A novel method for the preparation of 4-arylimidazolones

Article abstract of DOI:10.1021/ol401165e

A series of 4-arylimidazolones have been accessed via late-stage, palladium-mediated arylation of acetone- and cyclohexanone-derived 4-chloroimidazolones. The 4-chloroimidazolones were prepared via a novel rearrangement of the corresponding imidazolone N-

Full text of DOI:10.1021/ol401165e

ORGANIC
LETTERS
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Vol. XX, No. XX
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A Novel Method for the Preparation
of 4‑Arylimidazolones
Duane E. DeMong,* Irene Ng, Michael W. Miller, and Andrew W. Stamford
Discovery and Preclinical Sciences, Merck Research Laboratories,
2015 Galloping Hill Road, K15-2-A218, Kenilworth, New Jersey 07033, United States
duane.demong@merck.com
Received April 25, 2013
ABSTRACT
A series of 4-arylimidazolones have been accessed via late-stage, palladium-mediated arylation of acetone- and cyclohexanone-derived
4-chloroimidazolones. The 4-chloroimidazolones were prepared via a novel rearrangement of the corresponding imidazolone N-oxides. This
communication serves as an expansion of chemistry originally developed for our glucagon receptor antagonist program.
The imidazolone moiety is a structural motif found in
the Kottamide family of natural products and glycine
transporter type 1 inhibitors such as GSK 2137305.1,2 In
our laboratories, we have utilized the imidazolone hetero-
cycle in the preparation of a series of orally available
glucagon receptor antagonists for the potential treatment
of type II diabetes mellitus (T2DM).3
Previous reports had described the synthesis of imida-
zolone N-oxides for use as a chiral synthon in the case
of compounds 6 and 7aÀc (Figure 1) and as an example of
unique chemical matter (8a).4À8 More recently, imidazo-
lone N-oxides 8b and 9 were used to prepare a series of
structurally unique 4-alkenylimidazolones and 6-acyl-3-
benzyl-2,2-dialkyl-1,3-diazabicyclo[3.1.0]hexan-4-ones.9
Our initial approach to the synthesis of 4-aryl-substituted
spiroimidazolones (Scheme 1) involved starting with an
N-Boc-arylglycine (1), coupling with a primary amine to
afford amide 2, and deprotection resulting in amine 3.
Condensation of 3 with a ketone afforded 4, which upon
oxidation with NBS or t-BuOCl afforded the desired
4-arylimidazolone 5.
For our glucagon receptor antagonist program, it was
desired to develop an effective means to install 4-aryl
and 4-heteroaryl groups at a late stage in the synthetic
sequence, rather than at the first step, as was the case with
the N-Boc-arylglycine approach.
(3) (a) DeMong, D.; Miller, M. W.; Dai, X.; Stamford, A. Patent
Application WO 2012/009226 A1 20120119, 2012. (b) Wong, M. K.;
Lavey, B. J.; Yu, W.; Kozlowski, J. A.; DeMong, D. E.; Dai, X.; Stamford,
A. W.; Miller, M. W.; Zhou, G.; Yang, D.-Y.; Greenlee, W. J. Patent
Application WO 2011/119559 A1 20110929, 2011. (c) Stamford, A.; Miller,
M. W.; DeMong, D. E.; Greenlee, W. J.; Kozlowski, J. A.; Lavey, B. J.; Wong,
M. K. C.; Yu, W.; Dai, X.; Yang, D.-Y.; Zhou, G. Patent Application WO
2010/039789 A1 20100408, 2010. (d) Dai, X.; Miller, M.; Stamford, A.;
DeMong, D.; Yu, W.; Wong, M.; Lavey, B.; Greenlee, W.; Kozlowski, J.; Lin,
S.-I.; Zhou, G.; Yang, D.-Y.; Hwa, J.; Kang, L.; Lachowicz, J.; Soriano, A.;
Zhai, Y.; Patel, B.; Zhang, H.; Grotz, D. Abstracts of Papers, 244th ACS
National Meeting & Exposition, Philadelphia, PA, United States, (2012),
ORGN-16. (e) DeMong, D. E.; Miller, M.; Lin, S.-I.; Ng, I.; Dai, X.;
Stamford, A.; Zhao, H.; Dai, P. Abstracts of Papers, 241st ACS National
Meeting & Exposition, Anaheim, CA, United States, (2011), ORGN-698. (f)
DeMong, D. E.; Dai, X.; Miller, M.; Lin, S.-I.; Stamford, A.; Greenlee, W.;
Lachowicz, J.; Hwa, J.; Kang, L.; Zhai, Y.; Soriano, A.; Grotz, D. Abstracts
of Papers, 241st ACS National Meeting & Exposition, Anaheim, CA, United
States, (2011), MEDI-115. (g) Dai, X.; DeMong, D.; Miller, M.; Stamford,
A.; Yu, W.; Wong, M.; Lavey, B.; Greenlee, W.; Kozlowski, J.; Lin, S.-I.;
Zhou, G.; Yang, D.-Y.; Hwa, J.; Kang, L.; Lachowicz, J.; Soriano, A.; Zhai,
Y.; Zhang, H.; Grotz, D. Abstracts of Papers, 241st ACS National Meeting &
Exposition, Anaheim, CA, United States, (2011), MEDI-22.
(1) Appleton, D. R.; Page, M. J.; Lambert, G.; Berridge, M. V.;
Copp, B. R. J. Org. Chem. 2002, 67, 5402.
(2) (a) Graham, J. P.; Langlade, N.; Northall, J. M.; Roberts, A. J.;
Whitehead, A. J. Org. Process Res. Dev. 2011, 15, 44. (b) Blunt, R.;
Cooper, D. G.; Porter, R. A.; Wyman, P. A. Patent Application WO
2009/034061 A1, 2009. (c) Ahmad, N. M.; Lai, J. Y. Q.; Andreotti, D.;
Marshall, H. R.; Nash, D. J.; Porter, R. A. Patent Application WO 2008/
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WO 2008/092872 A1 20080807, 2008. (e) Ahmad, N. M.; Andreotti, D.;
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r
10.1021/ol401165e
XXXX American Chemical Society

Direct arylation of the 4-position of imidazolone N-oxides
has also been demonstrated.10
Scheme 2. Preparation of 4-Chloroimidazolone 16
Scheme 1. Initial Synthetic Approach to 4-Arylimidazolones
˚
the presence of 3 A molecular sieves afforded the dihy-
droimidazolone 14. Oxidation of 14 with 2.2 equiv of
m-CPBA afforded the nitrone 15.11,12 Treatment of 15
with POCl3 in the presence of Hunig’s base in refluxing
toluene, followed by quenching of the reaction with brine
and silica gel chromatography (run 1), afforded the chlo-
roimidazolone 16 in 56% yield. Conversely, quenching of
the reaction with saturated aqueous sodium bicarbonate
followed by silica gel chromatography (run 2) afforded
none of 16, but rather a 56% yield of the hydrolysis
product, hydroxyimidazolone 17.
Additionally, dihydroimidazolone 14 can be converted
to chloroimidazolone 16 via a second route. Treatment of
14 with tert-butyl hypochlorite resulted in N-chlorination
of the dihydroimidazolone. Subsequent treatment with
triethylamine resulted in elimination to the imidazolone 18.
Interestingly, treatment of 18 with m-CPBA did not provide
the nitrone 15, but rather the 4-hydroxyimidazolone 17.13
Figure 1. Proposed synthetic approach to 4-arylimidazolones.
For our purposes, we hypothesized that an imidazolone
N-oxide such as 10 could be transformed into the corre-
sponding 4-haloimidazolones 11a and 11b in a manner
analogous to the conversion of pyridine N-oxides to
2-halopyridines. Palladium catalyzed cross-coupling of
11a or 11b with the requisite boronic acid or ester would
afford the desired 4-arylimidazolone 5. This approach was
originally validated in our previously described glucagon
receptor antagonist efforts.3
(11) Proposed mechanism:
With this initial success, we decided to further probe the
generality of this chemistry. The results of our efforts are
described herein.
Glycinamide 12 was deprotected with TFA to afford
amine 13 (Scheme 2). Heating of 13 in refluxing acetone in
(5) (a) Demory, E.; Farran, D.; Baptiste, B.; Chavant, P. Y.; Blandin,
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C.; Blandin, V.; Chavant, P. Y. Tetrahedron: Asymmetry 2011, 22, 1274.
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Blandin, V. Tetrahedron: Asymmetry 2011, 22, 1266. (d) Thiverny, M.;
Philouze, C.; Chavant, P. Y.; Blandin, V. Org. Biomol. Chem. 2010, 8,
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J.; Lambrechts, A.; Van den Heuvel, D.; De Smaele, D. Org. Process
Res. Dev. 2002, 6, 911.
(13) Proposed mechanism:
(6) Pernet-Poil-Chevrier, A.; Cantagrel, F.; Le Jeune, K.; Philouze,
C.; Chavant, P. Y. Tetrahedron: Asymmetry 2006, 17, 1969.
(7) (a) Cantagrel, F.; Pinet, S.; Gimbert, Y.; Chavant, P. Y. Eur. J.
Org. Chem. 2005, 13, 2694. (b) Baldwin, S. W.; Long, A. Org. Lett. 2004,
6, 1653.
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(9) Dai, X.; Miller, M. W.; Stamford, A. W. Org. Lett. 2010, 12, 2718.
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W. Org. Lett. 2012, 14, 1872.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Arylation of Chloroimidazolone 7a
Table 2. Preparation of 4-Aryl Spirocyclohexylimidazolonesa
a Isolated yields.
As was seen with the treatment of nitrone 15, treatment of
17 with POCl3 and Hunig’s base in toluene at reflux also
afforded the chloroimidazolone 16.
To avoid hydrolysis of the chloroimidazolone on work-
up, the conversion of 15 to 16 was immediately followed
by removal of the volatile reactants in vacuo and Suzuki
coupling with the requisite boronic acid or boronic ester
to afford 4-arylimidazolones 19aÀl (Table 1). In general,
the Suzuki coupling products were isolated in modest
yields with a variety of substituted aromatics. Suzuki
products arising from coupling with methoxy-substituted
phenyl boronic acids were isolated in the lowest yields,
with only a minimal amount of the ortho-methoxyphenyl
imidazolone 19j being isolated. Pyridinylimidazolones
19k and 19l were isolated inyields similartothose observed
with phenylimidazolones.
a Isolated yields.
acetone-derived intermediates 15 and 16. With the excep-
tion of the N-methylpyrazole compound 22o, moderate
isolated yields were observed across the board, including
the o-methoxyphenyl compound 22k.
The imidazolone motif has seen a significant increase
in utility in recent years. A wide variety of unique
synthetic transformations have emerged from imidazo-
lone N-oxides in particular. In our laboratories, we have
demonstrated a novel method for the synthesis of 4-chlor-
oimidazolones, and their subsequent palladium-catalyzed
cross-coupling with arylboronic acids. This approach
allows for the rapid, late-stage incorporation of a wide
variety of aryl and heteroaryl groups that would not
be readily available via the original arylglycine-based
approach.
Atthispoint, weexplored the palladium-mediatedaryla-
tion of cyclohexanone-derived 4-chlorospiroimidazolones
(Table 2). The preparation of imidazolone N-oxide 20 and
4-chloroimidazolone 21 proceeded in a manner similar
to that observed with the preparation of the analogous
Org. Lett., Vol. XX, No. XX, XXXX
C

Acknowledgment. The authors would like to thank
Dr. William Greenlee (william@william-greenlee.com)
for support of this endeavor, Dr. Mikhail Reibarkh (MRL)
for his NMR spectroscopy support, and Mr. Ibrahim
Daaro (MRL) for his high-resolution mass spectroscopy
support.
Supporting Information Available. Experimental pro-
cedures and analytical data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
D
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