Novel methods to functionalize thiazolo[4,5-c]pyridines

Article abstract of DOI:10.1016/j.tetlet.2010.03.069

Novel substituted thiazole[4,5-c]pyridines have been synthesized in good yields from unsubstituted thiazole[4,5-c]pyridine using direct C-H coupling reactions and N-oxide rearrangement chemistry.

Full text of DOI:10.1016/j.tetlet.2010.03.069

Tetrahedron Letters 51 (2010) 2797–2799
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Novel methods to functionalize thiazolo[4,5-c]pyridines
*
Vinay Girijavallabhan , Ashok Arasappan, Frank Bennett, Yuhua Huang, F. George Njoroge,
Malcolm MacCoss
Department of Medicinal Chemistry, Merck Research Labs, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel substituted thiazole[4,5-c]pyridines have been synthesized in good yields from unsubstituted thi-
azole[4,5-c]pyridine using direct C–H coupling reactions and N-oxide rearrangement chemistry.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 16 February 2010
Revised 3 March 2010
Accepted 16 March 2010
Available online 21 March 2010
The use of heterocycles in medicinal chemistry has grown sig-
nificantly in the past 20 years. Therefore, novel heterocycles that
can be readily functionalized are highly sought after by medicinal
chemists. This Letter will describe the synthesis of a series of func-
tionalized thiazole[4,5-c]pyridine analogs that to the best of our
knowledge have not been previously reported in the literature.
These cores hold significant interest since similar core structures
have been found to be present in kinase inhibitors as well as
numerous other biological relevant compounds.1
It is known that the treatment of N-oxides of pyridine with
either phosphorus oxychloride or acetic anhydride at high temper-
atures can provide rearrangement products.3 We envisioned that
this chemistry could be used on compound 1 to provide substitu-
tion at the 4- or 6-position. Treatment of compound 1 with m-CPBA
provided the N-oxide 6 which was treated with refluxing phospho-
rus oxychloride to provide a good yield of the corresponding chlo-
ride 7 (Scheme 2).4 Treatment of the N-oxide 6 with refluxing
4
N
N
N
2
N
N
b
a
6
c
S
Boc
Boc
N
H
1
NH2
N
H
SH
The synthesis of thiazolo[4,5-c]pyridine (1) has been previously
reported in the literature.2 Since our interests lay in the function-
alizations of this ring system at the 2-, 4-, and 6-positions, it was
desirable to modify the literature procedure in order to have access
to multigram quantities of compound 5, a versatile intermediate
for further transformations (Scheme 1). The synthesis began with
the protection of 3-aminopyridine (2) with a Boc group using so-
dium hexamethyldisilazide as a base (Scheme 1). The use of trieth-
ylamine, Hunig’s base or DMAP in this reaction provided lower
yields of the desired product due to competing reactions between
the pyridine nitrogen and the 3-amino group. Compound 3 was
treated with two equivalents of n-BuLi and then quenched with
elemental sulfur to provide compound 4. The removal of the Boc
group was achieved by treatment of a solution of 4 in acetic acid
with 4 M HCl dioxane. The product could be easily filtered at this
stage to provide the hydrochloride salt of 5 or cyclized to the cor-
responding pyridylthiazole 1 by treatment with refluxing formic
acid. Using this chemistry, multigram quantities of compounds 1
and 5 could be synthesized and used for further transformation.
2
3
4
N
d
N
S
HCl
NH2
N
SH
5
1
Scheme 1. Synthesis of thiazole[4,5-c]pyridine. Reagents: (a) NaHMDS, Boc2O, 79%;
(b) 2.5 M n-BuLi, sulfur, 50%; (c) 4 M HCl dioxane, AcOH, 95%; (d) formic acid, 90%.
Cl
N
N
-O
b
S
N
S
N+
N
S
a
N
7
OH
O
6
1
c, d
N
S
N
S
e
N
N
8
9
Scheme 2. Functionalization of the 4-position. Reagents: (a) m-CPBA, CH2Cl2, 95%;
(b) POCl3, 80%; (c) Ac2O; (d) 7 M NH3 in MeOH (50% over two steps); (e) Ag2CO3, Etl,
chloroform, 55% (4:1 O vs N-alkylation).
* Corresponding author. Tel.: +1 908 740 4061.
E-mail address: Vinay.Girijavallabhan@spcorp.com (V. Girijavallabhan).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.069

2798
V. Girijavallabhan et al. / Tetrahedron Letters 51 (2010) 2797–2799
acetic anhydride, followed by 7 N ammonia in methanol provided
product 8. It is important to note that both these reactions pro-
vided exclusively the 4-substituted derivatives 7 and 8. Compound
8 could be further transformed to the O-alkyl pyridines such as
compound 9 by treatment with the corresponding alkyl halide
and silver carbonate in refluxing chloroform. This reaction pro-
vided a 4:1 O versus N ratio that was easily separable by column
chromatography.
The 4-chloro intermediate 7 is a very versatile intermediate that
could be used in various coupling reactions or nucleophilic dis-
placement reactions, but our research focused on the incorporation
of small alkyl functionality at this position. The use of Grignard re-
agents to incorporate small alkyl groups provided decomposition
of the starting material, but it was found that the commercially
available trialkylaluminums could be used in the presence of palla-
dium (0) sources to provide good yields of the corresponding 4-al-
kyl compounds 10–14 (Table 1).5 The cyclopropyl substituted
analog 14 was synthesized using the corresponding cyclo-
propylzincbromide in the presence of palladium (0) in good yield.6
Next, we turned our attention to the 6-position of the pyridyl-
thiazole. Since the N-oxide rearrangement chemistry worked well
to provide access to the 4-position of the heterocyclic core, this
chemistry was revisited using compound 10 with the hope that
the 4-methyl group would induce substitution at the 6-position.
Treatment of 10 with m-CPBA in methylene chloride provided a
good yield of the N-oxide 15 (Scheme 3). The N-oxide 15 was sub-
jected to refluxing phosphorus oxychloride, but the only product
isolated was the rearrangement product 16. This problem was
solved when the acetic anhydride rearrangement provided a mix-
ture of compounds 17 and 18 that could be easily separated by col-
umn chromatography. The synthesis of compound 18 allowed for
further transformation to compounds of type 19.
The functionalization of the 2-position could be carried out in
multiple ways. One of our thoughts was to treat compound 5 with
various acids in order to access novel substitution patterns. Thus,
the treatment of compound 5 with acetic acid or benzoic acid pro-
vided modest yields of products 20–21 (Table 2). The use of acid
chlorides or activated acids for the cyclization failed due to the
instability of compound 5 under basic conditions reaction condi-
tions. Treatment of compound 5 with ethylcyanoacetate provided
a good yield of compound 22, but when similar reactions were per-
formed with various benzonitriles very low yields of compounds
such as 23 were obtained.
Since our research required the ability to introduce a variety of
aryl groups at the 2-position, we required a more robust method to
incorporate these functionalities. We envisioned that compound 1
could be a good substrate for a direct C–H coupling reaction since it
is known that benzothiazole undergoes this reaction readily.7
When compound 1 was treated with a palladium (0) source, CuI,
cesium carbonate and a corresponding aryl/heteroaryl iodide/bro-
mide, good yields of the biaryl compounds 23–31 were achieved
(Scheme 4).8 Compounds 23–26 suggest that the position of ring
substitution does not greatly affect the yield of the direct coupling.
The vastly different yields obtained for compounds 27 and 28 sug-
gest that electronics may play a role in the direct coupling reaction,
but more detailed studies would be needed to confirm this hypoth-
esis. The good yield of compound 29 demonstrates that the direct
coupling is selective for the iodide versus the chloride. Compounds
30 and 31 confirm that the direct coupling reaction does not suffer
when using heteroaryl halides. The reasonable yield of 31 also sug-
gests that aryl bromides can be coupled efficiently using this
method.
Table 1
Pd-catalyzed alkylations
R
Cl
N
S
N
S
R3Al
N
N
Pd(PPh3)4
dioxane
100 ºC
10-14
7
R
Compound
Yield (%)
Me
Et
n-Propyl
i-Pr
Cyclopropyl
10
11
12
13
14
84
80
72
70
75a
In summary, we have developed methods to provide substi-
tuted novel pyridylthiazole ring systems. The chemistry developed
allowed for the multigram scale synthesis of these interesting het-
erocycles with a variety of functional groups. Further efforts are
ongoing to expand the scope of functionalization around this novel
thiazole[4,5-c]pyridine core.
a
Reaction was performed using 0.5 M cyclopropylzincbromide in THF in the
presence of Pd(PPh3)4.
Cl
Table 2
Functionalization of the 2-position using compound 5
N
S
N
N
Reagent
N
S
b
N
R
-O
a
16
NH2 .HCl
100 ºC
N
S
N+
N
S
N
SH
sealed tube
AcO
N
5
20-23
15
10
c
N
S
N
N
+
Compound
Reagent
R
Yield (%)
62
AcO
S
O
18
17
20
Me
Ph
2:1
d, e
HO
O
21
43
HO
N
N
O
O
S
EtO
22
23
80
NC
OEt
OEt
F
19
NC
Scheme 3. Functionalization of the 6-position. Reagents: (a) 77% m-CPBA, CH2Cl2,
95%; (b) POCl3, 85%, (c) Ac2O (30% of 18); (d) 7 M NH3 in MeOH; (e) Etl, Ag2CO3,
CHCl3 (51% d + e).
4-F-Ph
<10

V. Girijavallabhan et al. / Tetrahedron Letters 51 (2010) 2797–2799
2799
Ar-X
N
S
References and notes
N
S
N
N
Ar
Reagents
1. (a) Chong, J.; Fanger, C.; Larsen, G.; Lumma, W.; Moran, M.; Ripka, A.;
Underwood, D.; Weigele, M.; Zhen, X. US Pat. Appl. Publ. (2007), US
2007213321 A1 20070913.; (b) Liu, C.; Leftheris, K.; Lin, J. PCT Int. Appl., WO
2007016392, 2007.; (c) Rao, A.; Palani, A.; Chen, X.; Huang, Y.; Aslanian, R.;
West, R.; Williams, S.; Wu, R.; Hwa, J.; Sondey, C.; Lachowicz, J. Bioorg. Med.
Chem. Lett. 2009, 19, 6176–6180.
2. Haginoya, N.; Komoriya, S.; Osanai, K.; Yoshino, T.; Nagata, T.; Nagamochi, M.;
Muto, R.; Yamaguchi, M.; Nagahara, T.; Kanno, H. Heterocycles 2004, 63, 1555–
1561.
1
Compound
23
Ar
X
I
Yield %
F
70
3. (a) Anderson, W.; Dean, D.; Endo, T. J. Med. Chem. 1990, 33, 1667–1675; (b)
Walters, M.; Shay, J. Tetrahedron Lett. 1995, 36, 7575–7578.
F
F
4. Representative experimental for compound 7. Compound 1 (4.0 g, 29.4 mmol)
was dissolved in methylene chloride (150 mL) and 77% m-CPBA (11.4 g, 52 mmol)
was added. The reaction was stirred for 2 h and then quenched with a solution of
1 M potassium carbonate. The aqueous layer was saturated with brine and
extracted with methylene chloride several times. The organic layers were dried
over sodium sulfate and concentrated to provide the crude N-oxide 6 (4.25 g).
Crude compound 6 (4.25 g, 27.9 mmol) was dissolved in phosphorus oxychloride
(70 mL) and refluxed for 2 h. The reaction was concentrated under reduced
pressure and then slowly quenched with ice chips. The reaction mixture was
treated with saturated sodium bicarbonate solution and extracted with ethyl
acetate several times. The combinedorganic layers were driedover sodium sulfate
and concentrated. Column chromatography (1:1 ethyl acetate/hexanes) provided
provide compound 7 (3.79 g).
24
25
I
I
91
71
26
27
28
I
I
I
92
89
32
1H NMR spectrum (400 MHz, CDCl3 d: 9.15 (s, 1H), 8.4 (d, 1H), 7.9 (d, 1H).
Spectrum 13C NMR (DMSO-d6 d: 118, 143.4, 144.5, 144.8, 146.7, 159.8. LRMS:
[M+H] = 171.03.
CN
OMe
Cl
5. Joubert, N.; Pohl, R.; Klepetarova, B.; Hocek, M. J. Org. Chem. 2007, 72, 6797–
6805.
6. Representative experimental for compound 10. Compound 7 (1.6 g, 9.35 mmol),
and Pd(PPh3)4 (400 mg, 0.346 mmol) were dissolved in dioxane (30 mL) under a
nitrogen atmosphere and 2 M AlMe3 in hexanes (14 mL, 28 mmol) was added.
The reaction was refluxed for 3 h and then was cooled in an ice bath and slowly
quenched with water and then extracted with ethyl acetate several times. The
combined organic layers were dried over sodium sulfate and concentrated.
Column chromatography (2:1 ethyl acetate/hexanes) provided compound 10
(1.2 g).
1H NMR spectrum (400 MHz, CDCl3 d: 9.05 (s, 1H), 8.45 (d, 1H), 7.76 (d, 1H), 3.05
(s, 3H). Spectrum 13C NMR (DMSO-d6 d: 21.5, 115.9, 141.8, 143.4, 148.6, 154.1,
156.8. LRMS: [M+H] = 151.25.
29
30
31
I
I
83
75
64
7. Sommai, P.; Tetsuya, S.; Yoshiki, K.; Masahiro, M.; Masakatsu, N. B. Chem. Soc.
Jpn. 1998, 71, 467–473.
N
8. Experimental for compound 23. Compound
1 (200 mg, 1.45 mmol), 4-
fluoroiodophenol (383 mg, 1.74 mmol), Pd(PPh3)4, (83 mg, 0.072 mmol), CuI
(14 mg, 0.072 mmol), and cesium carbonate (1.41 g, 4.35 mmol) were combined
in DMF (10 mL) and stirred at 120 °C for 2 h. The reaction mixture was filtered
over Celite and diluted with water and ethyl acetate. The organic layer was
washed with water and brine, dried over sodium sulfate, and concentrated.
Column chromatography (1:1 ethyl acetate/hexanes) provided compound 23
(233 mg).
SMe
N
N
Br
1H NMR spectrum (400 MHz, CDCl3 d: 9.4 (s, 1H), 8.55 (d, 1H), 8.1–8.2 (m, 2H),
7.95 (d, 1H), 7.2–7.3 (m, 2H). Spectrum 13C NMR (DMSO-d6 d: 116.9, 117.1,
117.9, 130.4, 130.5, 142.9, 144.3, 144.9, 150.6, 163.4, 165.9, 168.1. LRMS:
[M+H] = 231.23.
Scheme 4. Direct coupling via C–H activation. Reagents: (a) Pd(PPh3)4, CuI, Cs2CO3,
Ar-I, DMF, 110 °C.