from EtOAc to afford
13b as colorless crystals (1.90 g, 4.75 mmol, 73%); mp
4.1.12. N-(3-Chlorophenyl)-N-(4-iodopyridin-2-yl)-
carbamic acid 1,1-dimethylethyl ester (12). Substrate 10
(3.50 g, 10.6 mmol, 1 equiv) was dissolved in dry THF
(50 mL), deprotonated with NaH (0.30 g, 12.7 mmol,
1.2 equiv) and treated with (Boc)2O (2.86 g, 12.7 mmol,
1.2 equiv) in dry THF (10 mL). The mixture was refluxed
for 3 h, poured onto water, and extracted with diethyl ether.
The combined organic layers were dried over Na2SO4 and
concentrated. The crude product was purified by column
chromatography (LP/EtOAc 8:1) to give 12 as colorless
crystals (3.65 g, 8.48 mmol, 80%); mp 91–94 8C (EtOAc);
1H NMR (d6-DMSO, 200 MHz): d 1.39 (s, 9H), 7.11–7.19
(m, 1H), 7.28–7.40 (m, 3H), 7.63 (dd, 1H, 3JZ5.1 Hz, 4JZ
3
1.3 Hz), 8.01 (d, JZ5.1 Hz, 1H), 8.08 (m, 1H); 13C NMR
1
(d6-DMSO, 50 MHz): d 27.6 (q), 81.7 (s), 107.0 (s), 126.4
(d), 126.6 (d), 127.7 (d), 129.2 (d), 129.6 (d), 130.2 (d),
132.7 (s), 142.4 (s), 148.5 (d), 152.2 (s), 154.5 (s). Anal.
Calcd for C16H16ClIN2O2 (430.67): C, 44.62; H, 3.74; N,
6.50. Found: C, 44.80; H, 3.79; N, 6.40.
172–175 8C (EtOAc); H NMR (d6-DMSO, 200 MHz): d
3
4
1.40 (s, 9H), 7.19 (dt, JZ8.2 Hz, JZ2.0 Hz, 1H), 7.26–
7.42 (m, 3H), 7.68 (s, 1H), 7.72 (dd, 3JZ5.2 Hz, 4JZ
3
1.5 Hz, 1H), 7.77–7.83 (m, 1H), 8.07 (s, 1H), 8.41 (d, JZ
5.2 Hz, 1H), 8.49 (d, 3JZ5.2 Hz, 1H); 13C NMR (d6-
2
DMSO, 50 MHz): d 27.8 (q), 81.7 (s), 107.4 (d, JCF
Z
4
4.1.13. N-(3-Chlorophenyl)-N-(20-fluoro-[4,40]-bipyridinyl-2-
yl)amine (13a). Method A. Substrate 13b (0.80 g,
2.00 mmol, 1 equiv) was suspended in dry dichloromethane
(30 mL) and trifluoroacetic acid (1.5 mL, 2.02 mmol,
1.01 equiv) was added. The mixture was stirred at room
temperature for 3 h, poured onto water, adjusted to basic
pH with saturated aqueous Na2CO3 solution and extracted
with ethyl acetate. The combined organic layers were dried
over Na2SO4 and concentrated in vacuo to give 6 as yellow
crystals (0.60 g, 100%).
39 Hz), 119.1 (d), 119.3 (d), 119.9 (d, JCFZ4 Hz), 126.3
(d), 126.4 (d), 127.4 (d), 130.3 (d), 132.8 (s), 142.8 (s),
3
145.3 (s), 148.8 (d, JCFZ16 Hz), 149.4 (d), 150.1 (s,
3JCFZ8 Hz), 152.5 (s), 155.5 (s), 164.0 (s, JCFZ239 Hz).
Anal. Calcd for C21H19ClFN3O2 (399.85): C, 63.08; H,
4.79; N, 10.51. Found: C, 62.82; H, 4.78; N, 10.41.
1
4.1.15. N-[3-(2-Chloropyrimidin-4-yl)-phenyl]-carbamic
acid 1,1-dimethylethyl ester (14). Substrate 5b (4.57 g,
16.8 mmol, 1 equiv) was dissolved in dry THF (120 mL)
and MeLi in diethyl ether (12.8 mL, 1.44 M, 18.5 mmol,
1.1 equiv) was added dropwise at C15 8C. After stirring for
30 min, the mixture was cooled to K85 8C and t-BuLi in
pentane (27.6 mL, 1.34 M, 37.0 mmol, 2.2 equiv) was
added dropwise. The solution was stirred for 30 min at
K75 8C and freshly dried ZnCl2 (7.55 g, 55.4 mmol,
3.3 equiv) in dry THF (80 mL) was added. The mixture
was stirred for further 30 min and then allowed to warm to
room temperature. Pd(PPh3)4 (0.19 g, 0.16 mmol,
0.01 equiv) and 2,4-dichloropyrimidine (2.50 g,
16.8 mmol, 1 equiv) in dry THF (15 mL) were added, and
the mixture was refluxed for 1 h. The solution was poured
onto a solution of EDTA (17 g) in water (200 mL), which
was adjusted to basic pH with saturated aqueous Na2CO3
solution, and extracted with diethyl ether. The combined
organic layers were dried over Na2SO4 and the solvent was
removed under reduced pressure. The crude product was
purified by column chromatography (LP/EtOAc 3:1/1:1)
to give 14 as yellow crystals (3.87 g, 12.7 mmol, 75%); mp
155–157 8C (DIPE); 1H NMR (d6-DMSO, 200 MHz): d
Method B. n-BuLi in hexane (0.85 mL, 2.13 M, 1.81 mmol,
2 equiv) was added to 1 (0.40 g, 1.81 mmol, 2 equiv) in dry
THF (100 mL) at K75 8C within 10 min. After 30 min
freshly dried ZnCl2 (0.25 g, 1.81 mmol, 2 equiv) in dry THF
(5 mL) was added. The reaction mixture was warmed to
room temperature and Pd(PPh3)4 (0.06 g, 0.05 mmol,
0.055 equiv) and 10 (0.30 g, 0.91 mmol, 1 equiv) in dry
THF (15 mL) were added. After refluxing for 3 h, the
mixture was stirred another 48 h at room temperature. More
Pd(PPh3)4 (0.05 g, 0.04 mmol, 0.05 equiv) was added and
the solution was refluxed for 2 h. The mixture was poured
onto water, adjusted to basic pH with saturated aqueous
Na2CO3 solution, and extracted with EtOAc. The combined
organic layers were dried over Na2SO4 and concentrated in
vacuo. The crude material was purified by column
chromatography (LP/EtOAc 7:1) to afford 13a as yellow
crystals (0.10 g, 0.33 mmol, 37%); mp 158–160 8C
1
(methanol); H NMR (d6-DMSO, 200 MHz): d 6.90–6.96
3
4
(m, 1H), 7.17 (s, 1H), 7.21 (dd, JZ5.5 Hz, JZ1.4 Hz,
3
3
3
1H), 7.28 (t, JZ8.2 Hz, 1H), 7.47–7.57 (m, 2H), 7.67 (dt,
1.24 (s, 9H), 7.19 (t, JZ8.5 Hz, 1H), 7.38 (d, JZ8.5 Hz,
3 3
1H), 7.50 (d, JZ8.5 Hz, 1H), 7.75 (d, JZ5.5 Hz, 1H),
3JZ5.5 Hz, 4JZ1.4 Hz, 1H), 8.03 (t, 4JZ2.1 Hz, 1H), 8.34
(d, 3JZ5.5 Hz, 1H), 8.38 (d, 3JZ5.5 Hz, 1H), 9.48 (s, 1H);
8.10 (s, 1H), 8.54 (d, JZ5.5 Hz, 1H), 9.32 (s, 1H); 13C
3

P. Stanetty et al. / Tetrahedron 62 (2006) 2380–2387
2387
NMR (d6-DMSO, 50 MHz): d 28.1 (q), 79.4 (s), 116.1 (d),
116.6 (d), 121.2 (d), 121.7 (d), 129.5 (d), 135.1 (s), 140.5
(s), 152.8 (s), 160.5 (s), 161.2 (d), 166.3 (s). Anal. Calcd for
C15H16ClN3O2 (305.76): C, 58.92; H, 5.27; N, 13.74.
Found: C, 58.71; H, 5.38; N, 13.53.
5.56 mmol, 0.85 equiv) were dissolved in dry dioxane
(40 mL) and refluxed for 4 h. The solvent was removed in
vacuo and the residue was suspended in water. The
suspension was adjusted to basic pH with saturated aqueous
Na2CO3 solution and extracted with EtOAc. The combined
organic layers were washed with brine, dried over Na2SO4,
and the solvent was removed in vacuo. The crude product
was purified by column chromatography ((LP/EtOAc 1:1/
1:3) to yield 18 as yellow crystals (2.34 g, 5.90 mmol, 90%);
mp 173–176 8C (EtOAc); 1H NMR (d6-DMSO, 200 MHz):
d 3.54 (s, 2H), 3.68 (s, 3H), 7.00 (d, 3JZ8.2 Hz, 1H), 7.28–
7.43 (m, 2H), 7.50 (t, 3JZ7.6 Hz, 1H), 7.68 (d, 3JZ8.2 Hz,
4.1.16. N-[3-(2-Methylpyrimidin-4-yl)-phenyl]-carbamic
acid 1,1-dimethylethyl ester (15). The title compound
formed as by-product during the formation of 14. (LP/EtOAc
3:1). Yellow crystals (0.42 g, 1.47 mmol, 9%); mp 156–
159 8C (EtOAc); 1H NMR (d6-DMSO, 200 MHz): d 1.49 (s,
3
3
9H), 2.67 (s, 3H), 7.40 (t, JZ8.4 Hz, 1H), 7.60 (d, JZ
8.5 Hz, 1H), 7.65–7.85 (m, 2H), 8.34 (s, 1H), 8.73 (d, 3JZ
5.5 Hz, 1H), 9.51 (s, 1H); 13C NMR (d6-DMSO, 50 MHz): d
25.9 (q), 28.1 (q), 79.2 (s), 114.0 (d), 116.5 (d), 120.7 (d),
120.8 (d), 129.2 (d), 136.8 (s), 140.2 (s), 152.8 (s), 158.1 (d),
162.8 (s), 167.4 (s). Anal. Calcd for C16H19N3O2 (285.34): C,
67.35; H, 6.71; N, 14.73. Found: C, 67.10; H, 6.75; N, 14.52.
4
1H), 7.80–7.95 (m, 2H), 7.99 (t, JZ2.2 Hz, 1H), 8.48 (s,
3
1H), 8.62 (d, JZ5.5 Hz, 1H), 9.92 (s, 1H), 10.39 (s, 1H);
13C NMR (d6-DMSO, 50 MHz): d 43.5 (t), 52.0 (q), 108.6
(d), 117.1 (d), 117.8 (d), 118.0 (d), 120.8 (d), 121.6 (d),
122.2 (d), 129.4 (d), 130.3 (d), 133.0 (s), 137.3 (s), 139.4 (s),
142.2 (s), 159.1 (d), 159.9 (s), 163.7 (s), 164.3 (s), 168.1 (s).
Anal. Calcd for C20H17ClN4O3 (396.83): C, 60.53; H, 4.32;
N, 14.12. Found: C, 60.59; H, 4.60; N, 13.96.
4.1.17. 2-Chloro-4-(3-aminophenyl)-pyrimidine (16).
Substrate 14 (4.43 g, 14.5 mmol, 1 equiv) was suspended
in dry dichloromethane (20 mL) and treated with trifluoro-
acetic acid (10 mL, 135 mmol, 9.3 equiv). The mixture was
stirred at room temperature for 3 h, poured onto water,
adjusted to basic pH with saturated aqueous Na2CO3
solution and extracted with EtOAc. The combined organic
layers were dried over Na2SO4 and concentrated in vacuo to
yield 16 as yellow crystals (2.93 g, 14.2 mmol, 98%); mp
References and notes
1. Nashizuka, Y. Nature 1984, 304, 693.
2. Dekker, L. V.; Parker, P. J. Trends Biochem. Sci. 1994, 19, 73.
3. Dekker, L. V.; McIntyre, P.; Parker, P. J. J. Biol. Chem. 1993,
268, 19498.
1
137–138 8C (MeOH); H NMR (d6-DMSO, 200 MHz): d
4. Buchanan, J. G.; Sable, H. Z. In Thyagarajan, B. S., Ed.;
Selective Organic Transformations; Wiley-Interscience: New
York, 1972; Vol. 2, pp 1–95.
5.40 (br s, 2H), 6.79 (dt, 3JZ8.0 Hz, 4JZ2.3 Hz, 1H), 7.19
(dd, 3JZ8.0 Hz, 1H), 7.28 (d, JZ8.0 Hz, 1H), 7.42 (t, 4JZ
3
2.3 Hz, 1H), 7.93 (d, JZ5.3 Hz, 1H), 8.74 (d, JZ5.3 Hz,
5. Lyle, F. R. U.S. Patent 5,973,257, 1985; Chem. Abstr. 1985,
65, 2870.
1H); 13C NMR (d6-DMSO, 50 MHz): d 112.1 (d), 114.9 (d),
115.8 (d), 117.6 (d), 129.7 (d), 135.1 (s), 149.4 (s), 160.5 (s),
160.7 (d), 167.0 (s). Anal. Calcd for C10H8ClN3 (205.65): C,
58.41; H, 3.92; N, 20.43. Found: C, 58.25; H, 4.19; N, 20.14.
6. Zimmermann, J. PCT Int. Appl. WO 9509853, CAN
123:55914, 1995.
7. Zimmermann, J. Eur. Pat. Appl. EP 564409, CAN
120:107056, 1993.
4.1.18. 3-{[3-(2-Chloropyrimidin-4-yl)-phenyl]-amino}-
3-oxopropanoic acid methyl ester (17). Substrate 16
(2.50 g, 12.2 mmol, 1 equiv) and triethylamine (1.35 g,
13.4 mmol, 1.1 equiv) were dissolved in dry THF (50 mL)
and cooled to 0 8C. 3-Chloro-3-oxopropanoic acid methyl
ester (1.83 g, 13.4 mmol, 1.1 equiv) in dry THF (5 mL) was
added dropwise within 10 min. After stirring for 2 h at 0 8C
the mixture was poured onto water and extracted with
EtOAc. The combined organic layers were washed with
brine, dried over Na2SO4, and the solvent was removed in
vacuo. The crude product was purified by column
chromatography (LP/EtOAc 1:1) to yield 17 as colorless
crystals (2.80 g, 9.16 mmol, 75%); mp 117–119 8C (DIPE);
1H NMR (d6-DMSO, 200 MHz): d 3.52 (s, 2H), 3.67 (s, 3H),
8. Eberle, M.; Stierli, D.; Pillonel, C.; Ziegler, H. PCT Int. Appl.
WO 2001093682, CAN 136:33324, 2001.
9. Furet, P.; Zimmermann, J.; Capraro, H. G.; Meyer, T.; Imbach,
P. J. Comput. Aided Mol. Des. 2000, 14, 403.
10. Stanetty, P.; Hattinger, G.; Schnu¨rch, M.; Mihovilovic, M. D.
J. Org. Chem. 2005, 70, 5215.
11. Karig, G.; Spencer, J. A.; Gallagher, T. Org. Lett. 2001, 3, 835.
12. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis 3rd ed.; Wiley: New york, 1999; pp 518–525.
13. Wibaut, J. P.; Tilman, G. Recl. Trav. Chim. Pays-Bas 1933, 52,
987.
14. Banks, C. K. J. Am. Chem. Soc. 1944, 66, 1127.
15. Cragoe, E. J., Jr.; Hamilton, C. S. J. Am. Chem. Soc. 1945, 67,
536.
3
3
¨
16. Schroter, S.; Stock, C.; Bach, T. Tetrahedron 2005, 61, 2245.
17. Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
18. Stanetty, P.; Schnu¨rch, M.; Mihovilovic, M. D. Synlett 2003,
7.52 (t, JZ8.3 Hz, 1H), 7.84–7.93 (m, 2H), 8.07 (d, JZ
4
3
5.5 Hz, 1H), 8.38 (t, JZ2.2 Hz, 1H), 8.82 (d, JZ5.5 Hz,
1H), 10.48 (s, 1H); 13C NMR (d6-DMSO, 50 MHz): d 43.5
(t), 52.0 (q), 116.0 (d), 117.5 (d), 122.4 (d), 122.5 (d), 129.7
(d), 135.0 (s), 139.6 (s), 160.5 (s), 161.2 (d), 164.3 (s), 165.8
(s), 168.0 (s). Anal. Calcd for C14H12ClN3O3 (305.72): C,
55.00; H, 3.96; N, 13.74. Found: C, 54.74; H, 4.12; N, 13.48.
12, 1862.
19. Estel, L.; Marsais, F.; Queguiner, G. J. Org. Chem. 1988, 53,
2740.
20. Rocca, P.; Chochennec, C.;Marsais, F.;Thomas-dit-Dumont, L.;
Mallet, M.; Godard, A.; Queguiner, G. J. Org. Chem. 1993, 58,
7832.
4.1.19. 3-{[3-[2-(3-Chlorophenylamino)-pyrimidin-4-yl]-
phenyl]-amino}-3-oxopropanoic acid methyl ester (18).
Substrate 17 (2.00 g, 6.54 mmol, 1 equiv), 3-chloroaniline
(1.25 g, 9.81 mmol, 1.5 equiv), and p-TSA$H2O (1.06 g,
¨
¨
21. Hametner, C.; Hattinger, G.; Rohrling, J.; Frohlich, J.;
Stanetty, P.; Mihovilovic, M. D. Magn. Reson. Chem. 2001,
39, 417.