Two-step synthesis of 3-aryl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-ones

Article abstract of DOI:10.1055/s-2006-947355

One-pot tandem palladium-catalysed amination and intramolecular amidation of tert-butyl (2-chloropyridin-3-yl)carbamate with substituted primary anilines allows for the preparation of 3-arylated 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2- ones (49-90% yield)

Full text of DOI:10.1055/s-2006-947355

LETTER
2083
Two-Step Synthesis of 3-Aryl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-ones
Synthesis
e
of 3-Aryl-1
r
,3-Dihyd
e
ro-2
H
-Imi
m
dazo[4,5-
b
]pyridin-
y
2-ones P. Scott*
Department of Process Research, Merck Sharp & Dohme, Hertford Road, Hoddesdon, EN11 9BU, UK
Fax +44(1992)452581; E-mail: jeremy_scott@merck.com
Received 5 May 2006
R2
N
Abstract: One-pot tandem palladium-catalysed amination and
intramolecular amidation of tert-butyl (2-chloropyridin-3-yl)carb-
amate with substituted primary anilines allows for the preparation
of 3-arylated 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-ones (49–
NHBoc
NHBoc
Cl
1
O
3
H
N
R1
N
R1
N
N
N
3
4
90% yield) in two steps from commercially available materials.
1: R1, R2 = H
2: R1, R2 = alkyl, aryl
Key words: palladium, amination, tandem reaction, ring closure
Scheme 1
The 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one ring
system (1) constitutes the heterocyclic core of compounds
possessing a diverse range of biological properties
(Scheme 1). Indeed members of this structural class have
demonstrated anti-inflammatory, analgesic and antide-
pressant activities amongst others.1 General approaches
which will allow facile exploration of structure–activity
relationships within this class are therefore of value. The
preparation of unsymmetrical 1,3-disubstituted imida-
zo[4,5-b]pyridin-2-ones 2 (R1 ≠ R2) from 2,3-diamino-
pyridine as precursor is challenging and has required the
use of protecting group strategies.2 Access to 2 has also
been described from 2-chloro-3-nitropyridine;1b,1c how-
ever, the sequence suffers from limited scope with low
overall yields for the multistep sequence. A elegant ap-
proach based on the chemo- and regioselective palladium-
catalysed amination of 3-iodo-2-chloropyridine has re-
cently been reported3 and permits the preparation of 2
(R1 = aryl, R2 = alkyl or aryl) in four steps from commer-
cially available materials. In this letter, we report an alter-
native general approach to 3-arylated imidazopyridinones
2 (R1 = substituted aryl and heteroaryl; R2 = H) based on
a tandem reaction sequence, which uses commercially
available 3-amino-2-chloropyridine as the ultimate build-
ing block.
tion to take place in preference to competing amidation
with the secondary carbamate moiety.5 The protected
aminochloropyridine 46 is readily prepared on multigram
scale from 2-chloro-3-aminopyridine using the conditions
reported by Kelly for related aminopyridines (NaHMDS,
Boc2O, THF, 81% yield) and can be isolated by crystalli-
sation from i-PrOH–water.7,8
An initial survey of bidentate phosphine ligands9 for the
Pd-catalysed amination of 4 with aniline quickly identi-
fied XantPhos10,11 as most promising and established the
viability of the proposed tandem process. The results of
further optimisation of base, Pd precatalyst and solvent
combination to maximise the conversion of chloropyri-
dine 4, by way of intermediate 3a, to imidazopyridine 2a
are summarised in Table 1. The ethereal solvents tetra-
hydrofuran and dioxane were found to facilitate the in-
tramolecular amidative conversion of 3a to 2a (entries 1–
3, 4–6) in comparison to toluene when using Cs2CO3 as
base with up to 86A% of 2a formed in a mixture of tolu-
ene and tetrahydrofuran (entry 3). The addition of catalyt-
ic triethylamine12 was not found to be beneficial (entry 7)
whilst water suppressed ring closure of 3a (entries 8–10).
Further screening (entries 11–18) identified the combina-
tion of Pd2(dba)3 (3 mol%), XantPhos (6 mol%) with
t-BuONa as base in refluxing tetrahydrofuran13 (15 mL/g)
as optimum. Under these conditions, 2a was formed in up
to 93A% (entry 16) and was isolated in 82% yield
following chromatography.14 Alternatively, a solvent
combination of toluene–isopropanol (4:1) was also effec-
tive (entry 19).
Our synthetic route is outlined in Scheme 1 and required
amination of tert-butyl (2-chloropyridin-3-yl)carbamate
(4) with a primary aniline (R1NH2) to afford an intermedi-
ate 2,3-diaminopyridine 3 (R1 = substituted aryl and het-
eroaryl). We speculated that the 2-anilino nitrogen of 3
could engage in an intramolecular amidative ring closure
to afford the desired cyclic ureas 2 (R1 = aryl/heteroaryl;
R2 = H) in one-pot. To our surprise, no examples of tran-
sition-metal-catalysed amination of an aryl halide bearing
a carbamate protected amine in the ortho-position have
been previously reported.4 A palladium-catalysed process
would, however, be expected to allow the desired amina-
Control experiments in which either Pd2(dba)3, XantPhos
or t-BuONa were absent led to no consumption of 4 estab-
lishing that all three components are required (Table 1,
entries 20–22). Thus, under these conditions, the process
is Pd-catalysed and does not proceed by way of a simple
SNAr displacement of the 2-chloropyridine 4 by the
aniline nucleophile. Further support for a mechanistic
rationale proceeding by way of 3a is provided by the
observation that although urea 5 (readily formed by
condensation of 3-amino-2-chloropyridine with phenyl-
SYNLETT 2006, No. 13, pp 2083–2086
1
7
.0
8
.2
0
0
6
Advanced online publication: 12.07.2006
DOI: 10.1055/s-2006-947355; Art ID: D13006ST
© Georg Thieme Verlag Stuttgart · New York

2084
J. P. Scott
LETTER
With conditions established for the one-pot conversion of
4 to 2a, the scope of the aniline nucleophile in this process
was evaluated (Table 2). A wide range of substituted
anilines were found to be viable coupling partners afford-
ing the desired 3-arylated dihydroimidazopyridinones
2b–m in moderate to excellent isolated yields. Electron-
H
N
H
N
2 mol% Pd2(dba)3
4 mol% XantPhos
NH2
Cl
PhNCO
Ph
2a
O
CH2Cl2
(80%)
t-BuONa, THF
Cl
N
N
5
(43%)
Scheme 2
donating
and
electron-withdrawing
substituents
isocyanate) does undergo intramolecular cyclisation to 2a
under the optimised conditions (Scheme 2), 5 is not ob-
served in the conversion of 4 to 2a.15
engendering ester, nitrile, alkoxy, fluoro, trifluoromethyl
and chloro were tolerated on the aniline aromatic ring un-
der the reaction conditions developed (entries 2–11).
Table 1 Optimisation of Reaction Conditionsa
H
N
NHBoc
Cl
NHBoc
4–6 mol% Pd
4–6 mol% XantPhos
– t-BuOH
XantPhos
O
H
N
150 mol% PhNH2
base, additive
solvent
O
N
N
N
N
Ph
Ph
PPh2
PPh2
4
3a
2a
Entryb
Pd precatalyst
(mol%)
Solvent
(mL/g)
Base (mol%),
additive (mol%)
HPLC of 2a
(A%)
HPLC of 3a
(A%)
HPLC of 4
(A%)
1
2
Pd(OAc)2 (4)
Pd(OAc)2 (4)
Pd(OAc)2 (4)
Pd2(dba)3 (2)
Pd2(dba)3 (2)
Pd2(dba)3 (2)
Pd2(dba)3 (2)
Pd2(dba)3 (2)
Pd2(dba)3 (2)
Pd2(dba)3 (2)
Pd2(dba)3 (2)
Pd2(dba)3 (2)
Pd2(dba)3 (3)
Pd2(dba)3 (3)
Pd2(dba)3 (3)
Pd2(dba)3 (3)
Pd2(dba)3 (3)
Pd2(dba)3 (3)
Pd2(dba)3 (3)
Pd2(dba)3 (3)
None
toluene (10)
dioxane (10)
Cs2CO3 (130)
Cs2CO3 (130)
Cs2CO3 (130)
Cs2CO3 (130)
Cs2CO3 (130)
Cs2CO3 (130)
64
73
86
78
76
65
65
4
17
0
19
26
6
3
toluene (10), THF (1)
toluene (10)
8
4
18
0
2
5
dioxane (10)
24
35
13
54
11
22
17
16
18
18
7
6
toluene (10), THF (1)
toluene (10)
0
7
Cs2CO3 (130), Et3N (10)
Cs2CO3 (130), H2O (130)
Cs2CO3 (130), H2O (250)
Na2CO3 (140), H2O (140)
t-BuONa (130)
21
42
49
75
0
8
toluene (10)
9
toluene (10)
40
3
10
11
12
13
14
15
16
17
18
19
20
21
22
toluene (10)
toluene (15), THF (5)
toluene (15), THF (5)
toluene (15)
83
84
67
63
87
93 (82)c
80
83
87
0
t-BuONa (250)
0
t-BuONa (140)
15
19
6
toluene (20)
t-BuONa (140)
toluene (15)
t-BuONa (140)
THF (15)
t-BuONa (140)
5
2
THF (15)
t-BuOK (140)
20
11
2
2
toluene (20)
t-BuOK (140)
6
toluene–i-PrOH (20)d
THF (15)
t-BuONa (140)
9
None
0
100
100
100
THF (15)
t-BuONa (140)
0
0
Pd2(dba)3 (3)
THF (15)
t-BuONa (140)(no XantPhos)
0
0
a Reactions were performed at reflux for 18–23 h under N2 with 150 mol% PhNH2. HPLC A% were determined by reverse-phase analysis on
a Betasil C18 4.6 ꢀ 250 mm, 3 mm column at 210 nm.
b Entries 1–12, XantPhos (4 mol%); entries 13–21, XantPhos (6 mol%); entry 22, no XantPhos added.
c Isolated yield following purification by chromatography.
d Toluene–i-PrOH (4:1).
Synlett 2006, No. 13, 2083–2086 © Thieme Stuttgart · New York

LETTER
Synthesis of 3-Aryl-1,3-Dihydro-2H-Imidazo[4,5-b]pyridin-2-ones
2085
ortho-Substituents were viable (entries 4, 11) although in To date, efforts to extend the scope of this tandem reaction
the case of 2-methylaniline, a significant level of interme- sequence to encompass primary alkylamines have met
diate 3k (R1 = 2-MeC6H4) remained after 24 hours, pre- with limited success. Under the conditions optimised for
sumably due to steric encumbrance in the cyclisation to aniline coupling partners, only low levels of amination to
form 2k. Use of heterocyclic amines was also possible form the desired 3-alkylated dihydroimidazopyridinones
with the coupling of 3-aminopyridine (entry 12) proceed- have been observed with unconverted chloropyridine 4
ing uneventfully. However, 2-aminopyrazine was unreac- predominating in most instances along with other uniden-
tive (entry 13). Due to the high polarity and consequent tified impurities.17 Indeed the amination reactions of pri-
low solubility of the product pyridinones, the solvent mary alkyl amines with heteroaryl chlorides, such as 2-
combination of toluene–isopropanol (4:1) was superior to chloropyridine, have typically had limited scope and
THF in some instances, resulting in less viscous reaction required high catalyst loadings.18,19 Further evaluation of
mixtures. In general, the product imidazopyridinones alternative catalyst systems to address this limitation is
were isolated by filtration through a silica plug followed currently pursued.15
by recrystallisation.14,16 The further functionalisation of
In summary, we have developed a new synthetic entry to
diversely substituted 3-arylated 1,3-dihydro-2H-imida-
the 1-position nitrogen of imidazopyridin-2-ones of type
2a–l by alkylation has been previously reported1a and
zo[4,5-b]pyridin-2-ones 2 (R1 = aryl, heteroaryl; R2 = H)
thereby provides potential access to diverse unsymmetri-
in only two steps from commercially available 3-amino-2-
cally 1,3-disubstituted imidazo[4,5-b]pyridin-2-ones 2.
chloropyridine. The tandem reaction sequence developed
is palladium-catalysed and demonstrates a broad range of
functional group tolerance with products isolated in
moderate to excellent yields. As such, this synthetic
approach should prove of utility in further evaluation of
the structure–activity relationships of these biologically
interesting compounds.
Table 2 Scope of Aniline Nucleophile (R1NH2)
3 mol% Pd2(dba)3
6 mol% XantPhos
H
N
NHBoc
Cl
O
150 mol% R1NH2
140 mol% t-BuONa
THF or toluene–i-PrOH
N
R1
N
N
4
2a–m
Entry
1
Product
2a
R1 substituent
Ph
Yield (%)a
82b
References and Notes
(1) (a) Clark, R. L.; Pessolano, A. A.; Shen, T.-Y.; Jacobus, D.
P.; Jones, H.; Lotti, V. J.; Flataker, L. M. J. Med. Chem.
1978, 21, 965. (b) Robinson, M. M.; Finch, N. US Patent
3719683, 1973. (c) von Bebenberg, W. US Patent 3819640,
1974. (d) Lesher, G. Y.; Brundage, R. P.; Opalka, C. J.;
Page, D. F. FP 2478637, 1981; Chem. Abstr. 1982, 96,
85551k. (e) Kuezynski, L.; Mrozikiewiez, A.; Poreba, K.
Pol. J. Pharmacol. Pharm. 1982, 34, 229. (f) Bianchi, M.;
Butti, A.; Rossi, S.; Barzaghi, F.; Marcaria, V. Eur. J. Med.
Chem. 1983, 18, 501. (g) Vaughn, J. R. Jr. US Patent
2637731, 1953. (h) Rochling, H. F. W.; Buchel, K.-H.;
Korte, F. W. A. G. K. US Patent 3459759, 1969.
(2) Meanwell, N. A.; Sit, S. Y.; Gao, J.; Wong, H. S.; Gao, Q.;
St. Laurent, D. R.; Balasubramanian, N. J. Org. Chem. 1995,
60, 1565.
F3C
2
3
2b
2c
86b
90b
O
O
4
5
6
7
8
9
2d
2e
2f
2-MeOC6H4
78c
67c
77b
70c
52c
85c
3-MeOC6H4
2,4-F2C6H3
4-t-BuO2CC6H4
3-CNC6H4
2g
2h
2i
(3) Kuethe, J. T.; Wong, A.; Davies, I. W. J. Org. Chem. 2004,
69, 7752.
3-ClC6H4
(4) An aryl bromide example with an ortho-ethylcarbamate,
presumably by way of an SNAr mechanism, has been
reported: Blanksma, J. J.; Verberg, G. Recl. Trav. Chim.
Pays-Bas 1934, 53, 988.
(5) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653.
(6) (a) Horino, H.; Ishiyama, T.; Tatematsu, T.; Makino, C.;
Ochiai, Y.; Kito, K.; Kanaya, N.; Hishida, K. Chem. Abstr.
2001, 135, 166835. (b) Li, J.; Zheng, L.-M.; King, I.; Doyle,
T.; Chen, S.-H. Curr. Med. Chem. 2001, 8, 121. (c) Niu, C.;
Li, J.; Doyle, T. W.; Chen, S.-H. Tetrahedron 1998, 54,
6311.
10
11
12
13
2j
83b
49b
86b
0b
2k
2l
2-MeC6H4
N
2m
2-Aminopyrazine
a Yield after chromatographic purification and/or crystallisation.
b THF (15 mL/g) was used as solvent at reflux for 18–24 h.
c Toluene–i-PrOH (4:1, 20 mL/g) was used as solvent at 85 °C for
18–24 h.
(7) Kelly, T. A.; McNeil, D. W. Tetrahedron Lett. 1994, 35,
9003.
(8) Preparation of tert-Butyl (2-Chloropyridin-3-
yl)carbamate (4).
To a stirred solution of NaHMDS (1 M in THF, 700 mL, 700
mmol) at –10 °C under N2 was added a solution of 2-chloro-
3-aminopyridine (40.9 g, 318 mmol) in THF (80 mL) over
Synlett 2006, No. 13, 2083–2086 © Thieme Stuttgart · New York

2086
J. P. Scott
LETTER
10 min. The mixture was aged 10 min and then Boc2O (72.9
g, 334 mmol) as a solution in THF (56 mL) was added over
10 min maintaining the internal temperature <8 °C. After
aging 0.5 h, 2 M HCl (600 mL) and isopropyl acetate (400
mL) were added. The organic layer was washed with H2O
(200 mL) and concentrated in vacuo. The residue was
crystallised from i-PrOH (250 mL) and H2O (300 mL) to
afford 58.9 g (81%) of 4 as an off-white solid. 1H NMR (400
MHz, CDCl3): d = 8.49 (1 H, d, J = 8.0 Hz), 8.02 (1 H, d,
J = 4.4 Hz), 7.21 (1 H, dd, J = 8.4, 4.8 Hz), 7.01 (1 H, br s),
1.53 (9 H, s). 13C NMR (100 MHz, CDCl3): d = 152.1, 142.5,
139.1, 132.6, 127.0, 123.2, 81.8, 28.2. Mp 84–85 °C. MS
(ES): m/z = 229 [M + H]+.
mmol), aniline (0.24 g, 2.63 mmol, 150 mol%) and t-BuONa
(0.24 g, 2.45 mmol, 140 mol%) in THF (6.0 mL, 15 mL/g)
was degassed with N2 and then heated at reflux for 18 h.
After cooling to ambient, the reaction mixture was diluted
with CH2Cl2 and filtered through a silica plug. Evaporation
in vacuo and flash chromatography (EtOAc–heptane)
afforded 2a as a white solid (0.30 g, 82%). 1H NMR (400
MHz, DMSO-d6): d = 11.40 (1 H, s), 7.94 (1 H, d, J = 4.8
Hz), 7.72–7.63 (2 H, m), 7.57–7.49 (2 H, m), 7.43–7.36 (2
H, m), 7.11–7.05 (1 H, m). 13C NMR (100 MHz, DMSO-d6):
d = 153.1, 144.3, 140.2, 134.0, 129.2, 127.6, 126.6, 123.3,
118.5, 115.8. Mp 240–241 °C; Lit.1a 240–241 °C. MS (ES):
m/z = 212 [M + H]+.
(9) BINAP and dppf were found to be inferior for the formation
of 2a than XantPhos.
(10) First reported by van Leeuwen: Kranenberg, M.; van der
Burgt, Y. E. M.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.
Organometallics 1995, 14, 3081.
(15) The approach used in Scheme 2 for the construction of 3-
phenyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one has
not been previously reported and given the diversity of
commercially available isocyanates, may constitute another
general entry to compounds in this class.
(11) XantPhos = 4,5-bis(diphenylphosphino)-9,9-dimethyl-
xanthene.
(16) All new compounds gave satisfactory spectroscopic
characterisation data.
(12) The addition of Et3N has been shown to provide rate
enhancement in Pd-catalysed aryl iodide aminations when
Cs2CO3 is employed as base. See: Ali, M. H.; Buchwald, S.
L. J. Org. Chem. 2001, 66, 2560.
(13) The THF used in our study had a water content between 60
mg/mL and 110 mg/mL as determined by Karl–Fischer
titration.
(14) Representative Procedure for the Preparation of 3-
Phenyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one
(2a).
(17) Alkylamines screened were cyclopropylamine, sec-butyl-
amine, (R)-1-phenylethylamine and 1-(2-aminoethyl)-
piperidine. In all instances <20A% of desired imidazo-
pyridin-2-one was identified by LCMS using either THF or
toluene–i-PrOH (4:1) as reaction solvent.
(18) Use of a Josiphos ligand for amination of 2-chloropyridine
with primary alkylamines has been recently reported: Shen,
Q.; Shekhar, S.; Stambuli, J. P.; Hartwig, J. F. Angew. Chem.
Int. Ed. 2005, 44, 1371.
(19) No examples of the preparation of 3-alkyl-substituted 1,3-
dihydro-2H-imidazo[4,5-b]pyridin-2-ones are documented
in ref. 3 which employs Pd2(dba)3/BINAP as catalyst system
for amination.
A mixture of XantPhos (61 mg, 0.11 mmol, 6 mol%),
Pd2(dba)3 (48 mg, 0.05 mmol, 3 mol%, 6 mol% Pd), tert-
butyl (2-chloropyridin-3-yl)carbamate (4, 0.40 g, 1.75
Synlett 2006, No. 13, 2083–2086 © Thieme Stuttgart · New York