Convenient synthesis of N-(4-(2-aminopyridin-4-yl)thiazol-2-yl)-2-phenylacetamides

Article abstract of DOI:10.1016/j.tetlet.2006.09.053

We report a facile one-pot, three-step synthesis of N-(4-(2-aminopyridin-4-yl)thiazol-2-yl)-2-phenylacetamides via condensation of 2-p-methoxybenzylamino-4-acetylpyridine with phenylacetylthioureas.

Full text of DOI:10.1016/j.tetlet.2006.09.053

Tetrahedron Letters 47 (2006) 8079–8081
Convenient synthesis of
N-(4-(2-aminopyridin-4-yl)thiazol-2-yl)-2-phenylacetamides
Upul K. Bandarage,* Jon H. Come and Jeremy Green
Vertex Pharmaceuticals Incorporated, 130, Waverley Street, Cambridge, MA 02139, United States
Received 17 August 2006; revised 8 September 2006; accepted 12 September 2006
Available online 4 October 2006
Abstract—We report a facile one-pot, three-step synthesis of N-(4-(2-aminopyridin-4-yl)thiazol-2-yl)-2-phenylacetamides via con-
densation of 2-p-methoxybenzylamino-4-acetylpyridine with phenylacetylthioureas.
Published by Elsevier Ltd.
As a part of our medicinal chemistry research program,
we were interested in synthesizing N-(4-(2-aminopyri-
H
N
S
R
din-4-yl)thiazol-2-yl)-2-phenylacetamides 1. The synthe-
sis of this class of compounds has not been previously
reported to our knowledge. The most straightforward
synthetic approach to introduce an amino group at the
2-position of pyridine is by thermal or microwave
assisted reaction of benzylamines with 2-chloro or
2-fluoropyridines 2 to afford 3,1 or by transition metal
assisted coupling of 2-halopyridines with benzyl amines
or ammonia equivalents2 (Fig. 1). These methods failed
in our hands despite attempts under various reaction
conditions.
O
N
1: X = NH2
2: X = F, Cl
3: X = NHCH2Ar
N
X
Figure 1. Thiazolyl pyridines.
Phenylacetylthioureas 5 could be readily synthesized
from commercially available phenylacetic acids 4,
which were first converted to acid chlorides with oxalyl
chloride and then reacted with excess thiourea to give
phenylacetylthioureas 5 in 30–50% yield4 (Scheme 1).
An alternative approach involves the Hantzsch reaction
between a phenylacetylthiourea and an appropriate
2-benzylamino-4-(2-bromoacetyl)pyridine. This reaction
has been utilized successfully to form the analogous N-
(4-(3-aminophenyl)thiazol-2-yl)acetamides starting from
3-nitroacetophenone.3 However we could not apply this
transformation directly to the pyridine systems as the re-
quired starting material, 2-nitro-4-acetylpyridine, is not
commercially available nor easily accessed synthetically.
Therefore, we modified the reaction sequence, and below
we report our successful efforts to prepare N-(4-(2-
aminopyridin-4-yl)thiazol-2-yl)-2-phenylacetamides in a
one-pot procedure using a modification of this route.
The synthesis of the other condensation partner,
2-p-methoxybenzylamino-4-(2-bromoacetyl)pyridine 6,
is outlined in Scheme 2. The reaction of 2-fluoro-4-
cyanopyridine 75 with p-methoxybenzylamine in DMA
at 130 ꢀC gave 8 in high yield. Compound 8 was subse-
quently converted to the 4-acetylpyridine 9 in good yield
by treatment with methyl magnesium bromide.
The reaction of 9 with bromine in a mixture of 48%
aqueous HBr and acetic acid at 70 ꢀC over 30 min gave
1. (COCl)2, CH2Cl2
H
cat. DMF
OH
N
NH2
R
R
2. thiourea
THF, reflux
O
O
S
Keywords: 2-Aminopyridine; Thiourea; Thiazole; Bromination;
a-Bromoketone.
Corresponding author. Tel.: +1 617 444 6882; fax: +1 617 444
7827; e-mail: upul_bandarage@vrtx.com
4
5
*
Scheme 1. Synthesis of monoacylated thiourea.
0040-4039/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.09.053

8080
U. K. Bandarage et al. / Tetrahedron Letters 47 (2006) 8079–8081
Table 1. Formation of N-(4-(2-aminopyridin-4-yl)thiazol-2-yl)-2-phenyl-
CN
N
MeO
F
CN
acetamides
1. 3M MeMgBr, ether
2. 6N HCl
NH2
H
N
O
N
H
DMA
130 °C, 1 h
1. Br2, 48% aq. HBr,
AcOH, 70 °C, 2 h
S
R
N
O
N
OMe
7
8
2. 5, EtOH, 70 °C, 1 h
N
N
H
Br
Br
OMe
N
NH2
O
O
O
9
1
Br2, 48% HBr
+
Entry
Product
Yield
56
70 °C
O
O
S
S
N
N
H
N
NH2
N
N
H
N
1
N
N
N
H
O
OMe
OMe
9
6
10
H2N
Scheme 2. Synthesis of 2-p-methoxybenzylamino-4-(2-bromoacetyl)-
pyridine 6.
N
2
3
4
46
52
36
N
H
H2N
F
O
S
N
N
N
N
N
N
H
H
N
F
O
S
R
1. Br2, 48% aq. HBr,
AcOH, 70 °C, 2 h
H2N
O
Cl
N
O
O
S
O
O
O
N
2. 5, EtOH, 70 °C, 1 h
N
H
N
N
H
H2N
N
NH2
OMe
S
S
9
1
N
5
6
38
43
N
H
O
Cl
Scheme 3. Preparation of N-(4-(2-aminopyridin-4-yl)thiazol-2-yl)-2-
phenylacetamides.
H2N
N
N
H
Cl
F
H2N
a mixture of the desired a-bromoketone 6 as well as the
debenzylated 2-amino-4-(2-bromoacetyl)pyridine 10.
Heating the reaction mixture for a longer period of time
(2 h) at 70 ꢀC, resulted in the formation of 10 exclusively
(Scheme 2).
O
S
N
7
8
48
52
28
48
N
N
H
H2N
F
O
O
S
S
The isolation of 10 proved problematic due to its high
water solubility. Therefore, generation of 10 in situ, fol-
lowed by reaction with 5 was next considered. Upon
completion of a-bromination and cleavage of the
p-methoxybenzyl (PMB) group, the resulting 10 was
directly reacted with an ethanolic solution of 5 to afford
the target molecule, 1 (Scheme 3). This one-pot, three-
step transformation was employed to produce a variety
of substituted N-(4-(2-aminopyridin-4-yl)thiazol-2-yl)-2-
phenylacetamides in moderate yields after chromatogra-
phy6 (Scheme 3). The results of the reactions between
various phenylacetylthioureas 5 and 9 are summarized
in Table 1.
N
N
N
N
H
H2N
N
9
N
H
OH
O
H2N
O
S
S
O
N
10
N
N
H
N
H
H2N
Acknowledgments
In conclusion, we have developed an efficient one-pot,
three-step synthesis of N-(4-(2-aminopyridin-4-yl)thi-
azol-2-yl)-2-phenylacetamides from readily available
starting materials in moderate yield. This method is par-
ticularly useful for the selective preparation of N-acyl-
aminothiazoles in the presence of an aminopyridine
group in the same molecule and therefore, provides easy
access for the variation of acylated thiazole moiety for
structure activity relationship studies in medicinal chem-
istry research.
The authors wish to acknowledge Dr. Robert Perni and
Joe Drumm at Vertex Pharmaceuticals for valuable
comments and suggestions.
References and notes
1. Usui, S.; Suzuki, T.; Hattori, Y.; Etoh, K.; Fujieda, H.;
Nishizuka, M.; Imagawa, M.; Nakagawa, H.; Kohda, K.;
Miyata, N. Bioorg. Med. Chem. Lett. 2005, 15, 1547–1551.

U. K. Bandarage et al. / Tetrahedron Letters 47 (2006) 8079–8081
8081
2. (a) Lee, S.; Jorgensen, M.; Hartwig, J. F. Org. Lett. 2001, 3,
2729–2732; (b) Hartwig, J. F. In Modern Amination
Methods; Ricci, A., Ed.; Wiley-VCH: Weinheim, 2000; (c)
Wolfe, J. P.; Wagaw, S.; Marcoux, J. F.; Buchwald, S. L.
Acc. Chem. Res. 1998, 31, 805–818.
3. (a) Kawamatsu, Y.; Sohda, T.; Imai, Y. Eur J. Med. Chem.
Chim. Ther. 1981, 16, 355–362; (b) Ohkubo, M.; Kuno, A.;
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1497–1504.
(500 MHz, DMSO-d6) 11.23 (s, 1H), 9.55 (br s, 1H), 9.36
(br s, 1H), 7.23 (dd, J = 7.9 Hz, 1H), 6.82–6.87 (m, 3H),
3.73 (s, 3H), 3.66 (s, 2H); Electrospray MS: m/z = 225
(MH+).
5. Frey, L. F.; Marcantonio, K.; Frantz, D. E.; Murry, J. A.;
Tillyer, R. D.; Grabowski, E. J. J.; Reider, P. J. Tetrahedron
Lett. 2001, 42, 6815–6818.
6. General procedure for the preparation of N-(4-(2-amino-
pyridin-4-yl)thiazol-2-yl)-2-phenylacetamides. Bromine (0.01
mL, 0.195 mmol) was added to a stirred solution of 2-p-
4. General procedure for the preparation of phenyl-
acetylthiourea. A solution of oxalyl chloride in CH2Cl2
(2 M, 4.5 mL, 9 mmol) was added to a stirred solution of m-
methoxyphenylacetic acid (1.0 g, 6.02 mmol) in DMF
(0.1 mL) and CH2Cl2 (25 mL) and the resulting clear
solution was stirred at ambient temperature for 1 h. The
solvent was removed under reduced pressure and the acid
chloride residue was dissolved in THF (25 mL), and
thiourea (1.82 g, 24 mmol) was added. The mixture was
refluxed for 6 h and cooled to room temperature. The
solution was poured into water (100 mL) and extracted
with EtOAc (3 · 50 mL). The organic extracts were dried
over Na2SO4 and concentrated under reduced pressure. The
crude product was purified by column chromatography on
silica gel (hexanes–EtOAc) to give N-(3-methoxyphenyl-
methoxybenzylamino-4-acetylpyridine
9
(0.05 g, 0.195
mmol) in 48% aqueous HBr (0.2 mL) and AcOH (0.4 mL),
and the solution was heated at 70 ꢀC for 2 h. A solution of
N-(3-methoxyphenylacetyl)-thiourea
5
(0.044 g, 0.195
mmol) in ethanol (3 mL) was then added and the heating
was continued for 1 h. The solution was poured into water
(10 mL) and made basic by the addition of concentrated
NH4OH and the product was extracted with EtOAc
(3 · 10 mL). The crude product was purified by preparative
HPLC (column: Kromasil C8 21.2 · 150 mm; 20 mL/min;
gradient 10–90% MeCN (0.1% TFA) in H2O (0.1% TFA)
1
over 15 min) to give 1 (Table 1, entry 1) (56%). H NMR
(500 MHz, DMSO-d6) 12.6 (br s, 1H), 7.93 (d, 1H), 7.86 (s,
1H), 7.24 (t, 1H), 7.09 (s, 2H), 6.83–6.93 (m, 5H), 3.77 (s,
2H), 3.73 (s, 3H); Electrospray MS: m/z = 341 (MH+).
1
acetyl)-thiourea 5 (0.48 g, 35%) as a white solid. H NMR