Synthesis of novel 4-(2-amino-5-thiazolyl)-pyrimidine-2-amines as potential protein kinase inhibitors

Article abstract of DOI:10.1007/s00706-008-0047-9

A short and efficient sequence for the synthesis of a series of 4-(2-amino-5-thiazolyl)-pyrimidine-2-amines was developed. 1-Phenyl-2-(6- pyrimidinyl)-ethanones, obtained via Weinreb's methodology, were used in a Hantzsch thiazole cyclization reaction, followed by introduction of the aniline moieties via nucleophilic substitution.

Full text of DOI:10.1007/s00706-008-0047-9

Monatsh Chem (2009) 140:423–430
DOI 10.1007/s00706-008-0047-9
ORIGINAL PAPER
Synthesis of novel 4-(2-amino-5-thiazolyl)-pyrimidine-2-amines
as potential protein kinase inhibitors
ˇ
Marko P. Susnik Æ Michael Schnu¨rch Æ
Marko D. Mihovilovic Æ Kurt Mereiter Æ
Peter Stanetty
Received: 2 June 2008 / Accepted: 15 August 2008 / Published online: 30 September 2008
Ó Springer-Verlag 2008
Abstract A short and efficient sequence for the synthesis
of a series of 4-(2-amino-5-thiazolyl)-pyrimidine-2-amines
was developed. 1-Phenyl-2-(6-pyrimidinyl)-ethanones, obtained
via Weinreb’s methodology, were used in a Hantzsch
thiazole cyclization reaction, followed by introduction of
the aniline moieties via nucleophilic substitution.
pyridyl-pyrimidine motif. In preceding studies we were
particularly interested in the variation of the number and
the positions of the ring nitrogens within the lead structure
[8–10] (Fig. 2).
Further variations were envisaged by retaining the
guanidine structural element of the CGP 60474 system,
considered as an essential feature for the biological activity
[7–10]. Aiming to improve the fungicidal activity, we
report now on the synthesis of the title compounds bearing
a thiazole ring in place of the pyridine ring in the PAP-type
PKIs [11].
Keywords Fungicides ꢀ Heterocycles ꢀ
Nucleophilic aromatic substitutions ꢀ Cyclizations ꢀ
Weinreb amide
Scheme 1 shows a retrosynthetic analysis of the target
system. A crucial step was the preparation of the thiazole
motif. The required a-bromoketone precursors for the
Hantzsch cyclization should be available via lateral lithi-
ation of 2, subsequent acylation with a suitable electrophile
to give ketones 3, followed by direct bromination in
a-position. Some recent publications also use this strategy
for the synthesis of imidazolyl-pyrimidine (p38 kinase
inhibitor) [12, 13] and pyrazolopyridinyl-pyrimidine
(TNF-a inhibitor) [14] derivatives (Scheme 2).
Introduction
The lead structure for the development of the phenylami-
nopyrimidine-type (PAP) protein kinase inhibitors (PKI)
was 3-{4-[2-(3-chlorophenylamino)-pyrimidin-4-yl]-pyri-
din-2-yl-amino}-propanol (CGP 60474) [1]. It led later to
the introduction of Imatinib (GleevecTM) as the first PKI in
the therapy of leukaemia by Novartis [2–5] (Fig. 1).
Additionally, CGP 60474 showed also good biological
activity as a fungicide [6, 7].
Continuing work within our research group on this topic
led to the synthesis of a series of analogs by modifying the
Results and discussions
Although the pyrimidine derivative 2 could be selectively
deprotonated with LDA at the methyl group in 4-position,
the reaction with benzoyl chloride did not afford the
desired ketone. The high reactivity of the acid chloride
even at -80 °C gave a mixture of various inseparable
products. We therefore switched to less reactive electro-
philes, namely Weinreb amides [15]. Benzoyl chloride and
4-methoxybenzoyl chloride were reacted with N-methoxy-
N-methylamine to give the desired Weinreb amides 1a [15]
and 1b. Lithiated 4-methyl-2-methylthiopyrimidine (2)
ˇ
M. P. Susnik ꢀ M. Schnu
¨rch ꢀ M. D. Mihovilovic ꢀ
P. Stanetty (&)
Institute of Applied Synthetic Chemistry,
Vienna University of Technology,
Getreidemarkt 9/163-OC, 1060 Vienna, Austria
e-mail: peter.stanetty@tuwien.ac.at
K. Mereiter
Institute for Chemical Technology and Analytics,
Vienna University of Technology,
Getreidemarkt 9/164, 1060 Vienna, Austria
123

ˇ
M. P. Susnik et al.
424
Cyclization reactions of 4a and 4b with N-substituted
thioureas afforded compounds 5a–e (Table 1, entries A1–
A5). Hantzsch reactions with 4a, N-methylthiourea and
N,N-dimethylthiourea were performed in chloroform and
triethylamine as base to give 5a (98%) and 5b (61%) in
good yields (Table 1, Entries A1, A2). In contrast, only
N,N-dimethylthiourea reacted smoothly with 4b in chlo-
roform and NEt3 as base to give 5e in 85% yield
(Table 1, entry A5). Reaction with thiourea gave
decomposition; changing the solvent to DMSO or dioxane
also proved unsuccessful. Only in water at reflux tem-
perature and NaOH as base was some conversion
observed, and 8% of 5c was obtained (Table 1, entry A3).
4-Methoxybenzoic acid was isolated as by-product, which
is probably formed upon cleavage of 4b. Further opti-
mization attempts on that reaction failed. In order to
obtain product 5c, we alternatively tried the cyclization
with N-acetylthiourea, which should give 5c after depro-
tection. However, also in this case all cyclization efforts
failed.
N
N
H
N
H
Cl
N
N
N
N
N
N
N
HN
O
. CH3SO3H
N
H
OH
Imatinib (GleevecTM
)
CGP 60474
Fig. 1 Lead structures
H
H
N
H
N
R'
Cl
N
X
N
N
N
R'
N
N
OH
N
H
OH
R''
N
H
N
H
R' = Ph, R'' = OH
R' = 3-Cl-Ph, R'' =OH
R' = 3-CF3-Ph, R'' =OH
X = CH, N
R' = (CH2)3OH
R' = Bn
R' = 3-Cl-Ph
On the other hand, cyclization of 4b with N-meth-
ylthiourea gave the desired product 5d in 46% overall
yield. The structure of 5d was confirmed by X-ray analysis
(Fig. 3).
R' = 3-Cl-Ph, R'' =N(CH3)2
Fig. 2 Modifications from the Stanetty laboratory
To perform the nucleophilic substitution in 2-position of
the pyrimidine ring, the S-methyl group had to be oxidized
with m-CPBA, and the corresponding sulfoxides 6a–c were
obtained in good yields (Table 1, entries B1–B3).
afforded ketones 3a and 3b (Scheme 3) in very good yields
(85 and 94%) and purity upon reaction with amides 1a and
1b. It is noteworthy that in solution both ketones are in
equilibrium with their enol form in ratios (keto:enol) 1:1.8
for 3a and 1.7:1 for 3b.
Subsequently, various aniline derivatives were applied
in the nucleophilic exchange step. Conversion of 6a gave
no desired products, in all experiments, only decomposed
material was observed. Since it was believed that the free
NH-proton caused the failure in the nucleophilic exchange
reaction, the NHMe group in compound 6a was protected
with an acetyl group to give 6d in excellent yield (Table 1,
entry B4). Still, the exchange reaction with 6d gave similar
disappointing results as for 6a. The nucleophilic substitu-
tion of 6b and 6c with aniline, 3-methoxyaniline, and
3-aminoacetophenone afforded the desired products 7a–f,
Bromination of 3a and 3b was initially carried out with
bromine in chloroform, but the desired compounds could
not be obtained. Alternatively, bromination in acetic acid
of technical purity (*98%) gave the desired products 4a
and 4b in good yields. Trace amounts of water were found
to be essential for this reaction, as no conversion was
observed when the reaction was carried out under compa-
rable conditions in glacial acetic acid. It has to be
mentioned that 4a and 4b have a limited stability of only a
few days when kept at room temperature.
Scheme 1
R''
H
N
N
N
S
N
S
X
N
N
N
+
O
Ar
Ar
Ar
S
N
O
R'
3
2
Ar = Ph, 4-MeOPh
R' = NH2, NHMe, NMe2, NMeAc
R'' = H, OMe, COMe, CH(OH)Me
X = Cl, NMe(OMe)
123

Synthesis of novel 4-(2-amino-5-thiazolyl)-pyrimidine-2-amines
425
Scheme 2
R'
R'
O
O
O
O
LDA
Br2
N
+
2
Br
R'
1a: R' = H (92%)
N
N
N
N
1b: R' = OMe (93%)
S
S
3a: R' = H (85%)
3b: R' = OMe (94%)
4a: R' = H (98%)
4b: R' = OMe (90%)
R'
R'
S
N
N
S
R''
H2N
R''
m-CPBA
R''
S
N
N
N
N
O
S
S
5a - 5e
6a - 6c
6a
6d
Scheme 3
R'
R'
N
S
R'''
NH2
N
S
R''
R''
NaBH4
N
N
7g, 7h
N
N
O
HN
R'''
S
6a - 6d
7a - 7f
Table 1 Summary of cyclization and oxidation experiments
Entry Substrate Product React. type Yield (%) R0
R00
A1
A2
A3
A4
A5
B1
B2
B3
B4
a
4a
4a
4b
4b
4b
5a
5a
5b
6a
5a
5b
5c
5d
5e
6a
6b
6c
6d
Cyclizationa 98
Cyclizationa 61
H
H
NHMe
NMe2
Cyclizationb
8
OMe NH2
Cyclizationa 46
Cyclizationa 85
OMe NHMe
OMe NMe2
Oxidationc
Oxidationc
Oxidationc
Acylationd
99
71
85
96
H
H
NHMe
NMe2
OMe NMe2
N(Me)Ac
H
NEt3, CHCl3, reflux, (5b, 5e: N,N-dimethylthiourea; 5a, 5d: N-
methylthiourea)
b
NaOH, H2O, reflux, thiourea
c
m-CPBA, CHCl3, rt
d
NEt3, acetic anhydride, dioxane, reflux
Fig. 3 Crystal structure of 5d
123

ˇ
M. P. Susnik et al.
426
Table 2 Nucleophilic
exchange and reduction
reactions to target products
Entry
Starting material
Product
React. type
Yield (%)
R0
R00
R000
C1
C2
C3
C4
C5
C6
C7
C8
6b
6b
6b
6c
6c
6c
7c
7f
7a
7b
7c
7d
7e
7f
Nuc. exa
Nuc. exb
Nuc. exc
Nuc. exa
Nuc. exb
Nuc. exc
Reductiond
Reductiond
51
37
18
39
47
41
99
99
H
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
H
H
OMe
H
Ac
OMe
OMe
OMe
H
H
a
Aniline, BF3, reflux
OMe
b
3-Methoxyaniline, BF3, reflux
Ac
c
3-Aminoacetophenone, BF3,
dioxane, reflux
7g
7h
CH(OH)Me
CH(OH)Me
OMe
d
NaBH4, EtOH
-80 °C, and 6.00 g 2 (42.86 mmol) in 20 cm3 THF was
added drop wise. The mixture was warmed to -5 °C and
stirred for 45 min. Then it was cooled again to -80 °C,
and 7.78 g 1a (47.15 mmol) dissolved in 20 cm3 THF was
added slowly. The mixture was warmed to room temper-
ature and then heated overnight at reflux. The mixture was
concentrated, hydrolyzed with 2n HCl, and extracted with
chloroform. The organic layer was washed with water and
brine and finally dried over Na2SO4. The crude product
was purified by Kugelrohr-distillation. Starting material
was obtained in a first fraction at 0.01 mbar and 100 °C.
Then 8.86 g (85%) of 3a at 0.01 mbar and 185 °C was
but the reactions again did not proceed without problems.
The crude materials contained considerable amounts of
impurities, which made purification by recrystallization
and column chromatography mandatory. The cumbersome
purification procedure explains the mediocre yields
(Table 2, entry C1–C6).
Finally, the carbonyl groups of 7c and 7f were reduced
with NaBH4 to give the corresponding alcohols 7g and 7h
in excellent yields (Table 2, entry C7, C8).
Conclusion
1
isolated. H-NMR (200 MHz, CDCl3): keto: d = 2.49 (s,
The described synthesis shows a straightforward approach
to various thiazolyl-pyrimidines as new structural variants
of PAP-related PKI. By applying different combinations of
substituted Weinreb amides and aniline derivatives, this
method can easily be extended to the formation of a larger
series of such thiazole derivatives. In addition, this method
can also be utilized for the synthesis of other heteroaryls.
SCH3), 4.35 (s, 2H, H2), 6.94 (d, J = 5.1 Hz, 1H, H50),
7.34–7.58 (m, 4H, H200, 300, 500, 600), 7.76–7.85 (m, 2H,
H400), 8.41 (d, J = 5.1 Hz, 1H, H60); enol: 2.57 (s, SCH3),
5.95 (s, 1H, H2), 6.59 (d, J = 5.5 Hz, 1H, H50), 7.34–7.58
(m, 4H, H20000, 300, 500, 600), 7.76–7.85 (m, 2H, H400), 8.26 (d,
J = 5.5 Hz, 1H, H60), 14.41–14.62 (bs, OH); 13C-NMR
(50 MHz, CDCl3): keto: d = 47.3 (t, C2), 116.5 (d, C50),
195.0 (s, C1); enol: 93.3 (d, C2), 125.7 (d, C50); keto and
enol: 13.8 (q, 2SCH3), 128.2, 128.3, 128.4, 128.5 (4d, C200,
C300, C500, C600), 130.3, 133.4 (2d, C400), 134.6, 136.0 (2s,
C100), 155.9, 156.7 (2d, C60), 163.7, 164.2 (2s, C40), 167.5,
169.4, 172.4 (3s, C20, enolic C1).
Experimental
Melting points were determined using a Kofler-type Leica
Galen III micro hot-stage microscope and are uncorrected.
Flash column chromatography was performed on silica gel
60 from Merck (40–63 lm). NMR spectra were recorded
from CDCl3 or d6-DMSO solutions on a Bruker AC 200
(200 MHz) spectrometer, and chemical shifts are reported
in ppm using TMS as internal standard.
1-(4-Methoxyphenyl)-2-[2-(methylthio-4-pyrimidinyl)]-
ethanone (3b, C14H14N2O2S)
Compound 3b was prepared following the procedure for 3a
from 2.77 g diisopropylamine (27.68 mmol), 12.2 cm3
2.27 M n-butyllithium in n-hexane (27.68 mmol), 4.50 g
2 (23.07 mmol), 3.23 g 1b (23.07 mmol), 80 cm3 of dry
THF under argon-atmosphere. The reaction mixture was
stirred for 80 h at reflux. After extraction, the crude
product was triturated with diisopropyl ether. This afforded
N,4-Dimethoxy-N-methyl-benzamide (1b)
1b was prepared according to reference [16] in 93% yield,
but pyridine was used as base instead of NEt3. Its identity
1
was proven according to H and 13C NMR spectra.
1
6.20 g (98%) of 3b as a brown resin. H-NMR (200 MHz,
2-[2-(Methylthio-4-pyrimidinyl)]-1-phenylethanone (3a)
LDA was prepared following standard procedure under
argon atmosphere in 60 cm3 THF with 5.19 g diisopropyl-
amine (51.43 mmol), 21.89 cm3 2.35 M n-butyllithium in
n-hexane (51.43 mmol). This solution was cooled to
CDCl3): keto: d = 2.51 (s, SCH3), 3.84 (s, ArOCH3), 4.30
(s, 2H, H2), 7.99 (d, 2H, J = 8.8 Hz, H200, H600), 8.41 (d,
1H, J = 4.9 Hz, H60), 14.56–14.63 (bs, 1H, OH); enol:
2.58 (s, SCH3), 3.83 (s, ArOCH3), 5.87 (s, 1H, H2), 6.57 (d,
1H, J = 5.4 Hz), 7.77 (d, 2H, J = 8.8 Hz, H200, H600), 8.23
123

Synthesis of novel 4-(2-amino-5-thiazolyl)-pyrimidine-2-amines
427
(d, 1H, J = 5.4 Hz, H60); keto and enol: 6.85–6.99 (keto:
3H, phenyl and pyrimidinyl-H; enol: 2H, phenyl and
pyrimidinyl-H); 13C-NMR (50 MHz, CDCl3): keto:
d = 47.3 (t, C2), 193.5 (s, C1); enol: 91.9 (d, C2); keto
and enol forms: 13.8, 13.9 (2q, SCH3), 55.2, 55.4 (2q,
OCH3), 112.3, 113.7 (4d, C300, C500), 116.4 (2d, C50), 127.1,
129.1 (2s, C100), 127.5, 130.9 (4d, C200, C600), 155.7, 156.8
(2d, C60), 161.5, 163.8, 164.1, 164.4 (4s, C40, C400), 167.8,
169.2, 172.4 (3s, C20, enolic C1).
brown powder. M.p.: 185–189 °C; 1H-NMR (200 MHz,
CDCl3): d = 2.53 (s, SCH3), 2.83 (s, NCH3), 6.49 (d,
J = 5.5 Hz, 1H, H50), 7.35–7.55 (m, 5H H200, H300, H400,
H500, H600), 8.09 (d, J = 5.5 Hz, 1H, H60); 13C-NMR
(50 MHz, CDCl3): d = 13.9 (q, SCH3), 32.3 (q, NCH3),
110.4 (d, C50), 119.2 (s, C5), 128.8 (d, C300, C500), 129.1
(d, C200, C600), 129.9 (d, C400), 132.8 (s, C100), 149.9 (s,
C4), 156.0 (d, C60), 157.4 (s, C40), 171.6, 172.1 (2s, C2,
C20).
2-Bromo-2-[2-(methylthio-4-pyrimidinyl)]-1-
N,N-Dimethyl-5-[2-(methylthio)-4-pyrimidinyl]-4-
phenyl-thiazol-2-amine (5b, C16H16N4S2)
phenylethanone (4a, C13H11BrN2OS)
A solution of 9.70 g 3a (35.4 mmol) in 200 cm3 acetic acid
(98% purity) was cooled to a maximum of 20 °C, and
5.66 g bromine (35.4 mmol) in 50 cm3 acetic acid was
added. After addition, the mixture was stirred overnight at
room temperature. The reaction mixture was concentrated
almost to dryness, and NaHCO3 solution was added. The
mixture was adjusted to basic pH using Na2CO3 and
extracted with chloroform. The organic layer was washed
with water and brine and dried over Na2SO4 to afford
8.51 g (83%) of 4a as brown oil. 1H-NMR (200 MHz,
CDCl3): d = 2.35 (s, SCH3), 6.16 (s, 1H, H2), 7.26 (d,
J = 5.1 Hz, 1H, H50), 7.46 (m, 4H, H200, H300, H500, H600),
7.91 (d, J = 7.2 Hz, 1H, H40), 8.41 (d, J = 5.1 Hz, 1H,
H60); 13C-NMR (50 MHz, CDCl3): d = 13.8 (q, SCH3),
48.6 (d, C2), 116.2 (d, C50), 128.6 (d, C300, C500), 129.0 (d,
C200, C600), 133.5 (s, C100), 133.9 (d, C400), 157.8 (d, C60),
163.9 (s, C40), 172.4 (s, C20), 189.7 (s, C1).
To obtain 5b 1.25 g 4a (3.87 mmol), 0.52 g N,N-dim-
ethylthiourea (5.03 mmol) and 0.30 g triethylamine
(5.03 mmol) were dissolved in 30 cm3 of chloroform.
Following the procedure for 5a, 0.78 g (61%) of 5b was
1
obtained as brown powder. M.p.: 134–137 °C; H-NMR
(200 MHz, CDCl3): d = 2.56 (s, SCH3), 3.21 (s, N(CH3)2),
6.51 (d, J = 5.5 Hz, 1H, H50), 7.42–7.57 (m, 5H, H200,
H300, H400, H500, H600), 8.02 (d, J = 5.5 Hz, 1H, H60); 13C-
NMR (50 MHz, CDCl3): d = 14.0 (q, SCH3), 40.0 (q,
N(CH3)2), 110.7 (d, C50), 120.6 (s, C5), 128.7 (d, C300,
C500), 128.9 (d, C200, C600), 129.0 (d, C400), 136.0 (s, C100),
155.5 (s, C2), 155.5 (d, C60), 158.9 (s, C40), 170.9, 171.7
(2s, C2, C20).
4-(4-Methoxyphenyl)-5-[2-(methylthio)-4-pyrimidinyl]-
thiazol-2-amine (5c, C15H14N4OS2)
To a suspension of 12 mg thiourea (0.16 mmol) in 5 cm3
water, 50 mg 4b (0.14 mmol) was added. The mixture was
stirred at reflux for 3 h. After cooling to room tempera-
ture, 9 mg sodium hydroxide (0.23 mmol) was added, and
the solution was stirred for an additional 1 h. The
precipitate was filtrated and dissolved in chloroform. This
organic layer was washed with 2n hydrochloric acid and
water. After drying over Na2SO4, 4 mg (8%) of 5c was
isolated. 1H-NMR (200 MHz, CDCl3): d = 2.55 (s,
SCH3), 3.89 (s, OCH3), 6.72 (d, J = 5.4 Hz, 1H, H50),
7.01 (d, J = 8.6 Hz, 2H, H300, H500), 7.50 (d, J = 8.6 Hz,
2H, H200, H600), 8.20 (d, J = 5.4 Hz, 1H, H60); 13C-NMR
(50 MHz, CDCl3): d = 14.1 (q, SCH3), 55.5 (q, OCH3),
111.0 (d, C50), 114.8 (d, C300, C500), 130.5 (d, C200, 600),
156.6 (d, C60), 157.2 (s, C40), 161.3 (s, C400), 172.7 (s,
C20).
2-Bromo-1-(4-methoxyphenyl)-2-[2-(methylthio-4-
pyrimidinyl)]-ethanone (4b, C14H13BrN2O2S)
The reaction proceeded as described for 4a with 5.50 g 3b
(20.07 mmol), 3.21 g bromine (20.07 mmol) in 500 cm3
acetic acid (98% purity) and afforded 7.02 g (99%) of 4b
1
as a brown oil. H-NMR (200 MHz, CDCl3): d = 2.44 (s,
SCH3), 3.79 (s, OCH3), 6.20 (s, 1H, H2), 6.88 (d,
J = 9.0 Hz, 2H, H300, 500), 7.34 (d, J = 5.1 Hz, 1H, H50),
7.96 (d, J = 9.0 Hz, 2H, H200, 600), 8.50 (d, J = 5.1 Hz,
1H, H60); 13C-NMR (50 MHz, CDCl3): d = 13.8 (q,
SCH3), 48.6 (d, C2), 55.3 (q, OCH3), 113.8 (2d, C300,
C500), 116.1 (d, C50), 126.2 (s, C100), 131.4 (2d, C200, 600),
157.6 (d, C60), 164.0, 164.1 (2s, C40, C400), 172.0 (s, C20),
188.1 (s, C1).
N-Methyl-5-[2-(methylthio)-4-pyrimidinyl]-4-
phenyl-thiazol-2-amine (5a, C15H14N4S2)
N-Methyl-5-[2-(methylthio)-4-pyrimidinyl]-4-phenyl-thia-
zol-2-amine (5d, C16H16N4OS2)
A solution of 2.90 g 4a (8.97 mmol), 0.97 g N-meth-
ylthiourea (10.77 mmol), and 1.09 g triethylamine
(10.77 mmol) in 50 cm3 chloroform was stirred at reflux
overnight. After cooling to room temperature, the mixture
was washed with 2n HCl, water and brine and dried over
Na2SO4. The crude oily product was stirred in diisopropyl
ether and gave after filtration 2.54 g (90%) of 5a as a
Procedure 1 The reaction proceeded as for 5c with 14 mg
N-methylthiourea (0.16 mmol), 50 mg 4b (0.14 mmol),
and 9 mg sodium hydroxide (0.23 mmol) in 5 cm3 of
water, and 8 mg (16%) of 5d was isolated.
Procedure 2 A solution of 370 mg 4b (1.05 mmol),
113 mg N-methylthiourea (1.26 mmol), and 127 mg tri-
ethylamine (1.26 mmol) in 15 cm3 chloroform was treated
123

ˇ
M. P. Susnik et al.
428
as described for 4a. After column chromatography (silica
gel; ethyl acetate:petroleum ether = 1:2), a first fraction of
51 mg (14%) of pure 5d was obtained. A second impure
fraction of 130 mg was dissolved in hot ethanol and left to
crystallize. An additional 115 mg of 5d was isolated. The
overall yield was 166 mg (46%) of a yellow solid. M.p.:
178–182 °C; 1H-NMR (200 MHz, CDCl3): d = 2.52 (s,
SCH3), 2.58 (s, NCH3), 3.85 (s, OCH3), 6.50 (d,
J = 5.5 Hz, 1H, H50), 6.96 (d, J = 8.5 Hz, 2H, H300,
H500), 7.42 (d, J = 8.5 Hz, 2H, H200, H600), 8.02 (d,
J = 5.5 Hz, 1H, H60), 8.50 (s, 1H, NH); 13C-NMR
(50 MHz, CDCl3): d = 14.0 (q, SCH3), 31.9 (q, NCH3),
55.3 (q, OCH3), 110.4 (d, C50), 114.2 (d, C300, C500), 119.3
(s, C5), 127.9 (s, C100), 130.2 (d, C200, C600), 154.4 (s, C4),
155.6 (d, C6), 158.8 (s, C40), 160.3 (s, C400), 171.8, 172.4
(2s, C2, C20); X-ray structure determination of 5d. Data
were collected at room temperature on a Bruker SMART
APEX CCD area detector system with Mo Ka radiation
N-Methyl-5-[2-(methylsulfinyl)-4-pyrimidinyl]-4-phenyl-
thiazol-2-amine (6a, C15H14N4OS2)
A solution of 1.20 g 5a (3.82 mmol) in 25 cm3 of
chloroform was cooled with an ice bath, and 1.32 g
m-CPBA (60% purity) (4.60 mmol) was added in five
portions within 1 h. The mixture was warmed to room
temperature and stirred an additional 1.5 h. This solution
was washed with sat. NaHCO3 solution and brine and then
1
dried over Na2SO4; 1.23 g (98%) of 6a was isolated. H-
NMR (200 MHz, CDCl3): d = 2.65 (s, SOCH3), 2.94 (s,
NCH3), 6.78 (d, J = 5.6 Hz, 1H, H50), 7.39–7.52 (m, 5H,
H200, H300, H400, H500, H600), 8.34 (d, J = 5.6 Hz, 1H, H60),
13C-NMR (50 MHz, CDCl3): d = 31.8 (q, NCH3), 39.9 (q,
SOCH3), 115.0 (d, C50), 118.4 (s, C5), 128.6 (d, C300, C500),
129.1 (d, C200, C600), 129.6 (d, C400), 135.3 (s, C100), 156.4
(s, C4), 156.6 (d, C60), 159.8 (s, C40), 173.1 (2s, C2, C20).
N,N-Dimethyl-5-[2-(methylsulfinyl)-4-pyrimidinyl]-4-
phenyl-thiazol-2-amine (6b, C16H16N4OS2)
˚
(k = 0.71073 A) using a narrow frame method. After data
To a solution of 0.52 g 5b (1.58 mmol) in 20 cm3 of
chloroform, 0.42 g m-CPBA (60% purity) (1.58 mmol) was
added following the procedure for 6a. After warming to
room temperature, the solution was stirred for an additional
5 h. Then 0.15 g m-CPBA was added, and the mixture was
stirred overnight at room temperature. Workup proceeded
as for 6a and afforded 0.52 g (96%) of 6b. 1H-NMR
(200 MHz, CDCl3): d = 2.87 (s, SOCH3), 3.12 (s,
N(CH3)2), 6.74 (d, J = 5.6 Hz, 1H, H50), 7.36–7.48 (m,
5H, H200, H300, H400, H500, H600), 8.24 (d, J = 5.6 Hz, 1H,
H60); 13C-NMR (50 MHz, CDCl3): d = 39.9 (q, SOCH3),
40.1 (q, N(CH3)2), 115.2 (d, C50), 119.3 (s, C5), 128.8 (d,
C300, C500), 129.0 (d, C200, C600), 129.4 (d, C400), 135.6 (s,
C100), 156.4 (d, C60), 157.6 (s, C4), 160.1 (s, C40), 171.4 (s,
C2), 172.9 (s, C20).
integration the structure was solved with direct methods
and refined on F2 using the program SHELXTL. Crystal
data: C16H16N4OS2, Mr = 344.45, triclinic, space group
˚
P-1 (no. 2), a = 4.773(2) A, b = 13.192(12) A, c =
˚
˚
14.125(6) A, a = 111.16(2)°, b = 95.92(1)°, c =
3
3
˚
92.42(1)°, V = 821.9(9) A , Z = 2, Dx = 1.392 g/cm ,
l = 0.333 mm-1, T = 297 K. One thousand nine hundred
eighty-five reflections with h \ 25.0° were measured and
used to refine 211 parameters at R1 = R||Fo| - |Fc||/
R|Fo| = 0.088, wR2 = [R(w(Fo - F2c)2)/R(w(Fo2)2)]
=
2
‘
0.237 for 1,185 observed data [I [ 2r(I)]. CCDC 698196
contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via http://www.
ccdc.cam.ac.uk/data_request/cif.
4-(4-Methoxyphenyl)-N,N-dimethyl-5-[2-(methylsulfinyl)-
4-pyrimidinyl]-thiazol-2-amine (6c, C17H18N4O2S2)
4-(4-Methoxyphenyl)-N,N-dimethyl-5-[2-(methylthio)-4-
pyrimidinyl]-thiazol-2-amine (5e, C17H18N4OS2)
A solution of 1.20 g 5e (3.35 mmol) in 20 cm3 of
chloroform was cooled with an ice bath. During 1 h, while
being cooled, 1.10 g m-CPBA (60% purity) (4.02 mmol)
was added in five portions. After stirring at room temper-
ature for 7 h, additional 0.30 g m-CPBA was added, and
the mixture was stirred at room temperature overnight.
Workup proceeded as for 6a and afforded 1.24 g (99%) of
A solution of 1.50 g 4b (4.25 mmol), 0.53 g N,N-dim-
ethylthiourea (5.10 mmol), and 0.30 g triethylamine
(5.03 mmol) in 30 cm3 of chloroform was treated as
described for 4a. Finally, 1.34 g (88%) of 5e was isolated
as light brown powder. M.p.: 160–163 °C; 1H-NMR
(200 MHz, CDCl3): d = 2.57 (s, SCH3), 3.20 (s,
N(CH3)2), 3.87 (s, OCH3), 6.59 (d, J = 5.4 Hz, 1H, H50),
6.96 (d, J = 8.7 Hz, 2H, H300, H500), 7.49 (d, J = 8.7 Hz, 2H,
H200, H600), 8.06 (d, J = 5.4 Hz, 1H, H60); 13C-NMR
(50 MHz, CDCl3): d = 14.0 (q, SCH3), 40.0 (q, N(CH3)2),
55.3 (q, OCH3), 110.6 (d, C50), 114.1 (d, C300, C500), 120.0 (s,
C5), 128.1 (s, C100), 130.4 (d, C200, C600), 155.3 (d, C60), 155.4
(s, C4), 159.1, 160.2 (s, C40, C400), 170.8, 171.6 (2s, C2, C20).
1
6c. H-NMR (200 MHz, CDCl3): d = 2.95 (s, SOCH3),
3.21 (s, N(CH3)2), 3.88 (s, OCH3), 6.92 (d, J = 5.7 Hz,
1H, H50), 6.98 (d, J = 8.7 Hz, 2H, H300, H500), 7.48 (d,
J = 8.7 Hz, 2H, H200, H600), 8.35 (d, J = 5.7, 1H, H60);
13C-NMR (50 MHz, CDCl3): d = 39.9 (q, SOCH3), 40.0
(q, N(CH3)2), 55.3 (q, OCH3), 114.3 (d, C300, C500), 115.2
(d, C50), 118.8 (s, C5), 127.8 (s, C100), 130.2 (d, C20, C60),
123

Synthesis of novel 4-(2-amino-5-thiazolyl)-pyrimidine-2-amines
429
156.3 (d, C60), 157.6 (s, C4), 160.4, 160.5 (2s, C40, C400),
171.4 (s, C2), 173.0 (s, C20).
J = 5.4 Hz, 1H, H5), 6.48–7.61 (m, 9H, ArH), 7.74 (d,
J = 8.0 Hz, 2H, H2000, H6000), 8.06 (d, J = 5.4 Hz, 1H, H6),
9.47 (s, NH); 13C-NMR (50 MHz, DMSO-d6): d = 39.6 (q,
N(CH3)2), 55.0 (q, OCH3), 104.2 and 106.4 (2d, C200, C400),
107.0 (d, C600), 111.2 (d, C5), 120.4 (s, C50), 128.6 (d, C3000,
C5000), 128.6 (d, C2000, C6000), 128.9 (d, C4000), 129.1 (d, C500),
136.0 (s, C1000), 141.8 (s, C100), 154.2 (s, C40), 157.0 (d, C6),
158.4 (s, C4), 159.5 (s, C300), 169.6, 169.7 (2s, C2, C20).
N-Acetyl-N-methyl-5-[2-(methylsulfinyl)-4-pyrimidinyl]-4-
phenyl-thiazol-2-amine (6d, C17H16N4O2S2)
A solution of 0.44 g 6a (1.33 mmol), 0.16 g acetic
anhydride (1.60 mmol), and ten drops of triethylamine
(catalytic) in 10 cm3 of dry dioxane was stirred overnight
at reflux. The mixture was concentrated and chloroform
was added. The organic layer was washed with saturated
Na2CO3 solution, water, and brine and dried over Na2SO4.
This procedure afforded 0.47 mg (95%) of 6d. M.p.: 98–
100 °C; 1H-NMR (200 MHz, CDCl3): d = 2.45 (s,
SOCH3), 2.94 (s, N(CH3)2), 3.75 (s, COCH3), 7.07 (d,
J = 5.4 Hz, 1H, H50), 7.39–7.56 (m, 5H, H200, H300, H400,
H500, H600), 8.52 (d, J = 5.4 Hz, 1H, H60); 13C-NMR
(50 MHz, CDCl3): d = 23.0 (q, CH3), 35.1 (q, NCH3),
39.8 (q, SOCH3), 117.3 (d, C50), 125.2 (s, C5), 128.8 (d,
C300, C500), 128.9 (d, C200, C600), 129.3 (d, C400), 135.0 (s,
C100), 152.0 (s, C4), 157.6 (d, C60), 160.5, 161.0 (2s, C2,
C40), 170.5 (s, CO), 173.5 (s, C20).
1-[3-[[4-(2-Dimethylamino-4-phenyl-5-thiazolyl)-2-pyri-
midinyl]-amino]-phenyl]-ethanone (7c, C23H21N5OS)
To a solution of 520 mg 6b (1.51 mmol) and 750 mg 3-
aminoacetophenone (5.56 mmol) in 10 cm3 of dry dioxane,
five drops of borontrifluoride etherate (catalytic) were
added. The mixture was stirred at reflux overnight. The
dioxane was removed by distillation and the residue
dissolved in chloroform. Further workup proceeded as for
7a. Final purification with column chromatography was
done on silica gel with petroleum ether and ethyl acetate in
a 2:1 ratio and 2.5 vol% triethylamine. This procedure
afforded 115 mg (18%) of 7c as yellow powder. M.p.:
212–214 °C; 1H-NMR (200 MHz, CDCl3): d = 2.70 (s,
3H, H2), 3.25 (s, N(CH3)2), 6.39 (d, J = 5.4 Hz, 1H, H500),
7.32–7.77 (m, 9H, ArH), 8.02 (d, J = 5.4 Hz, 1H, H600),
8.47 (s, NH); 13C-NMR (50 MHz, CDCl3): d = 27.0 (q,
C2), 40.1 (q, N(CH3)2), 108.0 (d, C500), 118.6 and 123.4
(2d, C20, C40), 121.0 (s, C5000), 122.0 (d, C60), 128.7, 129.0,
129.0 and 129.2 (4d, C50, C20000, C30000, C40000, C50000, C60000),
136.2 (s, C10000), 137.9 (s, C30), 140.2 (s, C10), 155.3 (s,
C400), 156.4 (d, C600), 159.1, 159.8 (2s, C2000, C4000), 170.7
(s, C200), 198.1 (s, C1).
4-(2-Dimethylamino-4-phenyl-5-thiazolyl)-N-phenyl-pyr-
imidin-2-amine (7a, C21H19N5S)
A solution of 140 mg 6b (0.41 mmol) and three drops of
borontrifluoride etherate (catalytic) in 5 cm3 of aniline was
stirred at reflux overnight. A main part of the aniline was
separated by Kugelrohr distillation, and the concentrated
mixture was dissolved in chloroform. This layer was
washed with 2n hydrochloric acid, satd. Na2CO3 solution,
water, and brine. The organic layer was dried over Na2SO4.
The crude product was dissolved in a small amount of ethyl
acetate and precipitated with petroleum ether. This solid
was filtered over 500 wt% silica gel with ethyl acetate and
4-[4-(4-Methoxyphenyl-2-dimethylamino-5-thiazolyl)]-N-
phenyl-pyrimidin-2-amine (7d, C22H21N5OS)
1
afforded 77 mg (50%) of 7a. M.p.: 211–215 °C; H-NMR
A solution of 135 mg 6c (0.36 mmol) in 5 cm3 of aniline
was treated as described for 7a. Final purification was
performed by column chromatography over silica gel and
petroleum ether:ethyl acetate = 3:1 as eluent and afforded
56 mg (39%) of 7d as a brown solid. M.p.: 228–232 °C;
1H-NMR (200 MHz, CDCl3): d = 3.13 (s, N(CH3)2), 3.81
(s, OCH3), 6.32 (d, J = 5.3 Hz, 1H, H5), 6.93–7.76 (m,
9H, ArH), 8.09 (d, J = 5.3 Hz, 1H, H6), 9.45 (bs, NH);
13C-NMR (50 MHz, CDCl3): d = 39.6 (q, N(CH3)2), 55.2
(q, OCH3), 106.4 (d, C5), 113.9 (d, C3000, C5000), 118.7 and
121.1 (2d, C200, C300, C500, C600), 119.7 (s, C50), 128.1 (s,
C1000), 128.4 (d, C400), 130.3 (d, C2000, C6000), 140.5 (s, C100),
154.0 (s, C40), 156.9 (d, C6), 158.7, 159.5, 159.6 (3s, C2,
C4, C4000), 169.5 (s, C20).
(200 MHz, DMSO-d6): d = 3.12 (s, N(CH3)2), 6.20 (d,
J = 5.4 Hz, 1H, H5), 6.92–7.74 (m, 10H, ArH), 8.06 (d,
J = 5.4 Hz, 1H, H6), 9.45 (s, NH); 13C-NMR (50 MHz,
DMSO-d6): d = 39.7 (q, N(CH3)2), 106.5 (d, C5), 118.8 (d,
C200), 120.4 (d, C400), 121.3 (s, C50), 128.4 (d, C3000, C5000),
128.7 (d, C2000, C6000), 128.9 (d, C4000), 136.1 (s, C1000), 140.5
(s, C100), 154.2 (s, C40), 157.0 (d, C6), 158.6 (s, C4), 159.5
(s, C2), 169.7 (s, C20).
4-(2-Dimethylamino-4-phenyl-5-thiazolyl)-N-(3-methoxy-
phenyl)-pyrimidin-2-amine (7b, C22H21N5OS)
A solution of 200 mg 6b (0.58 mmol) and three drops of
borontrifluoride etherate (catalytic) in 5 cm3 of 3-methoxy-
aniline was treated as described for 7a. After precipitation,
the product was purified by column chromatography over
silica gel. The eluent was petroleum ether and ethyl acetate
in a ratio of 4:1. This procedure afforded 86 mg (37%) of
N-(3-Methoxyphenyl)-4-[4-(4-methoxyphenyl-2-dimethyl-
amino-5-thiazolyl)]-pyrimidin-2-amine
(7e, C23H23N5O2S)
A solution of 384 mg 6c (1.03 mmol) in 5 cm3 of
3-methoxyaniline was treated as described for 7b. Final
1
6b. M.p.: 160–162 °C; H-NMR (200 MHz, DMSO-d6):
d = 3.11 (s, N(CH3)2), 3.78 (s, OCH3), 6.20 (d,
123

ˇ
M. P. Susnik et al.
430
purification was performed with column chromatography
over silica gel and petroleum ether:ethyl acetate = 2:1 as
eluent and afforded 210 mg (47%) of 7e as a green solid.
M.p.: 170–172 °C; 1H-NMR (200 MHz, CDCl3): d = 3.21
(s, N(CH3)2), 3.89 and 3.91 (2s, 2OCH3), 6.44 (d,
J = 5.5 Hz, 1H, H5), 6.62–7.59 (m, 8H, ArH), 8.03 (d,
J = 5.5 Hz, 1H, H6); 13C-NMR (50 MHz, CDCl3):
d = 40.0 (q, N(CH3)2), 55.3 and 55.4 (2q, 2OCH3),
104.5 and 107.7 (2d, C200, C400), 108.1 (d, C600), 111.3 (d,
C5), 114.1 (d, C3000, C5000), 120.6 (s, C50), 128.5 (s, C1000),
129.4 (d, C500), 130.5 (d, C2000, C6000), 141.1 (s, C100), 154.7
(s, C40), 156.5 (d, C6), 159.4, 159.8 (2s, C2, C4), 160.1,
160.2 (2s, C300, C4000), 170.4 (s, C20).
(s, C10), 154.9 (s, C400), 156.6 (d, C600), 159.4, 159.5
(2s, C2000, C4000), 170.6 (s, C200).
1-[3-[[4-(2-Dimethylamino-4-(4-methoxyphenyl)-5-
thiazolyl)-2-pyrimidinyl]-amino]-phenyl]-ethanol
(7h, C24H25N5O2S)
A suspension of 100 mg 7c (0.11 mmol) and 40 mg NaBH4
(1.08 mmol) in 15 cm3 of ethanol was treated as described
for 7g. After workup 99 mg (99%) of 7h was isolated as a
yellow solid. M.p.: 89–91 °C; 1H-NMR (200 MHz,
CDCl3): d = 1.58 (d, J = 6.5 Hz, 3H, H2), 2.19–2.29 (bs,
1H, OH), 3.22 (s, N(CH3)2), 3.89 (s, OCH3), 4.95 (dq,
J1 = 12.9 Hz, J2 = 6.5 Hz, 1H, H1), 6.43 (d, J = 5.6 Hz,
1H, H50), 6.94–7.53 (m, 8H, ArH), 7.95 (bs, NH), 8.00 (d,
J = 5.6 Hz, 1H, H60); 13C-NMR (50 MHz, CDCl3):
d = 25.2 (q, C2), 40.0 (q, N(CH3)2), 55.3 (q, OCH3), 70.6
(d, C1), 107.3 (d, C500), 114.1 (d, C30000, C50000), 116.1, 118.2,
119.3 (3d, C20, C40, C60), 120.7 (s, C500), 128.4 (s, C10000),
128.9 (d, C50), 130.5 (d, C20000, C60000), 139.8 (s, C30), 146.9
(s, C10), 155.3 (s, C400), 155.7 (d, C600), 158.9, 160.0, 160.2
(3s, C2000, C4000, C40000), 170.6 (s, C200).
1-[3-[[4-(2-Dimethylamino-4-(4-methoxyphenyl)-5-
thiazolyl)-2-pyrimidinyl]-amino]-phenyl]-ethanone
(7f, C24H23N5O2S)
A solution of 500 mg 6c (1.34 mmol) and 450 mg
3-aminoacetophenone (3.33 mmol) in 10 cm3 of dioxane
was treated according to the procedure for 7c. Final
purification was performed with column chromatography
over silica gel and petroleum ether:ethyl acetate = 1:1
with 2.5 vol% triethylamine and afforded 244 mg (41%) of
7f as a yellow solid. M.p.: 213–217 °C; 1H-NMR
(200 MHz, DMSO-d6): d = 2.70 (s, 3H, H2), 3.24 (s,
N(CH3)2), 3.89 (s, OCH3), 6.48 (d, J = 4.9 Hz, 1H, H500),
6.99–7.77 (m, 8H, ArH), 8.04 (d, J = 4.9 Hz, 1H, H600),
8.46 (bs, NH); 13C-NMR (50 MHz, DMSO-d6): d = 27.0
(q, C2), 40.1 (q, N(CH3)2), 55.4 (q, OCH3), 107.8 (d, C500),
114.1 (2d, C30000, C50000), 118.7, 122.1, 123.5 (3d, C20, C40,
C60), 120.4 (s, C5000), 128.4 (s, C10000), 129.0 (d, C50), 130.5
(d,00C20000, C60000), 137.9 (s, C30), 140.1 (s, C10), 155.5 (s,
C4 ), 155.7 (d, C600), 158.8, 160.2, 160.3 (3s, C2000, C4000,
C40000), 170.7 (s, C200), 198.1 (s, C1).
Acknowledgments We thank Syngenta Crop Protection, Basel, for
generous financial support.
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1
(99%) of 7g as a yellow powder. M.p.: 157–159 °C; H-
NMR (200 MHz, CDCl3): d = 1.59 (d, J = 6.5 Hz, 3H,
H2), 3.23 (s, N(CH3)2), 4.95 (q, J = 6.5 Hz, 1H, H1), 6.34
(d, J = 5.5 Hz, 1H, H500), 7.05–7.62 (m, 9H, ArH), 7.96–
8.01 (m, 2H, H6000 and NH); 13C-NMR (50 MHz, CDCl3):
d = 25.2 (q, C2), 40.1 (q, N(CH3)2), 70.6 (d, C1), 107.5 (d,
C500), 116.0, 118.1 and 119.1 (3d, C20, C40, C60), 121.4 (s,
C500), 128.7, 128.9, 128.9 and 129.2 (4d, C50, C20000/C60000,
C30000/C50000, C40000), 136.2 (s, C10000), 140.0 (s, C30), 146.9
123