Regioselective synthesis of benzimidazole thiophene inhibitors of polo-like kinase 1

Article abstract of DOI:10.1016/j.tetlet.2008.08.077

A regioselective synthesis of novel 1-(2-thienyl)-benzimidazole inhibitors of polo-like kinase 1 is described. Amination of substituted 2-iodo or -bromo nitrobenzenes with a 2-aminothiophene derivative catalyzed by Pd₂dba₃ and XANTPH

Full text of DOI:10.1016/j.tetlet.2008.08.077

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Tetrahedron Letters 49 (2008) 6348–6351
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Tetrahedron Letters
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Regioselective synthesis of benzimidazole thiophene inhibitors
of polo-like kinase 1
*
Keith R. Hornberger , Jennifer G. Badiang, James M. Salovich, Kevin W. Kuntz, Kyle A. Emmitte, Mui Cheung
Department of Medicinal Chemistry, Oncology Center of Excellence for Drug Discovery, GlaxoSmithKline, Research Triangle Park, NC 27709, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A regioselective synthesis of novel 1-(2-thienyl)-benzimidazole inhibitors of polo-like kinase 1 is
described. Amination of substituted 2-iodo or -bromo nitrobenzenes with a 2-aminothiophene derivative
catalyzed by Pd2dba3 and XANTPHOS in the presence of excess Cs2CO3 afforded good yields of the coupled
products. Subsequent reduction and cyclization of these intermediates provided the desired benzimid-
azole compounds.
Received 18 July 2008
Revised 11 August 2008
Accepted 21 August 2008
Available online 27 August 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Amination
Palladium-catalyzed
Catalysis
Benzimidazoles
PLK
Polo-like kinase (PLK) belongs to a family of highly conserved
serine/threonine kinases that regulate multiple critical processes
during mitosis.1 The unique role of PLK in the cell cycle has
prompted the pharmaceutical industry to explore development
of small molecule inhibitors of PLK as a therapy for the treatment
of cancer.2,3 Recently, we have discovered a novel class of inhibi-
tors of the polo-like kinase 1 (PLK1) represented by the generic
structure 1 (Fig. 1).4
A key challenge surrounding these compounds has been their
efficient synthesis. Our original synthetic route involved a non-reg-
ioselective addition of a substituted benzimidazole 2 to the enone
3 (Scheme 1).4b,5 In the early stages of our lead optimization pro-
gram, this methodology offered a facile entry into 1-(2-thienyl)-
N
N
HN
N
S
S
CO2Me
Cl
O
N
N
CO2Me
OH
+
CHCl3
R
R
2
3
~1:1 regioisomer
mixture
HO
N
X
S
N
CO2Me
X
NH3
MeOH
O
1
R
Δ
Mitsunobu
O
N
S
N
Scheme 1. Non-regioselective route to compounds of structure 1.
NH2
O
R
X
benzimidazoles necessary for a rapid build-up of structure-activity
relationships around the benzimidazole core. As we became inter-
ested in specific substitution patterns, however, we required a
more efficient route to specific regioisomers. Herein, we report a
convenient solution to this regiochemical problem utilizing a pal-
ladium-catalyzed amination reaction.
1
R = various substitutions
X = Cl, CF3
In seeking a solution to this regiochemical impasse, we focused
on N-substituted 2-nitroanilines such as 4 as the immediate syn-
thetic precursors to the ultimate benzimidazole targets. In this sys-
tem, the two nitrogen atoms are differentiated by oxidation state
Figure 1. Generic structure of PLK1 inhibitors.
* Corresponding author. Tel.: +1 919 483 6206; fax: +1 919 483 6053.
E-mail address: keith.r.hornberger@gsk.com (K. R. Hornberger).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.077
Please cite this article in press as: Hornberger, K. R. et al., Tetrahedron Lett. (2008), doi:10.1016/j.tetlet.2008.08.077

ARTICLE IN PRESS
K. R. Hornberger et al. / Tetrahedron Letters 49 (2008) 6348–6351
6349
(and thus nucleophilicity), providing a viable solution to the prob-
lem of regioselectivity. The subsequent reduction and cyclization
of substituted 2-nitroanilines to the corresponding benzimidazoles
are well-precedented;6 these operations may also conveniently be
carried out in a one-pot transformation.7 The most straightforward
route to 4 would entail conjugate addition of a nitroaniline to the
enone 3. In practice, however, such reactions gave no products un-
der a variety of conditions (data not shown), presumably due to the
poor nucleophilicity of nitroanilines. We then attempted to form
the key aniline bond via a nucleophilic aromatic substitution
(SNAr) reaction of 2-fluoronitrobenzene (5) with 2-aminothioph-
ene 6a8 (Table 1). Unfortunately, this model reaction proceeded
inefficiently under a variety of conditions, giving at best only 34%
isolated yield of 4 (Entry 7). The frequently observed side product
7 (arising via addtion of 4–5) further complicated the reaction
profile.
Reasoning that perhaps the poor nucleophilicity of 6a was the
culprit in this transformation, we next explored a variety of Pd-
and Cu-catalyzed aminations between 6a and 2-iodonitrobenzene
8 (Table 2).9 The combination of a Pd2dba3 catalyst and XANTPHOS
ligand, previously utilized in a single instance for an aminothioph-
ene substrate,10 proved uniquely effective in catalyzing this pro-
cess. In contrast to many published procedures, it was beneficial
to run this particular reaction in the presence of 5 equiv of base
(Cs2CO3) to obtain optimal yields (Table 2, compare entries 9 and
10). A full equivalent of base is likely consumed in the deprotona-
Table 1
SNAr reaction between 5 and 6aa
H
N
O2N
S
S
NO2
H2N
CO2Me
CF3
NO2
S
CO2Me
CF3
O2N
F
N
CO2Me
CF3
O
O
+
5
Me
6a
Me
O
Me
conditions
4
7
Entry
Base (equiv)
Solvent
Temp (°C)
Time (h)
4 (%)
7 (%)
1
2
3
4
5
6
7
8
9
K2CO3 (2.5)
K2CO3 (2.0)b
KHMDS (3.0)
PS-TBD (2.5)
LiOH (2.5)
LiOH (2.0)b
LiOH (5.1)
i-Pr2NEt
MeCN
DMSO
THF
MeCN
DMF
DMF
DMF
DMF
neat
60
80
0 to rt
60
60
19
18
20
19
19
18
72
10 min
1
11
0
0
0
0
17
34c
0
0
19
0
0
20
43
0
0
0
60
rt to 30
200d
80d
DBU (2.0)e
0
a
All reactions used 1 equiv of 6a, 2.0 equiv of 5 at a substrate concentration of 0.1 M in the indicated solvent. All yields are isolated yields of the indicated products.
1.1 equiv. of 5.
26% Recovered 6a.
Microwave heating.
1.0 equiv. of 5.
b
c
d
e
Table 2
Optimization of Pd- or Cu-catalyzed amination of 8 with 6a
H
N
O2N
S
NO2
S
H2N
CO2Me
CO2Me
CF3
I
O
O
CF3
PMBO
PMBO
8
Me
6a
Me
9
conditions
Entry
Cat. (mol %)
L (mol %)
None
Solvent
Base (equiv)
Temp (°C)
Time (h)
Yielda
b
1
2
3
4
5
6
7
8
9
(2)
PhMe
PhMe
THF
DME
DME
t-BuOH
PhMe
PhMe
1,4-Dioxane
1,4-Dioxane
NaOMe/Et3N (2.0/0.5)
NaOt-Bu (2.4)
NaOt-Bu (2.5)
K3PO4 (2.8)
K3PO4 (2.8)
K2CO3 (5.0)
Cs2CO3 (2.8)
Cs2CO3 (3.0)
Cs2CO3 (1.4)
Cs2CO3 (5.0)
60
rt
100
80
80
22
26
26
18
18
16
17
24
18
16.5
<10
19
0
0
0
19
0
0
59
78
c
Pd2dba3 (2.5)
PdCl2dppf (5)
Pd2dba3 (0.5)
Pd2dba3 (0.5)
Pd2dba3 (1)
Pd(OAc)2 (3)
CuBr(PPh3)3 (20)
Pd2dba3 (2)
(5)
dppf (15)
d
(2)
(2)
e
X-Phos (8)
BINAP (4.5)
None
XANTPHOS (4.4)
XANTPHOS (4.4)
80
100
110
60
10
Pd2dba3 (2)
60
a
Isolated yield.
b
c
Acetato(20-di-t-butylphosphino-1,10-biphenyl-2-yl)palladium (II).
1,10-Bis(di-t-butylphosphino)ferrocene.
d
e
2-(Dicyclohexylphosphino)-20-(N,N-dimethylamino)biphenyl.
2-(Dicyclohexylphosphino)biphenyl.
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ARTICLE IN PRESS
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K. R. Hornberger et al. / Tetrahedron Letters 49 (2008) 6348–6351
Table 3
Substrate scope of palladium-catalyzed amination between 6 and 10a
NO2
H
N
H2N
S
S
CO2Me
Y
Pd2dba3, XANTPHOS
Cs2CO3
CO2Me
Y
NO2
X
3
O
+
R
O
4 R
6
1,4-dioxane, 60 ºC
5
6a Y = CF3
6b Y = Cl
10
11
Entry
R
X
Y
Time (h)
Product
Yield (%)
1
2b
3c
4
5
6
7
8
9
10
11
4-OPMB
4-Br
4-CN
5-OPMB
5-OCF3
5-CH(OMe)2
4-O(CH2)2TMS, 5-Cl
4-Br, 5-OPMB
5-CH2OPiv
6-Me
I
Br
Cl
CF3
CF3
CF3
CF3
CF3
CF3
Cl
16.5
1.75
24
24
15.5
18
11a
11b
11c
11d
11e
11f
11g
11h
11i
78
61
67
74
79
81
44
37
dec
dec
dec
Br
Br
Br
Br
Br
OTf
Br
Br
20
Cl
ꢀ18
CF3
CF3
CF3
2
24
17
11j
11k
3-Me
a
Standard conditions: Pd2dba3 (2 mol %), XANTPHOS (4.4 mol %), 6 (1.05 equiv), 10 (1.0 equiv), Cs2CO3 (5.0 equiv), 1,4-dioxane (0.25 M concentration). All compounds had
satisfactory 1H NMR and HPLC/MS analyses.
b
Toluene was used as solvent.
1.4 equiv Cs2CO3, 0.10 M concentration.
c
tion of 9, whose aniline N–H has a substantially enhanced acidity
due to the electron-withdrawing substitutions of and attachment
to two aromatic rings.
NO2
N
H
N
S
S
N
CO2Me
CF3
CO2Me
CF3
a
With the optimal conditions now in hand, we explored the sub-
strate scope of this process (Table 3).11 A variety of coupling part-
ners 10 reacted with 6 to provide the desired products 11 in good
yields. Both electron-donating and electron-withdrawing substitu-
ents are tolerated (entries 1–5), as are alcohols and aldehydes
suitably protected for further elaborations (entries 1, 4, 6–8). Sub-
strates containing potentially labile protons (e.g., aldehydes, phe-
nols, and amides) underwent extensive decomposition (data not
shown). Aryl iodides and bromides are both useful coupling part-
ners, and in one sufficiently electron-deficient case (entry 3), an
aryl chloride could be used. Reaction with a triflate substrate (en-
try 9) was unsuccessful, presumably due to competitive hydrolysis
of the triflate moiety by adventitious water present in the reaction
medium. It was even possible to selectively couple a dibromo sub-
strate (entries 2, 8) by taking advantage of the activating effects of
the neighboring nitro group. Methyl substitution ortho to the ha-
lide (entry 10) was not tolerated, presumably due to increased ste-
ric hindrance. Interestingly, methyl substitution ortho to the nitro
group (entry 11) was also not tolerated, leading instead to sub-
strate decomposition.
The products listed in Table 3 could then be readily converted to
the corresponding benzimidazoles. For example, 11f was reduced
and cyclized in one pot7 to benzimidazole 12 by hydrogenation
over sulfided platinum on carbon in trimethyl orthoformate
(Scheme 2). Benzimidazole 12 was further transformed in three
steps (acetal deprotection, reductive amination, and ester aminol-
ysis) to amide 13 (GSK461364). Compound 13, a potent, kinase-
and PLK isoform-selective human PLK1 inhibitor with an IC50 of
3 nM, has been selected as a clinical candidate for the treatment
of cancer.4c
O
O
MeO OMe
MeO
N
OMe
11f
12
S
N
CONH2
CF3
b, c, d
O
N
N
Me
13
(GSK461364)
Scheme 2. Synthesis of 13 (GSK461364). Reagents and conditions: (a) H2 (50 psi),
Pt(S)/C (5 mol %), PPTS (10 mol %), HC(OMe)3, rt, 3 h. (b) PPTS (10 mol %), acetone,
water, rt, 2 h (58%, 2 steps). (c) N-methylpiperazine, AcOH, Na(AcO)3BH, DCE, rt,
1.5–3 h (93%). (d) 7 N NH3 in MeOH, sealed tube, 70 °C, 40–48 h (89%).
example.10 The structure-activity relationships of the benzimid-
azoles 1 as PLK1 inhibitors, leading to the identification of 13
(GSK461364), will be the subject of further communications.
Supplementary data
Experimental procedures for the synthesis of aminothiophene 6
and substrates 10a, 10d, 10f–i. Supplementary data associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2008.08.077.
In summary, we have developed an efficient method for the reg-
ioselective synthesis of 1-(2-thienyl)benzimidazoles via a palla-
dium-catalyzed amination reaction.12 The use of XANTPHOS as
ligand was uniquely effective in this setting, showing a generality
for this substrate class beyond a previously reported isolated
References and notes
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Please cite this article in press as: Hornberger, K. R. et al., Tetrahedron Lett. (2008), doi:10.1016/j.tetlet.2008.08.077

ARTICLE IN PRESS
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6351
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0.0088 mmol), aminothiophene 6a (72 mg, 0.21 mmol), iodobenzene
8
(77 mg, 0.20 mmol), Cs2CO3 (326 mg, 1.00 mmol), and 1,4-dioxane
(0.80 mL, degassed by sparging with N2 for 1 h). The flask was evacuated
and refilled with nitrogen (3ꢁ), then heated to 60 °C for 16.5 h. The reaction
was then cooled to room temperature, diluted with THF (10 mL), filtered to
remove solids (washing with another 10 mL THF), and concentrated.
Purification by flash column chromatography (10–40% ethyl acetate/
hexanes) afforded 94 mg (78%) of the coupled product
9 as a dark red
Identification of GSK461364,
a
novel small molecule polo-like kinase
1
foam, >95% HPLC/MS purity. 1H NMR (300 MHz, CDCl3): d 9.42 (br s, 1H),
7.90 (d, 1H, J = 8.3 Hz), 7.72 (d, 1H, J = 3.0 Hz), 7.61 (m, 2H), 7.42–7.34 (m,
3H), 7.25 (d, 1H, J = 9.1 Hz), 7.12 (m, 1H), 6.93 (m, 2H), 6.35 (s, 1H), 5.71 (q,
1H, J = 6.2 Hz), 4.99 (s, 2H), 3.87 (s, 3H), 3.83 (s, 3H), 1.72 (d, 3H, J = 6.2 Hz);
MS (ESI): 625.17 [M+Na]+; HRMS (ESI) calcd for C29H26F3N2O7S [M+H]+
603.1413, found 603.1409.
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