Palladium(II)-catalyzed oxidative arylation of quinoxalin-2(1 H)-ones with arylboronic acids

Article abstract of DOI:10.1021/ol4028946

A straightforward palladium-catalyzed oxidative C-3 arylation of quinoxalin-2(1H)-ones with arylboronic acids is reported. This protocol is compatible with a wide range of functional groups and allows construction of various biologically important quinoxalin-2(1H)-one backbones.

Full text of DOI:10.1021/ol4028946

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Palladium(II)-Catalyzed Oxidative
Arylation of Quinoxalin-2(1H)‑ones with
Arylboronic Acids
€
Amandine Carrer, Jean-Daniel Brion, Samir Messaoudi,* and Mouad Alami*
Univ. Paris-Sud, CNRS, BioCIS-UMR 8076, LabEx LERMIT, Laboratoire de Chimie
ꢀ
ꢀ
ꢀ
^
Therapeutique, Faculte de Pharmacie, 5 rue J.-B. Clement, Chatenay-Malabry,
92296 France
samir.messaoudi@u-psud.fr; mouad.alami@u-psud.fr
Received October 9, 2013
ABSTRACT
A straightforward palladium-catalyzed oxidative C-3 arylation of quinoxalin-2(1H)-ones with arylboronic acids is reported. This protocol is
compatible with a wide range of functional groups and allows construction of various biologically important quinoxalin-2(1H)-one backbones.
The transition-metal-catalyzed functionalization of
nitrogen heterocycles1 has emerged as anatom-economical
alternative to the traditional processes for constructing
heterocycleꢀaryl linkages, which constitute an important
class of structures in natural and non-natural products.
In contrast to the muchmore developed catalytic protocols
for the arylation of electron-rich heteroarenes or those
bearing a relatively acidic CꢀH bond, arylation of electron-
deficient heterocycles has received much less attention.2
In connection with our ongoing program directed to-
ward antagonists of the N-methyl-D-aspartate (NMDA)
receptor,3 we required the synthesis of 3-arylquinoxalin-
2(1H)-ones 3 (Scheme 1). Traditional strategies to prepare
such molecules involve the construction of the heterocycle
rings by nontrivial and nonconvergent multistep reaction
sequences4 (Scheme 1, path a).
(1) (a) Kuhl, N.; Hopkinson, M. N.; Wencel-Delord, J.; Glorius, F.
€
Angew. Chem., Int. Ed. 2012, 51, 10236–10254. (b) Bruckl, T.; Baxter,
R. D.; Ishihara, Y.; Baran, P. S. Acc. Chem. Res. 2012, 45, 826. (c)
€
Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011,
40, 4740–4761. (d) Baudoin, O. Chem. Soc. Rev. 2011, 40, 4902–4911. (e)
Ackermann, L. Chem. Rev. 2011, 111, 1315–1345. (f) You, S.-L.; Xia,
J.-B. Palladium-Catalyzed ArylꢀAryl Bond Formation through Double
CꢀH Activation. In CꢀH Activation; Yu, J.-Q., Shi, Z., Eds.; Top. Curr.
Chem.; Springer: Berlin, 2010; Vol. 292, pp 165ꢀ194. (g) Messaoudi, S.;
Brion, J.-B.; Alami, M. Eur. J. Org. Chem. 2010, 6495–6516.
(3) Stawski, P.; Janovjak, H.; Trauner, D. Bioorg. Med. Chem. 2010,
18, 7759–7772.
(2) Selected examples: (a) Wang, J.; Wang, S.; Wang, G.; Zhang, J.;
Yu, X.-Q. Chem. Commun. 2012, 48, 11769–11771. (b) Deb, A.; Manna,
S.; Maji, A.; Dutta, U.; Maiti, D. Eur. J. Org. Chem. 2013, 5208–5216. (c)
Kim, D.; Ham, K.; Hong, S. Org. Biomol. Chem. 2012, 10, 7305–7312.
(d) Khoobi, M.; Alipour, M.; Zarei, S.; Jafarpour, F.; Shafiee, A. Chem.
Commun. 2012, 48, 2985–2987. (e) Li, Y.; Qi, Z.; Wang, H.; Fu, X.;
Duan, C. J. Org. Chem. 2012, 77, 2053–2057. (f) Tiwari, V.-K.; Pawar,
G.-G.; Das, R.; Adhikary, A.; Kapur, M. Org. Lett. 2013, 15, 3310–
3313. (g) Zhao, H.; Wang, R.; Chen, P.; Gregg, B.-T.; Hsia, M.-M.;
Zhang, W. Org. Lett. 2012, 14, 1872–1875. (h) Ge, H.; Niphakis, M. J.;
Georg, G. I. J. Am. Chem. Soc. 2008, 130, 3708–3709. (i) Kim, Y. W.;
Niphakis, M. J.; Georg, G. I. J. Org. Chem. 2012, 77, 9496–9503. (j)
Molina, M. T.; Navarro, C.; Moreno, A.; Csaky, A. G. Org. Lett. 2009,
11, 4938–4941.
(4) (a) Shaw, A. Y.; Denning, C. R.; Hulme, C. Synthesis 2013, 45,
459–462. (b) Krupkova, S.; Funk, P.; Soural, M.; Hlavac, J. ACS Comb.
ꢁ
ꢀ
ꢀꢁ
Sci. 2013, 15, 20–28. (c) Weıwer, M.; Spoonamore, J.; Wei, J.; Guichard,
¨
B.; Ross, N. T.; Masson, K.; Silkworth, W.; Dandapani, S.; Palmer, M.;
Scherer, C. A.; Stern, A. M.; Schreiber, S. L.; Munoz, B. ACS Med.
Chem. Lett. 2012, 3, 1034–1038. (d) Xu, Z.; Shaw, A. Y.; Dietrich, J.;
Cappelli, A. P.; Nichol, G.; Hulme, C. Mol. Diversity 2012, 16, 73–79. (e)
Carta, A.; Briguglio, I.; Piras, S.; Corona, P.; Boatto, G.; Nieddu, M.;
Giunchedi, P.; Marongiu, M. E.; Giliberti, G.; Iuliano, F.; Blois, S.;
Ibba, C.; Busonera, B.; La Colla, P. Bioorg. Med. Chem. 2011, 19, 7070–
7084. (f) Dowlatabadi, R.; Khalaj, A.; Rahimian, S.; Montazeri, M.;
Amini, M.; Shahverdi, A.; Mahjub, E. Synth. Commun. 2011, 41, 1650–
1658. (g) Xue, Z.-Y.; Jiang, Y.; Peng, X.-Z.; Yuan, W.-C.; Zhang, X.-M.
Adv. Synth. Catal. 2010, 352, 2132–2136.
r
10.1021/ol4028946
XXXX American Chemical Society

Table 1. Optimization of 1a Coupling with Phenylboronic
Acid 2aa
Scheme 1
entry
[Pd]
PdCl2
L
ratio 1a/3a/4ab
yield (%)c
1
Phen
100/0/0
100/0/0
10/60/30
35/5/60
20/60/25
10/90/0
20/80/0
15/85/0
50/50/0
2
PdBr2
Phen
3
Pd(OAc)2
Pd(TFA)2
Pd(OPiv)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Phen
50
4
Phen
Since the pioneering work of Suzuki and Miyaura,5 the
5
Phen
6d
7d
8d
9d,e
Phen
5-NO2Phen
Bipy
85f
use of organoboron reagents as nucleophilic coupling
partners with various organic electrophiles provides a
powerful and general methodology for the formation of
carbonꢀcarbon2,6 and carbonꢀheteroatom6 bonds. As
part of our continuing effort on the development of
methods to functionalize heterocycles via transition-
metal catalysis,7 we report herein the C-3 arylation of
quinoxalin-2(1H)-ones 1 with arylboronic acids using a
catalytic amount of Pd(II) under oxygen atmosphere
(Scheme 1, path b).
Phen
a Conditions: 1a (0.5 mmol), 2a (1.5 equiv), Pd (5 mol %), ligand (7.5
mol %), DMF (2 mL) were heated in a sealed tube at 100 °C for 20 h
under oxygen atmosphere. b The ratio was determined by 1H NMR in
the crude reaction mixture based on the chemical shift of the proton
signal of ꢀCH3 (ppm) at the N1 position (1a: δ = 3.70, 3a: δ = 3.76, 4a:
δ = 3.42). c Yield of isolated 4a. d Under O2 balloon pressure for 20 h.
e 2.5 mol % of Pd(OAc)2 and 4 mol % of Phen were used. f No product
could be formed in the absence of Pd(OAc)2 and/or Phen.
In our initial study, 1-N-methylquinoxalin-2(1H)-one 1a
and phenylboronic acid 2a were chosen as model sub-
strates for the C-3 arylation process (Table 1). The reaction
was first investigated under Pd(II)-catalyzed conditions in
the presence of phenanthroline as a ligand (7.5 mol %) and
oxygen as an oxidant in DMF at 100 °C for 24 h. As
summarized in Table 1, the screening conditions revealed
that the source of palladium used has an important
influence on the outcome of the present reaction. Thus,
the use of PdCl2 or PdBr2 (5 mol %) did not promote the
arylation reaction (entries 1 and 2), while in the presence of
Pd(OAc)2, the reaction led to a concomitant formation of
the expected 3-phenyl quinoxalin-2(1H)-one 3a, together
with byproduct 4a derived from the addition of phenyl-
boronic acid to 1a under Pd catalysis.8 After a tedious
separation, 3a wasisolatedinamoderate50%yield(entry3).
Attempts to avoid the formation of 4a and increase the
yield of 3a have failed under various other palladium
catalysts (entries 4 and 5). However, performing the
reaction by bubbling oxygen for few a minutes (3 min)
and leaving the O2 balloon during the whole reaction time
under otherwise identical conditions of entry 3 dramati-
cally suppresses the formation of 4a and increases the
yield of 3a up to 85% (entry 6). Evaluation of other
ligands such as 5-nitrophenanthroline or 2,20-bipyridine
did not improve the conversion in 3a (entries 7 and 8).
Only 50% conversion was observed when the amount of
the catalytic system was split in two (entry 9). In sum-
mary, the best selected conditions were found to require 1
(0.5 mmol), 2 (0.75 mmol), Pd(OAc)2 (5 mol %), and
phenanthroline (7.5 mol %) under a balloon of O2 in
DMF at 100 °C for 20 h. For control experiments, no
conversion was observed in the absence of Pd(OAc)2 or
Phen and in the absence of Pd(OAc)2 and Phen.9
Prompted by these results, we subsequently investigated
the substrate scope for the Pd-catalyzed C-3 arylation of 1a
with a broad range of arylboronic acids. As illustrated in
Scheme 2, electron-rich and electron-deficient, para- and
meta-substituted arylboronic acids all underwent C-3 ar-
ylation of 1a efficiently from moderate to good yields
(products 3aꢀh and 3k). In the case of 3l, the yield was
moderate (40%) due to incomplete coupling reaction. The
sterically demanding ortho-substitution pattern was toler-
ated toward coupling reaction of 1a, leading to 3-aryl-
quinoxalin-2(1H)-one derivatives including compound 3j
having a pyrene moiety. Interestingly, the presence of a
(5) (a) Suzuki, A. Angew. Chem., Int. Ed. 2011, 50, 6723–6737. (b) For
recent review, see: Johansson Seechurm, C. C. C.; Kitching, M. O.;
Colacot, T. J.; Snieckus, V. Angew. Chem., Int. Ed. 2012, 51, 5062–5085.
(6) For reviews see: (a) Qiao, J. X.; Lam, P. Y. S. Synthesis 2011, 829–
856. (b) Rao, K. S.; Wu, T.-S. Tetrahedron 2012, 68, 7735–7754.
(7) (a) Sahnoun, S.; Messaoudi, S.; Peyrat, J.-F.; Brion, J. D.; Alami,
M. Tetrahedron Lett. 2008, 49, 7279–7283. (b) Sahnoun, S.; Messaoudi,
S.; Brion, J.-D.; Alami, M. Org. Biomol. Chem. 2009, 7, 4271–4278. (c)
Sahnoun, S.; Messaoudi, S.; Brion, J.-D.; Alami, M. Eur. J. Org. Chem.
2010, 6097–6102. (d) Sahnoun, S.; Messaoudi, S.; Brion, J.-D.; Alami,
M. ChemCatChem 2011, 3, 893–897. (e) Messaoudi, S.; Brion, J.-D.;
(9) (a) Tohma, S.; Rikimaru, K.; Endo, A.; Shimamoto, K.; Kan, T.;
Fukuyama, T. Synthesis 2004, 909–917. (b) Zhao, L.; Liao, X.; Li, C.-J.
Synlett. 2009, 2953–2956. The CdN double bond of quinoxalin-2(1H)-
one 1a cannot be regarded as a simple imine function, as it is not reactive
enough with phenylboronic acid under acidic conditions to furnish 3a.
As suggested by one of the referees, we checked the coupling of 1a with
2a using TFA in CH2Cl2 at room temperature (ref 7a). Under these
conditions, the reaction was revealed to be ineffective and only starting
material was recovered. In addition, performing the reaction of phenyl-
boronic acid with 1a or NH-free quinoxalin-2(1H)-one under Li’s
conditions (ref 7b), varying the reaction temperature (80ꢀ120 °C) as
well as reaction time (2ꢀ24 h), did not provide any arylated compounds
and only the starting material was recovered.
€
Alami, M. Org. Lett. 2012, 14, 1496–1499. (f) Carrer, A.; Brion, J.-D.;
Messaoudi, S.; Alami, M. Adv. Synth. Catal. 2013, 355, 2044–2054.
(8) For Ru-catalyzed addition of arylboronates to aldimines, see:
Park, Y. J.; Jo, E. A.; Jun, C. H. Chem. Commun. 2005, 1185–1187.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 2. Scope of Boronic Acid Coupling with Quinoxalin-
2(1H)-one 1aa
Scheme 3. Scope of Quinoxalin-2(1H)-one 1 Coupling with
Boronic Acidsa
a Conditions: quinoxalinone 1 (0.5 mmol), boronic acid 2 (1.5 or 2
equiv), Pd(OAc)2 (5 mol %), Phen (7.5 mol %), DMF (2 mL) under O2
(balloon pressure) at 100 °C for 20 h. b 2 equiv of boronic acid was used.
molecular diversity. We have been particularly interested
in the regioselective CꢀH functionalization of substrates
of type 3 using the nitrogen atom (N4) of the quinoxalin-
2(1H)-one nucleus as the Lewis basic directing group. In
this context, transition-metal-catalyzed chelation-assisted
CꢀH functionalization has emerged as a powerful tool for
the regioselective construction of carbonꢀcarbon and
carbonꢀheteroatom bonds.11 Notably, 3-arylquinoxalin-
2(1H)-ones 3vꢀx bearing an acetate group11d or a bromine
atom11i,j could easily be prepared via a regioselective
Pd-catalyzed chelation-assisted CꢀH functionalization
(Scheme 4).
a Conditions: quinoxalinone 1a (0.5 mmol), boronic acid 2 (1.5
equiv), Pd(OAc)2 (5 mol %), Phen (7.5 mol %), and DMF (2 mL)
under O2 (balloon pressure) at 100 °C for 20 h. b 2 equiv of arylboronic
acid was used. c 52% of starting material 1a was recovered unchanged.
hydroxyl and free amino groups on the arylboronic acid
partner did not interfere with the outcome of the present
reaction (compounds 3d and 3h).
To expand the scope of our method further, a series of
quinoxalin-2(1H)-ones as well as related heterocycles (e.g.,
pyrazin-2(1H)-one and benzo[g]quinoxalin-2(1H)-one)
were subjected to the coupling protocol with various
arylboronic acids (Scheme 3). We were pleased to observe
that N-alkyl- and N-benzylquinoxalin-2(1H)-ones having
electron-withdrawing or electron-donating groups on the
aromatic nucleus led to the corresponding compounds
3mꢀs in good yields. Interestingly, the reaction is not
effective with tautomerizable10 quinoxalin-2(1H)-one in
which the nitrogen atom is unsubstituted, probably due to
the very poor solubility of the substrate. Compounds 3qꢀs
bearing electrophilic functional groups are of particular
interest, as they contain reactive handles and, as such,
could be used as a foundation for the synthesis of more
complex molecules. Finally, the use of this protocol to
5,6-disubstituted pyrazin-2(1H)-one as well as benzo-
[g]quinoxalin-2(1H)-one was successful and provided the
arylated compounds 3t,u in 91 and 80% yields, respectively.
With substantial amounts of 3a and 3b in hand
(Scheme 2), we focused our attention on demonstrating
whether our method could be employed as a platform for
A possible mechanism for the C-3 arylation of quinox-
alin-2(1H)-ones is depicted in Scheme 5. Arylpalladium
complex I, which is formed in situ by the transmetalation
of an aryl group from boron to palladium,12 is envisioned
(11) For reviews, see: (a) Lyons, T. W.; Sanford, M. S. Chem. Rev.
2010, 110, 1147–1169. Selected article: (b) Sanhueza, I. A.; Wagner,
A. M.; Sanford, M. S.; Schoenebeck, F. Chem. Sci. 2013, 4, 2767–2775.
(c) Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res. 2012, 45, 936–946.
(d) Kalyani, D.; Sanford, M. S. Org. Lett. 2005, 7, 4149–4152. (e)
Thirunavukkarasu, V. S.; Raghuvanshi, K.; Ackermann, L. Org. Lett.
2013, 15, 3286–3486. (f) Phani Kumar, N. Y.; Jeyachandran, R.;
Ackermann, L. J. Org. Chem. 2013, 78, 4145–4152. (g) Ackermann,
L.; Lygin, A. V. Org. Lett. 2011, 13, 3332–3335. (h) Truong, T.;
Klimovica, K.; Daugulis, O. J. Am. Chem. Soc. 2013, 135, 9342–9345.
(i) Kalyani, D.; Dick, A. R.; Anani, W. Q.; Sanford, M. S. Tetrahedron
2006, 62, 11483–11498. (j) Kalyani, D.; Dick, A. R.; Anani, W. Q.;
Sanford, M. S. Org. Lett. 2006, 8, 2523–2526. (k) Lakshman, M. K.;
Deb, A. C.; Chamala, R. R.; Pradhan, P.; Pratap, R. Angew. Chem., Int.
Ed. 2011, 50, 11400–11404.
(12) (a) Ramnauth, J.; Poulin, O.; Bratovanov, S. S.; Rakhit, S.;
Maddaford, S. P. Org. Lett. 2001, 3, 2571–2573. (b) Xiong, D.-C.;
Zhang, L.-H.; Ye, X.-S. Org. Lett. 2009, 11, 1709–1712.
(13) (a) Ishiyama, T.; Hartwig, J. F. J. Am. Chem. Soc. 2000, 122,
12043–12044. (b) Krug, C.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126,
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Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Regioselective Pd-Catalyzed Chelation-Assisted
CꢀH Functionalization of 3a,b
Scheme 6
to take place as an initial step. This later evolves through
the migratory insertion mechanism into quinoxalin-2(1H)-
one 1a to give a palladium(II) complex II.9,13 Subsequent
β-hydrogen elimination from II produces a Heck-type
product 3a and hydridopalladium(II) acetate III (path a).
Compound 3a could also be formed through oxygen-
promoted oxidation of 4a which arises from protonolysis
of II (path b).
oxygen furnished a mixture of 3a and 4a in a 8/92 ratio
(Scheme 6). This result clearly suggests that 4a is the
reaction product which is oxidized into 3a off the catalytic
cycle. To further strengthen the above hypothesis, submit-
ting the isolated compound 4a to aerobic conditions
(DMF, O2, 100 °C) furnished the oxidized product 3a
quantitatively within only 2.5 h. Summarizing all the
information, we assume that pathway b involving a pro-
tonolysis followed by oxidation of 4a might be considered
more likely, while the β-hydrogen elimination (path a)
cannot be discarded.
In conclusion, we successfully developed an efficient and
practical Pd(OAc)2/phenanthroline-catalyzed system for
CꢀH arylation of various quinoxalin-2(1H)-ones with
arylboronic acids. The protocol exhibited a broad sub-
strate scope with respect to both the coupling partners,
thus providing an attractive alternative to the existing
methods for the synthesis of 3-arylquinoxalin-2(1H)-ones
3 of biological interest. Moreover, we have demonstrated
that the nitrogen atom of the quinoxalinone nucleus can be
used in a regioselective Pd-catalyzed chelation-assisted
CꢀH functionalization of 3-arylquinoxalin-2(1H)-ones 3.
Scheme 5. Plausible Catalytic Cycle for the C-3 Arylation of
Quinoxalin-2(1H)-ones
Acknowledgment. The CNRS is gratefully acknowl-
edged for financial support of this research. Our labora-
tory BioCIS-UMR 8076 is a member of the laboratory of
Excellence LERMIT supported by a grant from ANR
(ANR-10-LABX-33). The ANR is also acknowledged for
the postdoctoral fellowship to A.C.
To gain insight into this reaction, we conducted the
following experiments (Scheme 6). First, we studied the
transformation in the absence of O2. If the reaction
involves a β-hydride elimination step from II (path a),
theoretically the C-3 arylation of 1a to furnish 3a is
expected to be difficult because the Pd(II) species cannot
be regenerated from Pd(0). It was observed that the
reaction of 1a with 2a under optimal conditions of entry
6 (Table 1) but using an argon atmosphere instead of
Supporting Information Available. Experimental pro-
cedures and spectroscopic data of 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
Org. Lett., Vol. XX, No. XX, XXXX