Palladium-catalyzed direct arylation of imidazolone N-oxides with aryl bromides and its application in the synthesis of GSK2137305

Article abstract of DOI:10.1021/ol300468g

The palladium-catalyzed direct arylation of imidazolone N-oxides with aryl bromides to afford the corresponding 4-aryl imidazolone N-oxides is described. This method has been successfully used for the synthesis of GSK2137305.

Full text of DOI:10.1021/ol300468g

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1872–1875
Palladium-Catalyzed Direct Arylation of
Imidazolone N-Oxides with Aryl Bromides
and Its Application in the Synthesis of
GSK2137305
He Zhao,* Ruifang Wang,* Ping Chen, Brian T. Gregg, Ming Min Hsia, and Wei Zhang
Medicinal Chemistry Department, AMRI, 26 Corporate Circle, P.O. Box 15098,
Albany, New York 12212-5098, United States
He.Zhao@amriglobal.com; Ruifang.Wang@amriglobal.com
Received February 24, 2012
ABSTRACT
The palladium-catalyzed direct arylation of imidazolone N-oxides with aryl bromides to afford the corresponding 4-aryl imidazolone N-oxides is
described. This method has been successfully used for the synthesis of GSK2137305.
The imidazolone skeleton is an important structural
motif found in both synthetic and natural products such
as GSK2137305 (1) and Kottamides AÀD (Figure 1).1
These specific natural product alkaloids exhibit a range of
biological activities including anti-inflammatory, antitumor,
and antimetabolic properties. Additionally, researchers at
GlaxoSmithKline prepared a number of imidazolone-
containing derivatives leading to the discovery of the
developmental candidate GSK2137305 (1), a potent and
selective Glycine transporter type-1 (GlyT1) inhibitor for
potential treatment of neurological and neuropsychiatric
disorders.2 Merck scientists have also explored the imida-
zolone core structure and identified many synthetic analo-
gues which show antagonist activities against the glucagon
receptor, a biological target for type 2 diabetes.3 Despite its
importance, imidazolones have received less attention
regarding their chemical reactivity and properties than
other more common heterocycles.
(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) Ueda, S.; Su,
M.; Buchwald, S. L. J. Am. Chem. Soc. 2012, 134, 700. (c) Blunt, R.;
Cooper, D. G.; Porter, R. A. WO 2009034061, 2009. (d) Ahmad, N. M.;
Lai, J. Y. Q.; Andreotti, D. WO 2008092876, 2008. (e) Coulton, S.; Porter,
R. A. WO 2008092872, 2008
(3) (a) Demong, D. E.; Miller, M. W.; Dai, X.; Wong, M. K.; Lavey,
B. J.; Yu, W.; Zhou, G.; Stamford, A. W.; Kozlowski, J. A.; Greenlee,
W. J.; Zhao, H.; Chen, P.; Lin, P.; Dai, P.; Davis, J. L. WO 2011119541,
2011. (b) 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. WO 2010039789, 2010.
Figure 1. Biologically active imidazolone compounds.
In the past two decades, the field of transition-
metal-catalyzed direct arylation of (hetero)arenes has
grown rapidly.4 However, the direct arylation reaction of
π-electron-deficient heterocycles including pyridines and
pyriding N-oxides remained challenging until a few years ago.
r
10.1021/ol300468g
Published on Web 03/23/2012
2012 American Chemical Society

In 2005, Fagnou and co-workers first reported that
pyridine N-oxides undergo direct ortho arylation in syn-
thetically useful yields.5 The resulting arylated derivatives
were then converted to 2-arylpyridines by hydrogenolysis.
Since then the N-oxide strategy has been further explored
and quickly extended to many other heterocycles.6,7
To the best of our knowledge, imidazolone N-oxides
havenot been investigatedinthe context of metal catalyzed
cross-coupling reactions. With our interests in palladium-
catalyzed coupling reactions,8 we selected imidazolone
N-oxides as substrates and systematically studied their
direct arylation reactions. Subsequently, we applied our
results to the synthesis of GSK2137305 (1).
In our initial exploration, we used similar palladium-
catalyzed direct coupling conditions to those reported by
Fagnou et al.7g for our imidazolone N-oxide substrates;
using only 1 equiv of phenyl bromide 4a in order to achieve
an economic and efficient method. The starting imidazo-
lone N-oxide substrate 3a was easily prepared by a
reported procedure.9 Upon treating 3a with phenyl bro-
mide (4a, 1 equiv) in the presence of Pd(OAc)2 (5 mol %),
triphenylphosphine (15 mol %), and K2CO3 (2 equiv) in
toluene, and heating in a sealed tube for 18 h at 110 °C, the
desired coupling product 5a was obtained in reasonable
yield (Table 1, entry 1). Upon changing the solvent to
dioxane, the yield was only slightly improved from 49% to
53%. With these encouraging results, we decided to mask
the NH with Boc and 2,4-dimethoxybenzyl protecting
groups10 to determine the effect on overall reaction yield.
As expected, Boc protected imidazolone N-oxide 3b9
showed a significant increase in yield to 88% (Table 1,
entry 2). A drawback for the Boc protecting group is that a
minor amount of deprotected product 5a (6%) was also
formed during the reaction. In contrast, the 2,4-dimethox-
ybenzyl imidazolone N-oxide 3c11 yielded 5c in 91%
yield without any observed 5a formation. In addition,
we coupled 4a with 2,4-dimethoxybenzyl imidazolone
N-oxide 3d giving the desired product 7 in 94% yield.
Based on the similar yields for the dimethyl and spiro-
cyclohexyl analogues, we conclude that substituents at
the 2-position on the core ring are too far away from the
reactive site at the 4-position to impose any steric effects
on the observed reaction yield. Therefore, we selected 3c as
the substrate to explore the scope of reaction and establish
a general and practical method for the preparation of
4-substituted imidazolones.
Table 1. Influence of N-Substitition and 2-Substitution
First, we continued to use the current method for the
exploration of aryl halides and trifluoromethanesulfonate
on the directed arylation. As shown in Table 2, all but
phenyl bromide displayed poor reactivity. For example,
phenyl iodide gave only a 32% yield (Table 2, entry 1)
compared to 91% from phenyl bromide. Phenyl chloride
gave the desired product in only a 4% yield with unreacted
a Isolated yields. b DMB = 2,4-dimethoxybenzyl.
(7) For recent examples of palladium-catalyzed direct arylation with
N-oxide, see: (a) Duric, S.; Tzschucke, C. C. Org. Lett. 2011, 13, 2310.
(b) Ackermann, L.; Fenner, S. Chem. Commun. 2011, 47, 430. (c) Sun,
H.-Y.; Gorelsky, S. I.; Stuart, D. R.; Campeau, L.-C.; Fagnou, K. J. Org.
Chem. 2010, 75, 8180. (d) Schipper, D. J.; Mohamed, E.-S.; Whipp, C. J.;
Fagnou, K. Tetrahedron 2009, 65, 4977. (e) Schipper, D. J.; Campeau,
L.-C.; Fagnou, K. Tetrahedron 2009, 65, 3155. (f) Huestis, M. P.;
Fagnou, K. Org. Lett. 2009, 11, 1357. (g) Campeau, L.-C.; Stuart,
D. R.; Leclerc, J.-P.; Megan, B.-L.; Villemure, E.; Sun, H.-Y.; Lasserre,
S.; Guimond, N.; Lecavallier, M.; Fagnou, K. J. Am. Chem. Soc. 2009,
131, 3291. (h) Campeau, L.-C.; Megan, B.-L.; Leclerc, J.-P.; Villemure,
E.; Gorelsky, S.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 3276. (i)
Campeau, L.-C.; Schipper, D. J.; Fagnou, K. J. Am. Chem. Soc. 2008,
130, 3266. (j) Leclerc, J.-P.; Fagnou, K. Angew. Chem., Int. Ed. 2006, 45,
7781.
(4) For recent reviews on direct arylation, see: (a) Yeung, C. S.;
Dong, V. M. Chem. Rev. 2011, 111, 1215. (b) Han, W.; Ofial, A. R.
Synlett 2011, 1951. (c) Hirano, K.; Miura, M. Synlett 2011, 294. (d)
Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (e) Colby,
D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624. (f) Sun,
C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Commun. 2010, 46, 677. (g) Chen, X.;
Engle, K.-M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48,
5094. (h) Ackermann, L. Pure Appl. Chem. 2009, 82, 1403. (i) Lewis,
J. C.; Bergman, R. C.; Ellman, J. A. Acc. Chem. Res. 2008, 41, 1013. (j)
Li, B.-J.; Yang, S.-D.; Shi, Z.-J. Synlett 2008, 949. (k) Seregin, I. V.;
Gevorgyan, V. Chem. Soc. Rew. 2007, 36, 1173. (l) Satoh, T.; Miura, M.
Chem. Lett. 2007, 36, 200.
(8) Bliss, B. I.; Ahmed, F.; Iyer, S.; Lin, W.; Walker, J.; Zhao, H.
Tetrahedron Lett. 2010, 51, 3259.
(5) Campeau, L.-C.; Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc.
2005, 127, 18020.
(9) Cheng, S.; Wu, H.; Hu, X. Synth. Commun. 2007, 37, 297.
(10) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis; John Wiley & Sons: New York, 1999; pp 639À640.
(11) Compound 3c was prepared according to a similar procedure
reported in the reference: Dai, X.; Miller, M. W.; Stamford, A. W. Org.
Lett. 2010, 12, 2718. See Supporting Information for detailed
experimental.
(6) For selected reviews containing N-oxide substrates, see: (a)
Bellina, F.; Rossi, R. Tetrahedron 2009, 65, 10269. (b) Ackermann, L.;
Vicente, R.; Kapai, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792. (c)
McGlacken, G. P.; Bateman, L. M. Chem. Soc. Rev. 2009, 38, 2447.
(d) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174.
(e) Campeau, L.-C.; Stuart, D. R.; Fagnou, K. Aldrichimica Acta 2007,
40, 35.
Org. Lett., Vol. 14, No. 7, 2012
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Table 2. Reactivities of Phenyl Halides and Triflate
Table 3. Reactivities of Aryl Bromides
a Isolated yields. b DMB = 2,4-dimethoxybenzyl.
starting materials remaining. When the 4-methoxyphenyl
halogen reagents were used, the yields of the coupling
reactions were slightly lower than their corresponding
phenyl halides. However, the reactivity pattern remained
the same: Br > I > Cl. Thus, we focused on aryl bromides
for our studies on palladium-catalyzed direct arylation.
A range of substituted phenyl bromides with diverse
functional groups including alkyl (ortho, meta, and para),
ester, trifluoromethyl, and cyano groups were evaluated,
and all afforded the desired products in modest to high
yields (Table 3, entries 1À6). Other aryl bromides, in
particular 3-pyridyl bromide (8g) and imidazole-substi-
tuted aryl bromide (8i), also gave good isolated yields
(entries 7À9). The reaction tolerates both electron-with-
drawing and -donating substitution on the aryl bromides.
This proves that imidazolone N-oxides can undergo palla-
dium-catalyzed direct arylation in synthetically useful
yields under current reaction conditions.
Next, we investigated deoxygenation and removal of the
2,4-dimethoxybenzyl group. Although deoxygenation of
N-heteroarene N-oxides has been well documented,12 there
isnoavailableprocedurefor theconversionofimidazolone
N-oxides to the corresponding imidazolones from a litera-
ture search.
Having successfully demonstrated the direct arylation
of the core ring, we now set out to continue the synthetic
route toward the synthesis of GSK2137305 (1) by N-oxide
deprotection. Three different deoxygenation reaction con-
ditions are typically employed for a range of heteroarene
a Isolated yields. b DMB = 2,4-dimethoxybenzyl.
N-oxides.7g These include 10% Pd/C with ammonium
formate,13 Zn dust in aqueous ammonium chloride/
THF,14 and Fe dust in acetic acid.15 Upon application of
these conditions to our imidazolone N-oxides, the forma-
tion of undesired imidazolidinones occurred as a result of
full or partial reduction. We next moved our attention to
“non-hydrogen donor”-type deoxygenated reagents such
as P(n-Bu)316 and PCl3.17 However, the starting materials
(12) For recent examples on deoxygenation of heteroarene N-oxides,
see: (a) Kokatla, H. P.; Thomson, P. F.; Bae, S.; Doddi, V. R.; Laksh-
man, M. K. J. Org. Chem. 2011, 76, 7842. (b) Mikami, Y.; Noujima, A.;
Mitsudome, T.; Mizugaki, T.; Jitsukawa, K.; Kaneda, K. Chem.;Eur.
J. 2011, 17, 1768. (c) Gowda, N. B.; Rao, G. K.; Ramakrishna, R. A.
Tetrahedron Lett. 2009, 51, 5690. (d) Caliskan, H.; Zaim, O. Synth.
Commun. 2010, 40, 3078. (e) Reis, P. M.; Royo, B. Tetrahedron Lett.
2009, 50, 949. (f) Fuentes, J. A.; Clarke, M. L. Synlett 2008, 2579. (g)
Ponaras, A. A.; Zaim, O. J. Heterocycl. Chem. 2007, 44, 487. (h) Saini,
A.; Kumar, S.; Sandhu, J. S. Synlett 2006, 395.
(13) Balicki, R. Synthesis 1989, 645.
(14) Aoyagi, Y.; Abe, T.; Ohta, A. Synthesis 1997, 891.
(15) Julemont, F.; deLeval, X.; Michaux, C.; Renard, J.-F.; Winum,
J.-Y.; Montero, J.-L.; Damas, J.; Dogne, J.-M.; Pirotte, B. J. Med.
Chem. 2004, 47, 6749.
(16) Cividino, P.; Dheu-Andries, M.-L.; Ou, J.; Milet, A.; Py, S.; Toy,
P. H. Tetrahedron Lett. 2009, 51, 7038.
(17) Kanyiva, K. S.; Nakao, Y.; Hiyama, T. Angew. Chem., Int. Ed.
2007, 46, 8872.
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Org. Lett., Vol. 14, No. 7, 2012

still remained and survived these reaction conditions.
18
Eventually we found that PBr3 is a preferred reagent
Scheme 2. Synthesis of GSK2137305
for deoxygenating imidazolone N-oxides, as exemplified
in Scheme 1. Treatment of 5c with PBr3 (10 equiv) in DMF
led to deoxygenated compound 10 in 76% yield.19 In
contrast, unprotected 5a gave the desired product 11 in
only 4% yield. As expected, ceric ammonium nitrate
(CAN) cleaved the 2,4-dimethoxybenzyl (DMB) protect-
ing group from both amides 5c and 10 in good yields
(Scheme 1).
Scheme 1. Deoxygenation and Cleavage of DMBa
a DMB = 2,4-dimethoxybenzyl.
Finally, we applied our direct arylation method and
strategy on the synthesis of GSK2137305 (1) as shown in
Scheme 2. Commercially available glycylglycinamide 12
was coupled with 4-trifluoroaniline in the presence of
propylphosphonic anhydride (T3P) and diisopropylethy-
lamine (DIEA) in anhydrous DCM giving the desired
product 13 in 96% isolated yield. After hydrogenolysis of
the Cbz protecting group, aminoamide 14 was used di-
rectly in the next step to give the cyclized spiro imidazoli-
dinone 15 in 33% yield over two steps. Imidazolone
N-oxide 16 was obtained by the subsequent m-CPBA
oxidation of 15, which was then coupled with aryl bromide
1720 using the above established method affording the
product 18 in 64% yield. Finally N-oxide removal with
PBr3 gave GSK2137305 (1) in 82% yield, which demon-
strated identical analytical data to those reported.2a
Notably, the N-oxide 16 could be a useful intermediate to
access analogues of compound 1 by direct arylations at the
4-position.
In conclusion, we have systematically investigated
the direct arylaton of imidazolone N-oxides with aryl
bromides and their equivalents, catalyzed by palladium,
to afford the corresponding 4-aryl imidazolone N-oxides.
Deoxygenation and cleavage of 2,4-dimethoxybenzyl
(DMB) on imidazolones and imidazolone N-oxides were
also discussed. We have successfully applied our synthetic
method and strategy to the preparation of GSK 2137305
(1). Further investigation on imidazolone chemistry is in
progress.
Acknowledgment. The authors thank the AMRI Ana-
lytical Chemistry Department for the collection of HRMS
data.
(18) For examples on deoxygenation of heteroarene N-oxides with
PBr3, see: (a) Familoni, O. B.; Klaas, P. J.; Lobb, K. A.; Pakade, V. E.;
Kaye, P. T. Org. Biomol. Chem. 2006, 4, 3960. (b) Bremner, D. H.; Dunn,
A. D.; Wilson, K. A.; Sturrock, K. R.; Wishart, G. Synthesis 1997, 949.
(19) We noticed that bromonation of the DMB group occasionally
formed during the workup process. We are continuing our efforts for a
better deoxygenation method.
Supporting Information Available. Experimental pro-
cedures, 1H and 13C NMR spectra for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(20) Bruton, G.; Cooper, I. R.; Orlek, B. S. WO 2006040192, 2006
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 7, 2012
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