Synthesis of dihydroquinoxaline-2(1H)-ones via palladium-catalyzed intramolecular C–N bond formation

Article abstract of DOI:10.1016/j.tetlet.2016.06.008

A new strategy for the preparation of highly-substituted dihydroquinoxaline-2(1H)-ones is reported. The strategy harnesses a divergent NaI-catalyzed amine substitution of mesylates to prepare a range of sterically hindered amidoamine substrates. These substrates are then subjected to Pd(dba)₂/P(^tBu)₃mediated cyclization. The preparation of amidoalcohol substrates occurs with reasonable yields (40–84%), with lower yields being obtained with aromatic and bulky amines. Palladium-catalyzed intramolecular C–N bond formation is slow, requiring 10?mol?% catalyst loadings for complete conversion in 16?h. All substrates cyclized with reasonable yields (48–73%).

Full text of DOI:10.1016/j.tetlet.2016.06.008

Accepted Manuscript
Synthesis of dihydroquinoxaline-2(1H)-ones via palladium-catalyzed intramo-
lecular C-N bond formation
Jetsuda Areephong, Bright Huo, Ifenna I. Mbaezue, Kai E.O. Ylijoki
PII:
S0040-4039(16)30668-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.06.008
TETL 47735
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
14 May 2016
30 May 2016
1 June 2016
Please cite this article as: Areephong, J., Huo, B., Mbaezue, I.I., Ylijoki, K.E.O., Synthesis of
dihydroquinoxaline-2(1H)-ones via palladium-catalyzed intramolecular C-N bond formation, Tetrahedron Letters
(2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.06.008
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Synthesis of dihydroquinoxaline-2(1H)-ones
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bond formation.
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Jetsuda Areephong, Bright Huo, Ifenna I. Mbaezue,
and Kai E. O. Ylijoki*

1
Tetrahedron Letters
Synthesis of dihydroquinoxaline-2(1H)-ones via palladium-catalyzed intramolecular
C-N bond formation.
Jetsuda Areephong, Bright Huo, Ifenna I. Mbaezue, and Kai E. O. Ylijoki*
Department of Chemistry, Saint Mary's University, Halifax, Nova Scotia, Canada B3H 3C3
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A new strategy for the preparation of highly-substituted dihydroquinoxaline-2(1H)-ones is
reported. The strategy harnesses a divergent NaI-catalyzed amine substitution of mesylates to
prepare a range of sterically hindered amidoamine substrates. These substrates are then
subjected to Pd(dba)2/P(tBu)3 mediated cyclization. The preparation of amidoalcohol substrates
occurs with resonable yields (40 - 84%), with lower yields being obtained with aromatic and
bulky amines. Palladium-catalyzed intramolecular C-N bond formation is slow, requiring 20
mol% catalyst loadings for complete conversion in 16 hours. All substrates cyclized with
reasonable yields (48 - 73%).
Available online
Keywords:
Palladium catalysis
Cyclization
C-N bond formation
dihydroquinoxaline-2(1H)-ones
2009 Elsevier Ltd. All rights reserved.
The synthesis of the dihydroquinoxaline-2(1H)-one framework,
which is a derivative of the extensively biologically studied
2(1H)-quinoxalinone system,1 has been the subject of recent
investigations due to its prevalence in the cores of bioactive
products. The dihydroquinoxaline-2(1H)-one core is found in
compounds active against HIV,2 potent Bradykinin B1 receptor
antagonists,3 and potential antimicrobial agents.4 An aspect of
this organic moiety that has not been fully explored is the range
of substituents that can be incorporated into the molecule by
is elegant, however the range of substituents at N4 is limited to
amide functionalities. We have previously reported the synthesis
of the related 2H-1,4-benzoxazin-3-(4H)-one framework (2) via
palladium-catalyzed cyclization of amidoalcohols (1) (Scheme
2).9 We reasoned that these palladium-catalysis methods could be
adapted for the divergent preparation of highly substituted
dihydroquinoxaline-2(1H)-one frameworks by controlled
assembly of amidoamine analogues of our amidoalcohols. This
route would allow introduction of a range of nitrogen substituents
from a common precursor. Here we report our preliminary
results in the synthesis of amidoamine substrates through NaI-
catalyzed SN2 substitution and their subsequent palladium-
catalyzed cyclization.
varying the groups at the nitrogen and -carbon positions.
A
recent strategy for preparation of dihydroquinoxaline-2(1H)-ones
harnesses Ugi reaction5 for one-pot substrate synthesis followed
by palladium-catalyzed cyclization (Scheme 1).6-8 This strategy
Our synthetic strategy begins from alcohol compounds 1a and
1b, which are prepared by coupling 2-bromo-N-methylaniline10
Scheme 1: Ugi reaction approach to dihydroquinoxaline-
2(1H)-ones.
Scheme 2: Preparation of 2H-1,4-benzoxazin-3-(4H)-ones.
———
Corresponding Author.
*
E-mail address: kai.ylijoki@smu.ca (Kai E. O. Ylijoki)

2
Tetrahedron
Table 1: Synthesis of amine substrates.11
The presence of the bromine atom may be responsible for this
decomposition, given that related reactions have been
demonstrated from non-halogenated analogues of 3.18
Scheme 3: The synthesis of key mesyl substrate 4.
With the requisite amidoamines 5 in hand we turned our
attention to palladium-catalyzed cyclization. We first explored
cyclization of 5a under our previously reported conditions for
benzoxazinone preparation (1 mol% Pd(dba)2,
2 mol%
[HP(tBu)3]BF4,19 and 1.2 equiv. Cs2CO3 in toluene at 80 °C),9
with very low conversions being obtained. Increasing the
Table 2: Pd-catalyzed cyclization.11
with either benzoylformic acid or pyruvic acid via the acyl halide
intermediate, followed by NaBH4 reduction in MeOH (Scheme
3).9,12 The alcohol is then activated for nucleophilic substitution
by conversion to the mesylate.13 Direct substitution of the
mesylate with benzylamine was not effective, with excess amine
at 80 - 100 °C in toluene resulting in no conversion. This
problem was circumvented through application of a Finkelstein-
type process, catalyzing the SN2 substitution with NaI (Table
1).14,15 Finkelstein reactions are generally performed for
substitution at primary positions due to the slower rate of SN2
reactions at sterically hindered secondary positions. As can be
seen from Table 1, steric hindrance plays a significant role in the
substitution reaction, with the sterically hindered products 5a-c
being formed in relatively low yields (ca. 50%) when compared
to the much less hindered 5g and 5h, where the yields are ca.
80%. The relatively unhindered n-hexylamine is a good
nucleophile (5d, 80%), while the larger benzyl-, furfuryl-, and
cyclohexylamines saw significantly lower yields (5a-c, ca. 50%).
While the Finkelstein catalysis method was effective for
substitution with aliphatic amine nucleophiles, it failed for
aromatic amines. Here, we adapted a literature procedure using
Na2CO3 in wet EtOH solvent, resulting in acceptable yields of
amine products 5e and 5f (40 and 16%).16
Attempts to incorporate the amine directly from compound 3
through reductive amination were not successful.17 This is
attributed to failure to form the necessary imine intermediate.
Attempts to discretely prepare the imine failed under acid-
catalyzed Dean-Stark distillation, with no reaction occurring in
benzene and only decomposition occurring at reflux in toluene.

3
temperature to 100 °C resulted in enhanced conversion, yet still
incomplete reaction. To achieve full conversion at 100 °C, it was
necessary to increase the catalyst loading to 10 mol%. Varying
the base did not result in significant changes to the conversion
rate, with Cs2CO3 proving the most effective.20 The yield of
dihydroquinoxaline-2(1H)-one products was reasonable in most
cases, averaging 60% (Table 2).21 Both aliphatic and aryl amines
cyclized in approximately the same amounts, showing no
negative impact from the moderately electron-withdrawing aryl
substituents.
References and notes
1.
a) Li, X.; Yang, K.; Li, W.; Xu, W. Drugs Future 2006, 31, 979.
b) Carta, A.; Piras, S.; Loriga, G.; Paglietti, G. Mini-Rev. Med.
Chem. 2006, 6, 1179. c) Ramli, Y.; Moussaif, A.; Karrouchi, K.;
Essassi, E. M. J. Chem. 2014, DOI:10.1155/563406. d) Abu-
Hashem, A. A. Am. J. Org. Chem. 2015, 5, 14.
2.
3.
Zhou, J.; Ba, M.; Wang, B.; Zhou, H.; Bie, J.; Fu, D.; Cao, Y.; Xu,
B.; Guo, Y. Med. Chem. Commun. 2014, 5, 441.
a) Su, D.-S.; Markowitz, M. K.; DiPardo, R. M.; Murphy, K. L.;
Herrell, C. M.; O'Malley, S. S.; Ransom, R. W.; Chang, R. S. L.;
Ha, S.; Hess, F. J.; Pettibone, D. J.; Mason, G. S.; Boyce, S.;
Freidinger, R. M.; Bock, M. G. J. Am. Chem. Soc. 2003, 125,
7516. b) Chen, J. J.; Qian, W.; Biswas, K.; Viswanadhan, V. K.;
Askew, B. C.; Hitchcock, S.; Hungate, R. W.; Arik, L.; Johnson,
E. Bioorg. Med. Chem. Lett. 2003, 13, 2297.
The observations are consistent with our previous study on the
synthesis of benzoxazinone species; therefore, we propose a
similar mechanism is at play (Scheme 4). From the active
Pd(P(tBu3))2 catalyst, C-Br bond activation occurs to yield
carbonyl-stabilized palladacycle 7.22 Anion exchange yields
carbonate complex 8, followed by deprotonation to yield
palladium amide complex 9. Previous reports have proposed that
the superior reactivity of carbonate bases in palladium-catalyzed
reactions arises from intramolecular deprotonation.23 The
catalytic cycle is closed through reductive elimination of the C-N
bond and regeneration of the Pd-catalyst.
4.
5.
6.
a) Nasir, W.; Munawar, M. A.; Ahmed, E.; Sharif, A.; Ahmed, S.;
Ayub, A.; Khan, M. A. K.; Nasim, F. H. Arch. Pharm. Res. 2011,
34, 1605. b) Ghadage, R. V.; Shirote, P. J. J. Chem. Pharm. Res.
2011, 3, 260. c) Bonuga, Y. R.; Nath, A. R.; Balram, B.; Ram, B.
Der Pharma Chem. 2013, 5, 296.
a) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168. b)
Ugi, I. Pure Appl. Chem. 2001, 73, 187. For use of Ugi products
in heterocyclic synthesis see Sharma, U. K.; Sharma, N.;
Vachhani, D. D.; Van der Eycken, E. V. Chem. Soc. Rev. 2015,
44, 1836.
a) Kalinski, C.; Umkehrer, M.; Ross, G.; Kolb, J.; Burdack, C.;
Hiller, W. Tetrahedron Lett. 2006, 47, 3423. b) Erb, W.; Neuville,
L.; Zhu, J. J. Org. Chem. 2009, 74, 3109.
R2
Pd(dba)2
N
R1
O
Br
P(tBu)3
O
7.
8.
For a non-Ugi reaction route, see Luo, X.; Chenard, E.; Martens,
P.; Cheng, Y.-X., Tomaszewski, M. J. Org. Lett. 2010, 12, 3574.
a) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 1995, 34, 1348. b) Louie, J.; Hartwig, J. F. Tetrahedron
Lett. 1995, 36, 3609. c) Wolfe, J. P.; Rennels, R. A.; Buchwald,
S. L. Tetrahedron 1996, 21, 7525. d) Hartwig, J. F. Acc. Chem.
Res. 1998, 31, 858. e) Yang, B. H.; Buchwald, S. L. Org. Lett.
1999, 1, 35. f) Yang, B. H.; Buchwald, S. L. J. Organomet.
Chem. 1999, 576, 125. g) Hartwig, J. F. Nature 2008, 455, 314.
h) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2011, 2, 27.
Ylijoki, K. E. O.; Kündig, E. P. Chem. Commun. 2011, 47, 10608.
R1
2 DBA
Pd(PtBu3)2
N
N
6
NHR2
5
tBu3P
PtBu3
tBu3P
Pd
R2
N
Br
tBu3P
9.
R1
Pd
N
O
10. Würtz, S.; Lohre, C.; Fröhlich, R.; Bergander, K.; Glorius, F. J.
Am. Chem. Soc. 2009, 131, 8344.
N
R1
O
9
11. See Supplementary Material for complete experimental details.
12. Extension of this methodology to substituted benzoyl formic acid
species is readily achieved, see: Fizet, C. Helv. Chim. Acta 1982,
65, 2024 and Ref. 9.
NHR2
7
Cs2CO3
13. Jiang, X.; Qing, F.-L. Beilstein J. Org. Chem. 2013, 9, 2862.
14. Finkelstein, H. Ber. Dtsch. Chem. Ges. 1910, 43, 1528.
15. General procedure for preparation of 5: To a toluene solution (ca.
50 - 100 mM) of mesylate compound 4 (1 equiv.) and a catalytic
amount of NaI, amine (2 equiv.) was added slowly under nitrogen
atmosphere. The reaction mixture was heated at 80 ˚C for 24 h.
The reaction was then quenched with water and extracted with
EtOAc. The organic extract was washed with brine and dried over
anhydrous MgSO4. The crude product was purified by silica gel
column chromatography, eluted with DCM then 1-3% MeOH in
DCM. The fractions were concentrated and residual solvent
removed under vacuum.
OCs
HCO3Cs
O
O
tBu3P
Pd
N
O
CsBr
R1
NHR2
8
Scheme 4: Proposed catalytic cycle.
16. George, D. M.; Breinlinger, E. C.; Argiriadi, M. A.; Zhang, Y.;
Wang, J.; Bansal-Pakala, P.; Duignan, D. B.; Honore, P.; Lang, Q.
Y.; Mittelstadt, S.; Rundell, L.; Schwartz, A.; Sun, J.; Edmunds, J.
J. J. Med. Chem. 2015, 58, 333.
17. Abel-Magid, A. F.; Mehrman, S. J. Org. Proc. Res. Devel. 2006,
10, 971.
18. a) Knust, H.; Nettekoven, M.; Pinard, E.; Roche, O.; Rogers-
Evans, M. WO Patent 2009/016087 A1, 2009. b) Fuse, S.; Masui,
H.; Tannna, A.; Shimizu, F.; Takahashi, T. ACS Comb. Sci. 2012,
14, 17.
19. Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295.
20. This reduced reactivity is consistent with the work of Kalinski et
al. where 5 mol% Pd2(dba)3 and 10 mol% P(o-tol)3 at 100 °C
required 72 - 96 hours to achieve average yields of 39%.6a
21. General procedure for preparation of 6: In a Schlenk flask,
Pd(dba)2 (20 mol%), [HPtBu3]BF4 (40 mol%), and Cs2CO3 (1.2
equiv.) were dissolved in toluene (50 - 100 mM with respect to 5)
and heated at 100 °C for 15 min under nitrogen. The solution
changed from a red/purple colour to yellow. To this, 5 (1 equiv.)
was added and stirred for 16 hours. The reaction was diluted with
In summary, we have demonstrated a new NaI-catalyzed SN2
substitution for synthesis of amidoamine substrates and their
subsequent
palladium-catalyzed
cyclization
to
yield
dihydroquinoxaline-2(1H)-ones. The substitution reaction is
effective for alkylamines and has lower yield for arylamines.
The cyclization reaction does not display significant substitution
dependence, proceeding well for both alkyl and aryl substituted
substrates. The resulting products are currently being screened
for biological activity.
Acknowledgments
Financial support from the Canada Foundation for Innovation
(CFI), the Faculties of Science and Graduate Studies and
Research of Saint Mary's University, and ACEnet (ACEnet
Research Fellowship to I.I.M.) is gratefully acknowledged.

4
Tetrahedron
diethyl ether and was filtered through a short plug of Celite. The
Banerjee, D.; Besnard, C.; Sunoj, R. B.; Kündig, E. P. Chem. Eur.
filtrate was concentrated under reduced pressure. The crude
product was purified by flash column chromatography with 5-10%
EtOAc/hexane.
J. 2013, 19, 11916.
23. Donati, L.; Michel, S.; Tillequin, F.; Porée, F.-H. Org. Lett. 2010,
12, 156.
22. Analogous intermediates have been characterized
crystallographically: Katayev, D.; Jia, Y.-X.; Sharma, A. K.;

5
Highlights
- Pd-catalyzed C-N coupling for heterocycle
preparation.
- NaI-catalyzed SN2 substitution with alkyl and aryl
amine nucleophiles.
- Divergent synthesis of aminoalchols.
- Highly-substituted dihydroquinoxaline-2(1H)-one
synthesis.