An Aniline-Mediated Regioselective Synthesis of Quinoxalin-2-ones via the Condensation of α-Ketimine Esters with 2-Aminoanilines

Article abstract of DOI:10.1055/s-0037-1609345

A highly regioselective method for the condensation of α-ketimine esters with 2-aminoanilines for the construction of quinoxalin-2-one derivatives is described. The substrate scope with 2-aminoaniline derivatives and different α-keto esters is explored with yields ranging from 44 to 90% and typical isolated regioselectivities between 6.4 to >25:1.

Full text of DOI:10.1055/s-0037-1609345

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–J
paper
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H. V. Huynh et al.
Paper
Synthesis
An Aniline-Mediated Regioselective Synthesis of Quinoxalin-2-ones
via the Condensation of α-Ketimine Esters with 2-Aminoanilines
Huy V. Huynh*a
Selçuk Çalimsiza
Hilaire V. Kemami Wangunb
Trevor J. Raineyc
Teague M. McGinitieb
Xiaoming Liaod
R2
X
X
O
PTSA·H2O
reflux
MTBE, AcOH, 21 °C
N
O
+
R1
N
NH
O
O
H2N
R1
O
R2
R1
NH2
O
H2N
Lizhi Yud
17 examples
44–90% yield
up to >25:1 regioselectivity
one-pot direct isolation
a Department of Process Chemistry, Gilead Alberta ULC, 1021
Hayter Road NW, Edmonton, Alberta T6S 1A1, Canada
b Department of Analytical Chemistry, Gilead Alberta ULC,
1021 Hayter Road NW, Edmonton, Alberta T6S 1A1, Canada
c Department of Process Chemistry, Gilead Sciences, 333
Lakeside Drive, Foster City, CA 94404, USA
d Department of Process Development and Manufacturing,
Pharmaron Beijing, Co. Ltd., 6 Tai-He Road, BDA, Beijing,
100176, P. R. of China
Huy.Huynh@gilead.com
Received: 15.01.2018
Accepted after revision: 18.02.2018
Published online: 03.04.2018
cient and regioselective method for the synthesis of substi-
tuted quinoxalin-2-ones. While a survey of the literature
identified several potential routes to unsymmetrical qui-
noxalin-2-ones, most were found to suffer from poor regi-
oselectivity,13 thus hindering their synthetic utility from a
process chemistry point of view. Only a limited number of
methods have been reported to generate quinoxalin-2-ones
regioselectively; examples include the reactions of di-
amines with ynones via a base-promoted C-α-CH2-extru-
sion,14 the reactions of o-alkynylaldehydes with ring-fused
diamines,15 and the ortho-C–H bond activation reaction of
aryl diamines with terminal alkynes.16 Another regioselec-
tive route to quinoxalin-2-ones has been reported between
an α-keto ester and unsymmetrical 2-aminoanilines, but
the reaction required microwave irradiation at 200 °C and
250 psi,17 which are not easily accessible conditions in com-
mercial manufacturing.
Herein, we report a mild, expedient, one-pot synthesis
of substituted quinoxalin-2-ones via the in situ conversion
of α-keto esters into α-ketimine esters using a functional-
ized aniline followed by cyclocondensation with a function-
alized 2-aminoaniline (Scheme 1). We envisioned that con-
densation of the carbonyl and amine would result in the
formation of a more basic ketimine moiety, which would
DOI: 10.1055/s-0037-1609345; Art ID: ss-2018-m0027-op
Abstract A highly regioselective method for the condensation of α-ke-
timine esters with 2-aminoanilines for the construction of quinoxalin-2-
one derivatives is described. The substrate scope with 2-aminoaniline
derivatives and different α-keto esters is explored with yields ranging
from 44 to 90% and typical isolated regioselectivities between 6.4 to
>25:1.
Key words quinoxalin-2-ones, 2-aminoanilines, α-ketimine esters,
one-pot synthesis, transimination, regioselectivity
Quinoxalines are important nitrogen-containing hetero-
cycles that have been utilized extensively in the pharma-
ceutical and specialty chemical industry. In particular, qui-
noxaline derivatives are desirable synthetic targets due to
their extensive applications as antibiotic,1 anticancer,2 anti-
viral,3 antimalarial,4 and antileishmanial5 agents. Further-
more, quinoxalines have been utilized as electrolumines-
cent materials,6 dyes,7 organic semiconductors,8 and ligands
in coordination chemistry.9
As part of our efforts toward designing efficient routes
to biologically active compounds,10–12 we required an effi-
X
MTBE
AcOH
21 °C
H
N
O
O
toluene
O
R1
N
+
X
R2
H2N
H2N
PTSA·H2O
110 °C
O
H2N
R1
N
O
R2
R1
O
Scheme 1 General reaction for ketimine formation and transimination to quinoxalin-2-ones
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

B
H. V. Huynh et al.
Paper
Synthesis
facilitate selective acid-mediated protonation and activa-
tion of the ketimine versus the ester, thereby enabling se-
lective attack of the more nucleophilic dianiline amine. This
transimination would then be followed by a fast and irre-
versible cyclization to furnish the quinoxalin-2-one core.
The design of this catalytic process hinged upon the in-
creased Brønsted basicity of the ketimine intermediate
which, upon protonation, forms a ketiminium ion with en-
hanced electrophilicity at the ketiminium carbon relative to
the ester, thereby affording a regioselective cyclization of
the 1,2-diamine.
Previously, difluoroalkylquinoxalin-2-ones were report-
ed as important synthetic building blocks for the construc-
tion of HCV serine protease scaffolds.1 Issues that plagued
these early efforts were the low yield and poor regioselec-
tivity of the heterocycle construction.
For this reason, we opted to utilize the β,β-difluoro-α-
keto ester 118 as the model substrate for our studies. Initial-
ly, a series of aliphatic and aromatic amines for ketimine
formation were screened in THF with aniline-based amines
exhibiting the best conversion into the ketimine. Specifical-
ly, 4-chloroaniline provided the best combination of regi-
oselectivity, conversion, and cost (see the Supporting Infor-
mation). Other solvents for the condensation step were
screened (toluene, acetonitrile, dichloromethane, ethyl ace-
tate, isopropyl acetate, N,N-dimethylformamide) with
methyl tert-butyl ether (MTBE) showing the best combina-
tion of regioselectivity, yield, and removal of the undesired
minor regioisomer.
Table 1 Scope of Substituted 2-Aminoanilines for the Synthesis of Quinoxalin-2-ones
Cl
Cl
MTBE
AcOH
21 °C
H
N
toluene
PTSA·H2O
O
O
N
O
R
+
H2N
H2N
110 °C
O
N
F
F
O
R
NH2
F
F
F
F
O
4a–h
1
2
3a–h
Entry
1d
Substrate
Major product
Minor product
Regioisomer ratio
(major/minor)
Yield (%)c
Crudea
Isolatedb
2.6:1d
>25:1d
53
H2N
H2N
OMe
OMe
F
H
H
O
O
O
O
N
O
O
N
OMe
N
OMe
OMe
N
3a
F
F
F
F
F
F
F
F
F
F
F
F
4a′
4a
4a
2
3
4
5
6.3:1
6.1:1
1.5:1
2.1:1
>25:1
6.9:1e
>25:1
>25:1
68
61f
50
44
H
N
H2N
H2N
H
N
N
OMe
N
3a
4a′
4b′
4c′
4d′
H2N
H2N
H
N
H
N
F
O
O
O
N
N
F
3b
F
F
F
F
F
F
4b
H2N
H2N
Cl
H
N
H
N
Cl
N
Cl
N
3c
4c
4d
H
H2N
H2N
Br
H
N
O
N
Br
N
N
Br
3d
F
F
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

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H. V. Huynh et al.
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Synthesis
Table 1 (continued)
Entry
Substrate
Major product
Minor product
Regioisomer ratio
(major/minor)
Yield (%)c
Crudea
Isolatedb
6
4.4:1
>25:1
69
O
O
H
H
O
N
O
N
H2N
H2N
OMe
OMe
OMe
N
N
F
F
O
F
F
3e
4e
4f
4e′
7
8
1.9:1
1.5:1e
>25:1
44f
55
H
H2N
H
O
N
O
N
H2N
N
N
3f
F
F
F
F
F
4f′
11.2:1
H
N
H
N
O
H2N
O
N
H2N
3g
N
F
F
F
4g′
4g
9
11.1:1
>25:1
52
Cl
H
Cl
O
N
Cl
H
H2N
O
N
N
H2N
Cl
N
Cl
F
F
Cl
F
F
3h
4h′
4h
a Determined from the ratio of products in the 19F NMR (DMSO-d6) spectrum of the reaction mixture.
b Determined from the ratio of products in the 19F NMR (DMSO-d6) spectrum of the isolated product.
c Yield of isolated product.
d Control reaction with no 4-chloroaniline added.
e Regioisomeric ratio after column chromatography.
f Required isolation by column chromatography.
Under the optimized conditions, the reaction proceeds
by mixing 1 equivalent of the α-keto ester 1 with 1.15
equivalents of 4-chloroaniline in the presence of a catalytic
amount of p-toluenesulfonic acid monohydrate (PTSA·H2O)
in toluene at reflux to provide ketimine 2 after 16 hours.
Water was removed azeotropically during the process
thereby facilitating the expedient conversion into the de-
sired ketimine intermediate. Addition of MTBE, acetic acid,
and 3,4-diaminoanisole to the reaction mixture followed by
stirring for an additional 16 hours at ambient temperature
afforded 4a as the major regioisomer in 68% yield with
>25:1 regioselectivity after filtration of the one-pot reaction
mixture (Table 1, entry 2). Notably, under the optimized con-
ditions, no further purification of the isolated solid was re-
quired to remove any undesired minor regioisomer.
case, the opposite regioisomer was the major product com-
pared to our ketimine activation protocol of 6.3:1 affording
4a as the major isomer.
Using the optimized reaction conditions, different func-
tionalized 2-aminoanilines were evaluated covering a range
of electron-donating and electron-withdrawing substitu-
ents on the aromatic ring (Table 1). Through simple filtra-
tion and rinsing of the resulting slurry, a single regioisomer
could be isolated with >25:1 regioselectivity and yields of
44-69% (entries 2, 4-6, 8-9). Only products 4b and 4f re-
quired further purification by column chromatography
since neither quinoxalin-2-one product was amenable to
direct crystallization from the reaction medium and thus,
were isolated as a mixture of regioisomers. In most cases,
the structures of the major regioisomers were established
1
To confirm that the ketimine was the source of the en-
hanced regioselectivity, a control study using 3,4-diamino-
anisole in the absence of 4-chloroaniline was conducted
with 1 and 3a (Table 1, entry 1). The cyclization proceeded
as expected but resulted in a crude regioisomer ratio of
2.6:1 with undesired 4a′ as the major regioisomer. In this
by NOESY and ROESY H NMR with a nOe correlation be-
tween the amide proton (Hy, 12.7 ppm) and the phenyl pro-
ton doublet (Hx, 6.8 ppm) (Figure 1). Additionally, the nOe
correlation was confirmed for 4g between the amide proton
and methyl proton; 4h was assigned by analogy.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

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H. V. Huynh et al.
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Synthesis
carbon was ruled out due to the higher relative energy of
this transition state (see the Supporting Information for
more details).
Hy
On the basis of the observed results and supported by
the electronic structure calculations, the following conclu-
sions can be made. The reaction pathway and resulting re-
gioselectivity is determined by the functional group on the
2-aminoaniline ring; electron-donating substituents in-
crease the nucleophilicity of the para nitrogen, whereas
electron-withdrawing groups decrease the reactivity of the
para group relative to the meta nitrogen. The electronic
structure calculations support pathway 2 (Scheme 2),
which suggests attack will occur preferentially at the ket-
amine/ketiminium ion (5a) versus the less electrophilic es-
ter. For example, a strong electron donor, such as the 4-me-
thoxy group present in 3a, leads to a 6.3:1 ratio at the end
of reaction. Conversely, the regioselectivity is reversed to
4.4:1 when a strong electron-withdrawing ester, such as 3e,
is employed. In this case, the para-NH2 is now deactivated
resulting in the meta-NH2 acting as the predominate nucle-
ophile. Attempts to use stronger electron-withdrawing sub-
stituents such as a nitro group led to poor reactivity, pre-
sumably since both NH2 groups are deactivated toward nu-
cleophilic attack onto the α-ketimine ester.
MeO
Hx
Hy
Hx
N
O
N
F
F
4a
Figure 1 1H NMR NOESY evidence for the major regioisomer
To evaluate the mechanism and the origin of the ob-
served selectivity, electronic structure calculations were
conducted at the M06-2X-D3 (PBF, methyl tert-butyl
ether)/cc-PVTZ(-f)//M06-2X/LACVP** level.19 Transition
states and intermediates for the reaction of both the elec-
tron-rich methoxyaniline 3a as well as the electron-defi-
cient ester aniline 3e were evaluated. In both cases, nucleo-
philic attack of the more electron-rich aniline nitrogen
upon imine substrate 2 in a general acid-catalyzed mecha-
nism was calculated to have the lower activation barrier;
for instance, attack of the para-amino group is favored over
the meta-amino group by 3.1 kcal/mol in the case of 3a.
Similarly, attack of the meta-amino group is favored over
the para-amino group by 1.0 kcal/mol in the case of 3e.
Subsequent cyclocondensation then furnishes the final
product that conforms to the experimentally isolated major
regioisomer. It should be noted that the kinetically most
facile pathway is also the most thermodynamically favor-
able. An alternative pathway in which attack of the para-
NH2 onto the ester group of 2 preceded attack at the imine
Furthermore, functional groups with weak to moderate
electronic effects have, as expected, a more variable impact
on the reaction regioisomer ratio.
As anticipated, the sterics of the 2-aminoanilines also
play a role in the regioselectivity (Table 1, entries 8 and 9),
with the major product being formed via initial attack of
the ketimine from the less sterically encumbered aniline.
The result is a highly selective crude reaction mixture ratio
of 11:1 in both cases. This steric phenomenon has also pre-
viously been reported for the condensation of 2-aminoani-
lines with methyl trimethoxyacetate.20
The scope of the chemistry was extended to study pos-
sible substituent effects of the α-keto ester starting materi-
al (Table 2). Additional screening of α-keto esters found that
OMe
H2N
Cl
Cl
N
N
OMe
or
N
NH2
F
pathway 1
H
N
NH
O
F
N
O
F
F
O
O
F
F
O
N
OMe
F
F
O
5a'
6a'
4a' minor regioisomer
2
+
Cl
OMe
H2N
OMe
H2N
N
OMe
NH2
H2N
N
H
pathway 2
3a
F
N
NH
or
F
O
F
F
O
O
F
F
O
OMe
6a
5a
4a major regioisomer
Scheme 2 Possible intermediates leading to the quinoxalin-2-one regioisomers
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

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H. V. Huynh et al.
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Synthesis
those with enolizable protons resulted in complex reaction
mixtures during the initial ketimine formation with 4-chlo-
roaniline. However, functionalized aryl α-keto esters 7a–i
were found to be compatible with ketimine formation and
subsequent ring-closing condensation. In these examples,
the selective removal of the minor regioisomer from the re-
action mixture was found to be less effective, presumably
due to the decreased solubility of the products in the reac-
tion/isolation medium, thereby resulting in the isolated
product being a mixture of both quinoxalin-2-one regioiso-
mers. The yields from these substrates ranged between 74–
91% with 6.4:1 to 14.3:1 ratios of regioisomers in the isolat-
ed solids.
Table 2 Scope of Substituted α-Keto Esters for the Synthesis of Quinoxalin-2-ones
Cl
Cl
MTBE
AcOH
21 °C
toluene
PTSA·H2O
H
N
O
O
R
OMe
N
O
+
R
H2N
H2N
O
110 °C
NH2
R
N
O
O
OMe
3a
7a–i
8a–i
Entry
1d
Substrate
Major product
Minor product
Regioisomer Ratio
(major:minor)
Isolated
Yield(%)c
Crudea
Isolatedb
2.1:1d
2.2:1d
89
H
H
O
O
N
O
N
OMe
O
N
OMe
OMe
N
O
7a
7a
8a′
8a
2
3
8.9:1
7.3:1
9.2:1
90
H
N
H
N
O
O
O
O
N
N
OMe
O
8a
8a′
14.3:1
89
91f
90f
87
H
N
H
N
F3C
O
OMe
OMe
OMe
OMe
O
O
O
N
N
OMe
O
F3C
7b
F3C
8b
8b′
4
5
6
N/Ae
N/Ae
7.0:1
11.5:1
H
NC
H
N
O
O
O
N
O
O
O
O
O
O
O
N
N
OMe
OMe
OMe
O
NC
7c
NC
8c
8c′
6.7:1
H
H
O2N
N
N
O
N
N
O
7d
O2N
O2N
8d
8d′
11.4:1
Me
H
H
O
N
N
N
N
O
7e
Me
Me
8e
8e′
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H. V. Huynh et al.
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Table 2 (continued)
Entry
Substrate
Major product
Minor product
Regioisomer Ratio
(major:minor)
Isolated
Yield(%)c
Crudea
Isolatedb
7
7.7:1
8.0:1
80f
H
O
H
N
O
N
O
OMe
O
N
OMe
O
N
MeO
MeO
8f′
7f
MeO
8f
8
5.8:1
6.4:1
78
Me2N
H
H
N
O
N
OMe
O
O
O
N
N
OMe
O
7g
Me2N
Me2N
8g
8g′
9
7.2:1
8.2:1
10.1:1
9.0:1
74
90
H
H
Me
O
N
O
N
OMe
O
O
O
N
OMe
N
7h
7i
8h
8h′
8i′
10
H
O
H
N
O
N
O
S
OMe
O
N
OMe
S
O
N
S
8i
a Determined from the ratio of products in the 19F NMR (DMSO-d6) spectrum of the reaction mixture.
b Determined from the ratio of products in the 19F NMR (DMSO-d6) spectrum of the isolated product.
c Yield of isolated product.
d Control reaction with no 4-chloroaniline added.
e Sampling gave inconsistent results due to sample inhomogeneity.
f Required an additional slurry wash in 5.2 mL/g MTBE to remove excess 4-chloroaniline.
Indeed, the importance of preforming the ketimine is
again confirmed by the reverse 2.1:1 regioisomer ratio that
results from reacting 7a directly with 3a in the absence of
4-chloroaniline (Table 2, entry 1) compared to the 8.9:1 ra-
tio when the ketimine is formed (entry 2). The typical re-
gioisomeric ratios using aryl α-keto esters can range be-
tween 7.0:1 to 8.9:1 regardless of whether the ketimine is
made electron-rich or deficient by arene functionalization.
Contrary to the trends for substituted 2-aminoanilines, the
relatively consistent crude regioisomeric ratios suggest al-
terations to the α-keto ester substrate electronics play a
smaller role in the resulting regioisomer ratio. In addition, a
heteroarene derivative was found to have a minimal impact
on the reaction (entry 10), affording a comparable regioiso-
mer ratio and yield to those of the phenyl-substituted de-
rivatives.
In conclusion, a simple one-pot protocol for an en-
hanced regioselective synthesis toward non-symmetric
quinoxalin-2-ones is reported. The process relies on the re-
action of an in situ formed α-ketimine ester moiety with
functionalized 2-aminoanilines. When a β,β-difluoro α-
keto ester substrate is utilized, the major regioisomer can
typically be isolated directly from the reaction mixture in a
>25:1 ratio of regioisomers, with no further purification re-
quired. In addition, the regioselectivity can be further
tuned depending on the electronic nature of the 2-amino-
aniline. Further investigations on the role of the dianiline
electronics are ongoing.
All reactions were performed in dry glassware under an atmosphere
of nitrogen unless otherwise noted. Melting points (mp) were mea-
sured with a Büchi Melting Point B-545 instrument and are uncor-
rected. IR spectra were recorded using a Nicolet iS50 FT spectrometer,
with the absorption bands given in cm–1. NMR spectra were obtained
with a Bruker ASCEND 400 spectrometer at 400 MHz for 1H NMR, 100
MHz for 13C NMR, and 377 MHz for 19F NMR. Chemical shifts (δ) are
A possible steric interaction is also found to have mini-
mal impact on the resulting regioisomer ratio when there is
a methyl group ortho to the ketamine (7h), affording a 7.2:1
ratio of regioisomers.
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H. V. Huynh et al.
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given in parts per million (ppm) relative to the residual solvent peak
[δ = 2.54 (1H NMR) and δ = 39.51 (13C NMR) in DMSO-d6] with cou-
pling constants (J) in Hertz (Hz). 19F NMR spectra were recorded using
a proton decoupled method with no internal reference. The multiplic-
ities are indicated as standard abbreviations. High-resolution mass
spectra (HRMS) were measured with a Thermo LTQ Orbitrap XL in-
strument.
3-(1,1-Difluorobut-3-en-1-yl)-7-fluoroquinoxalin-2-one (4b)
The ketimine formation required 16 h and the cyclization required 72
h. The final solids was isolated by column chromatography using a 3%
MeOH in DCM eluent.
Yield: 2.0 g (61%); light orange solid; mp 129–130 °C.
IR (ATR): 1676, 1614, 1510, 1152, 1008, 812 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 12.93 (s, 1 H), 7.92 (dd, J = 3.2, 9.0
Hz, 1H), 7.24 (dt, J = 2.8, 8.8 Hz, 1H), 7.07 (dd, J = 2.8, 9.4 Hz, 1 H), 5.77
(m, 1 H), 5.22 (m, 2 H), 3.24 (dt, J = 7.2, 10.0 Hz, 2 H). Isolated as a
6.9:1 regioisomer ratio; only signals of the major regioisomer are list-
ed.
13C NMR (100 MHz, DMSO-d6): δ = 164.7, 162.3, 159.1, 156.7, 153.4,
152.2, 149.4 (t, J = 28.0 Hz), 134.7 (d, J = 13.0 Hz), 132.2 (d, J = 11.0
Hz), 130.0, 128.7 (m), 127.4, 121.0, 120.3 (d, J = 24.0 Hz), 119.1 (t, J =
243.0 Hz), 117.1 (d, J = 9.0 Hz), 114.5 (d, J = 23.0 Hz), 112.1 (d, J = 24.0
Hz), 101.4 (d, J = 27.0 Hz), 39.1 (t, J = 25.0 Hz). Isolated as a 6.9:1 ratio
of regioisomers; both sets of signals are listed.
Quinoxalin-2-ones; General Procedure
To the appropriate α-keto ester (9.5 mmol) in toluene (22.5 mL) were
added p-toluenesulfonic acid monohydrate (18.2 mg, 0.095 mmol)
and 4-chloroaniline (1.40 g, 11.0 mmol) at 21 °C. After heating the re-
action mixture at 110 °C for 1 d using a Dean–Stark apparatus, the re-
action mixture was distilled to a volume of 6 mL. Next, at 21 °C, the
appropriate diamine (1.2 equiv), MTBE (12.4 mL) and AcOH (1.3 mL)
were combined with the reaction mixture. After stirring for 1–4 d, the
resulting slurry was filtered and rinsed with MTBE (2 × 6 mL). The
solid was dried in a vacuum oven at 40 °C (with N2 purging) to afford
the desired quinoxalin-2-one. No further purification was required
unless otherwise stated.
19F NMR (377 MHz, DMSO-d6): δ (major regioisomer) = –99.9 (s, 2 F),
–106.0 (s, 1 F); δ (minor regioisomer) = –100.1 (s, 2 F), –118.4 (s, 1 F).
HRMS (ESI): m/z [M + H]+ calcd for C12H10F3N2O: 255.0745; found:
255.0742.
Control Reaction; General Procedure
To the appropriate α-keto ester (9.5 mmol) in toluene (6 mL) were
added p-toluenesulfonic acid monohydrate (22.1 mg, 0.12 mmol),
3,4-diaminoanisole (1.2 equiv), MTBE (10 mL) and AcOH (1.3 mL). Af-
ter stirring for 1 d, the resulting slurry was filtered and rinsed with
MTBE (2 × 6 mL). The solid was dried in a vacuum oven at 40 °C (with
N2 purging) to afford the desired quinoxalin-2-one.
7-Chloro-3-(1,1-difluorobut-3-en-1-yl)quinoxalin-2-one (4c)
The ketimine formation required 16 h and the cyclization required 96 h.
Yield: 1.65 g (50%); dark purple solid; mp 179–186 °C.
IR (ATR): 1662, 1645, 996, 927, 834 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 12.88 (s, 1 H), 7.87 (d, J = 8.8 Hz, 1
H), 7.35–7.40 (m, 2 H), 5.51–5.75 (m, 1 H), 5.18–5.27 (m, 2 H), 3.22
(dt, J = 24.0, 31.2 Hz, 2 H).
3-(1,1-Difluorobut-3-en-1-yl)-6-methoxyquinoxalin-2-one (4a′)
The cyclization required 16 h.
13C NMR (100 MHz, DMSO-d6): δ = 152.2, 150.6 (t, J = 26.0 Hz), 136.4,
134.1, 131.2, 129.0, 128.7 (t, J = 5.0 Hz), 123.9, 121.1, 119.1 (t, J =
243.0 Hz), 114.8, 39.3 (unresolved triplet due to solvent).
19F NMR (377 MHz, DMSO-d6): δ = –100.0 (s, 2 F).
HRMS (ESI): m/z [M + H]+ calcd for C12H10ClF2N2O: 271.0450; found:
Yield: 1.46 g (53%); beige solid; mp 180–181 °C.
IR (ATR): 1665, 1495, 1376, 1127, 1028, 1002, 831 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 12.80 (s, 1 H), 7.43 (br s, 1 H), 7.34
(br s, 2 H), 5.75–5.86 (m, 1 H), 5.26 (d, J = 25.8 Hz, 1 H), 5.23 (d, J =
18.8 Hz, 1 H), 3.87 (s, 3 H), 3.29 (dt, J = 7.1, 17.1 Hz, 2 H).
.
13C NMR (100 MHz, DMSO-d6): δ = 156.7, 152.1, 150.4 (t, J = 24.6 Hz),
130.9, 128.8 (t, J = 5.0 Hz), 127.3, 122.1, 121.0, 119.3 (t, J = 244.0 Hz),
118.4, 116.5, 110.4, 55.7.
271.0444.
7-Bromo-3-(1,1-difluorobut-3-en-1-yl)quinoxalin-2-one (4d)
The ketimine formation required 16 h and the cyclization required 72 h.
Yield: 1.30 g (44%); brown-tan solid; mp 186–187 °C.
19F NMR (377 MHz, DMSO-d6): δ = –99.7 (s, 2 F).
HRMS (ESI): m/z [M + H]+ calcd for C13H13F2N2O2: 267.0945; found:
IR (ATR): 1663, 1644, 1151, 1044, 1001, 836 cm–1
.
267.0961.
1H NMR (400 MHz, DMSO-d6): δ = 12.86 (s, 1 H), 7.80 (d, J = 8.4 Hz, 1
H), 7.50–7.53 (m, 2 H), 5.73–5.83 (m, 1 H), 5.18–5.27 (m, 2 H), 3.22
(dt, J = 7.1, 17.3 Hz, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 152.2, 150.8 (t, J = 26.0 Hz), 134.2,
131.3, 129.3, 128.6 (t, J = 5.0 Hz), 126.7, 125.1, 121.1, 119.1 (t, J =
244.0 Hz), 117.8, 39.1 (t, J = 24.0 Hz).
3-(1,1-Difluorobut-3-en-1-yl)-7-methoxyquinoxalin-2-one (4a)12
The ketimine formation required 16 h and the cyclization required 16 h.
Yield: 5.22 g (68%); off-white solid; mp 161–162 °C.
IR (ATR): 1659, 1615, 1512, 1199, 1172, 1124, 1017, 834 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 12.68 (s, 1 H), 7.73 (d, J = 8.8 Hz, 1
H), 6.92 (dd, J = 2.0, 9.2 Hz, 1 H), 6.75 (d, J = 2.4 Hz, 1 H), 5.71–5.82 (m,
1 H), 5.15–5.25 (m, 2 H), 3.84 (s, 3 H), 3.21 (dt, J = 7.2, 17.2 Hz, 2 H).
19F NMR (377 MHz, DMSO-d6): δ = –100.1 (s, 2 F).
HRMS (ESI): m/z [M + H]+ calcd for C12H10BrF2N2O: 314.9945; found:
13C NMR (100 MHz, DMSO-d6): δ = 162.1, 152.8, 146.4 (t, J = 25.0 Hz),
134.9, 130.9, 129.0 (t, J = 5.0 Hz), 125.3, 120.8, 119.4, 112.9 (t, J =
243.0 Hz), 97.5, 55.7, 39.2 (t, J = 31.0 Hz).
314.9939.
Methyl 3-(1,1-Difluorobut-3-en-1-yl)-2-hydroxyquinoxaline-6-
carboxylate (4e)
19F NMR (377 MHz, DMSO-d6): δ = –99.2 (s, 2 F).
The ketimine formation required 16 h and the cyclization required 96 h.
HRMS (ESI): m/z [M + H]+ calcd for C13H13F2N2O2: 267.0945; found:
Yield: 2.13 g (69%); tan solid; mp 171–173 °C.
267.0940.
IR (ATR): 1721, 1662, 1612, 1274, 1101, 1071, 765 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

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H. V. Huynh et al.
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Synthesis
1H NMR (400 MHz, DMSO-d6): δ = 13.09 (s, 1 H), 8.33 (s, 1 H), 8.15 (d,
J = 8.4 Hz, 1 H), 7.43 (d, J = 8.4 Hz, 1 H), 5.77–5.84 (m, 1 H), 5.19–5.29
(m, 2 H), 3.88 (s, 3 H), 3.23 (dt, J = 6.8, 17.2 Hz, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 165.2, 152.5, 151.6 (t, J = 26.0 Hz),
136.5, 132.1, 130.8, 129.5, 128.7 (t, J = 5.0 Hz), 124.8, 121.1, 119.0 (t,
J = 243.0 Hz), 116.1, 52.3, 39.1 (t, J = 27.0 Hz).
19F NMR (377 MHz, DMSO-d6): δ = –100.3 (s, 2 F).
HRMS (ESI): m/z [M + H]+ calcd for C12H9Cl2F2N2O: 305.0060; found:
305.0055.
7-Methoxy-3-phenyl-quinoxalin-2-one (8a)21
The ketimine formation required 25 h and the cyclization required 96 h.
19F NMR (377 MHz, DMSO-d6): δ = –100.2 (s, 2 F).
HRMS (ESI): m/z [M + H]+ calcd for C14H13F2N2O3: 295.0894; found:
Yield: 2.55 g (90%); light yellow solid; mp 232–233 °C (dec.).
IR (ATR): 1658, 1615, 1273, 1252, 1177, 827 cm–1
.
295.0888.
1H NMR (400 MHz, DMSO-d6): δ = 12.46 (s, 1 H), 8.27–8.28 (m, 2 H),
7.74 (d, J = 8.8 Hz, 1 H), 7.46–7.48 (m, 3 H), 6.93 (dd, J = 2.8, 8.8 Hz, 1
H), 6.79 (d, J = 2.8 Hz, 1 H), 3.84 (s, 3 H). Isolated as a 9.2:1 ratio of
regioisomers; only signals of the major regioisomer are listed.
13C NMR (100 MHz, DMSO-d6): δ = 160.7, 155.4, 154.8, 154.22,
154.16, 150.4, 135.9, 135.8, 133.7, 132.7, 130.1, 129.6, 129.2, 128.9,
128.1, 127.8, 127.1, 126.3, 125.6, 119.8, 116.0, 112.2, 110.0, 97.3, 55.6,
55.5. Isolated as a 9.2:1 ratio of regioisomers; both sets of signals are
listed.
3-(1,1-Difluorobut-3-en-1-yl)-7-methylquinoxalin-2-one (4f)
The ketimine formation required 16 h and the cyclization required 18 h.
The final solids was isolated by column chromatography using a 4:1
heptanes:EtOAc eluent.
Yield: 1.98 g (44%); light orange solid; mp 122–123 °C.
IR (ATR): 1667, 1029, 993, 819 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 12.74 (s, 1 H), 7.70–7.72 (m, 1 H),
7.22–7.25 (m, 1 H), 7.11–7.17 (m, 1 H), 5.72–5.82 (m, 1 H), 5.16–5.25
(m, 2 H), 3.23 (dt, J = 7.2, 17.2 Hz, 2 H), 2.41 (3 H). Isolated as a 1.5:1
ratio of regioisomers; only signals of the major regioisomer are listed.
HRMS (ESI): m/z [M + H]+ calcd for C15H13N2O2: 253.0977; found:
253.0972.
13C NMR (100 MHz, DMSO-d6): δ = 152.6, 152.4, 150.1 (t, J = 25.4 Hz),
149.0 (t, J = 25.4 Hz), 142.9, 133.4, 133.2, 132.9, 130.8, 130.2, 129.2,
128.9 (m), 128.6, 125.3, 120.9, 119.3 (t, J = 243.0 Hz), 115.3, 115.0,
39.2 (t, J = 25.0 Hz), 21.4, 20.3. Isolated as a 1.5:1 ratio of regioiso-
mers; both sets of signals are listed.
7-Methoxy-3-[4-(trifluoromethyl)phenyl]quinoxalin-2-one (8b)
The ketimine formation required 17 h and the cyclization required 48 h.
Yield: 2.25 g (89%); light yellow solid; mp 280–287 °C (dec.).
IR (ATR): 1661, 1324, 1109, 1070, 1016, 828 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 12.59 (s, 1 H), 8.50 (d, J = 8.4 Hz, 2
H), 7.83 (d, J = 8.4 Hz, 2 H), 7.77 (d, J = 8.8 Hz, 1 H), 6.96 (dd, J = 2.8, 8.8
Hz, 1 H), 6.79 (d, J = 2.4 Hz, 1 H), 3.85 (s, 3 H). Isolated as a 14.3:1 ratio
of regioisomers; only signals of the major regioisomer are listed.
13C NMR (100 MHz, DMSO-d6): δ = 161.3, 154.7, 154.1, 148.7, 139.6,
134.0, 130.5, 129.9, 129.6, 129.5, 129.3, 129.0, 128.3, 127.0, 125.6,
124.7 (m), 122.9, 120.7, 120.2, 112.6, 110.1, 97.3, 55.7. Isolated as a
14.3:1 ratio of regioisomers; both sets of signals are listed.
19F NMR (377 MHz, DMSO-d6): δ (major regioisomer) = –61.2 (s, 3 F);
δ (minor regioisomer) = –61.2 (s, 3 F).
HRMS (ESI): m/z [M + H]+ calcd for C16H12F3N2O2: 321.0851; found:
19F NMR (377 MHz, DMSO-d6): δ (major regioisomer) = –99.6 (s, 2 F);
δ (minor regioisomer) = –99.7 (s, 2 F). Isolated as a 1.5:1 ratio of re-
gioisomers; both sets of signals are listed.
HRMS (ESI): m/z [M + H]+ calcd for C13H13F2N2O: 251.0996; found:
251.0991.
3-(1,1-Difluorobut-3-en-1-yl)-8-methyl-quinoxalin-2-one (4g)
The ketimine formation required 16 h and the cyclization required 18 h.
Yield: 1.98 g (55%); pale yellow solid; mp 150–151 °C.
IR (ATR): 1660, 1600, 1018, 875 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 12.13 (s, 1 H), 7.69 (d, J = 7.8 Hz, 1
H), 7.47 (d, J = 7.6 Hz, 1 H), 7.25–7.29 (m, 1 H), 5.73–5.83 (m, 1 H),
5.17–5.27 (m, 2 H), 3.26 (dt, J = 7.2, 17.2 Hz, 2 H), 2.44 (s, 3 H).
321.0845.
4-(6-Methoxy-3-oxo-3,4-dihydroquinoxalin-2-yl)benzonitrile (8c)
13C NMR (100 MHz, DMSO-d6): δ = 153.0, 149.8 (t, J = 27.5 Hz), 133.2,
131.5, 130.4, 128.8 (t, J = 5.0 Hz), 127.5, 124.4, 123.4, 121.0, 119.2 (t,
J = 243.0 Hz), 39.2 (t, J = 24.0 Hz), 16.8.
The ketimine formation required 21 h and the cyclization required 18
h. The final solids required an additional slurry wash in 5.2 mL/g
MTBE to remove residual 4-chloroaniline.
19F NMR (377 MHz, DMSO-d6): δ = –99.8 (s, 2 F).
Yield: 1.73 g (91%); yellow solid; mp >300 °C (dec.).
HRMS (ESI): m/z [M + H]+ calcd for C13H13F2N2O: 251.0996; found:
IR (ATR): 1659, 1620, 1273, 1207, 1033, 819 cm–1
.
251.0991.
1H NMR (400 MHz, DMSO-d6): δ = 12.61 (s, 1 H), 8.47 (d, J = 8.8 Hz, 2
H), 7.93 (d, J = 8.8 Hz, 2 H), 7.78 (d, J = 9.2 Hz, 1 H), 6.97 (dd, J = 2.4, 8.8
Hz, 1 H), 6.80 (d, J = 2.4 Hz, 1 H), 3.86 (s, 3 H). Isolated as an 11.5:1
ratio of regioisomers; only signals of the major regioisomer are listed.
13C NMR (100 MHz, DMSO-d6): δ = 161.5, 155.6, 154.7, 154.1, 152.5,
148.4, 140.0, 139.9, 134.2, 133.0, 132.6, 131.8, 130.6, 129.8, 129.4,
128.5, 127.1, 126.7, 125.5, 120.9, 118.8, 118.7, 116.2, 115.3, 112.8,
112.2, 111.7, 110.1, 97.3, 55.8, 55.7. Isolated as an 11.5:1 ratio of
regioisomers; both sets of signals are listed.
6,8-Dichloro-3-(1,1-difluorobut-3-en-1-yl)quinoxalin-2-one (4h)
The ketimine formation required 16 h and the cyclization required 16 h.
Yield: 1.51 g (52%); pale yellow solid; mp 170–173 °C.
IR (ATR): 1668, 1480, 1064, 1009, 937 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 12.62 (s, 1 H), 7.98 (s, 2 H), 5.74–
5.83 (m, 1 H), 5.19–5.29 (m, 2 H), 3.23 (dt, J = 7.2, 17.6 Hz, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 152.8, 131.7 (br s), 131.4, 130.1,
128.5 (t, J = 4.8 Hz), 127.9, 127.3 (br s), 121.4, 121.2, 120.0 (br s),
116.5, 39. 4.
.
HRMS (ESI): m/z [M + H]+ calcd for C16H12N3O2: 278.0930; found:
278.0924.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

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H. V. Huynh et al.
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Synthesis
7-Methoxy-3-(4-nitrophenyl)quinoxalin-2-one (8d)
Yield: 2.03 g (78%); light yellow solid; mp 233–244 °C (dec.).
IR (ATR): 1656, 1602, 1529, 1297, 1187, 1128, 1033, 802 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 12.25 (s, 1 H), 8.34 (d, J = 8.0 Hz, 2
H), 7.66 (d, J = 9.2 Hz, 1 H), 6.89 (dd, J = 2.8, 9.2 Hz, 1 H), 6.75–6.77 (m,
3 H), 3.83 (s, 3 H), 2.99 (s, 6 H). Isolated as a 6.4:1 ratio of regioiso-
mers; only signals of the major regioisomer are listed.
The ketimine formation required 21 h and the cyclization required 18
h. The final solids required an additional slurry wash in 5.2 mL/g
MTBE to remove residual 4-chloroaniline.
.
Yield: 1.92 g (90%); yellow solid; mp >300 °C (dec.).
IR (ATR): 1663, 1621, 1508, 1346, 1279, 1205, 1031, 826 cm–1
.
13C NMR (100 MHz, DMSO-d6): δ = 159.7, 155.4, 155.1, 154.6, 153.0,
151.6, 151.2, 149.7, 133.0, 132.8, 130.7, 130.2, 129.3, 128.2, 128.1,
127.2, 125.5, 123.4, 123.1, 118.1, 115.6, 111.8, 110.9, 110.8, 109.5,
97.4, 55.5. Isolated as a 6.4:1 ratio of regioisomers; both sets of sig-
nals are listed.
HRMS (ESI): m/z [M + H]+ calcd for C17H18N3O2: 296.1399; found:
296.1394.
1H NMR (400 MHz, DMSO-d6): δ = 12.71 (s, 1 H), 8.62 (d, J = 9.2 Hz, 2
H), 8.37 (d, J = 8.8 Hz, 2 H), 7.85 (d, J = 8.8 Hz, 1 H), 7.03 (dd, J = 2.8, 9.2
Hz, 1 H), 6.86 (d, J = 2.4 Hz, 1 H), 3.91 (s, 3 H). Isolated as a 6.7:1 ratio
of regioisomer; only signals of the major regioisomer are listed.
13C NMR (100 MHz, DMSO-d6): δ = 161.6, 155.6, 154.6, 154.0, 148.0,
147.9, 147.6, 141.7, 141.6, 134.2, 132.6, 130.6, 130.2, 129.8, 127.1,
122.9, 121.0, 116.1, 112.7, 110.2, 97.4, 55.7, 55.6. Isolated as a 6.7:1
ratio of regioisomer; both sets of signals are listed.
7-Methoxy-3-(o-tolyl)quinoxalin-2-one (8h)
HRMS (ESI): m/z [M + H]+ calcd for C15H12N3O4: 298.0828; found:
The ketimine formation required 72 h and the cyclization required 23 h.
298.0822.
Yield: 1.78 g (74%); light yellow solid; mp 182–183 °C.
7-Methoxy-3-(p-tolyl)quinoxalin-2-one (8e)
IR (ATR): 1660, 1624, 1515, 1295, 1173, 1034, 846 cm–1
.
The ketimine formation required 17 h and the cyclization required 48 h.
1H NMR (400 MHz, DMSO-d6): δ = 12.44 (s, 1 H), 7.70 (d, J = 8.8 Hz, 1
H), 7.22–7.41 (m, 4 H), 6.93 (dd, J = 2.8, 8.8 Hz, 1 H), 6.81 (d, J = 2.4 Hz,
1 H), 3.85 (s, 3 H), 2.23 (s, 3 H). Isolated as a 10.1:1 ratio of regioiso-
mers; only signals of the major regioisomer are listed..
13C NMR (100 MHz, DMSO-d6): δ = 160.8, 155.4, 154.5, 153.9, 147.7,
136.5, 136.3, 133.8, 132.6, 130.1, 129.9, 129.5, 129.4, 128.8, 128.6,
128.5, 126.9, 125.1, 119.7, 118.7, 116.2, 115.2, 112.0, 110.2, 97.7, 55.6,
55.6, 19.5. Isolated as a 10.1:1 ratio of regioisomers; both sets of sig-
nals are listed.
Yield: 2.35 g (87%); light yellow solid; mp 253–254 °C (dec.).
IR (ATR): 1653, 1619, 1288, 1169, 1137, 1036, 816 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 12.43 (s, 1 H), 8.23 (d, J = 8.0 Hz, 2
H), 7.73 (d, J = 8.8 Hz, 1 H), 7.28 (d, J = 8.0 Hz, 2 H), 6.93 (dd, J = 2.8, 8.8
Hz, 1 H), 6.79 (d, J = 2.4 Hz, 1 H), 3.84 (s, 3 H), 2.38 (s, 3 H). Isolated as
an 11.4:1 ratio of regioisomers; only signals of the major regioisomer
are listed.
13C NMR (100 MHz, DMSO-d6): δ = 160.6, 155.4, 154.9, 154.3, 153.8,
150.1, 140.0, 139.4, 133.5, 133.1, 133.0, 132.7, 130.0, 129.2, 128.9,
128.4, 127.0, 126.2, 119.5, 115.9, 112.1, 109.9, 67.3, 55.6, 55.5, 21.0.
Isolated as an 11.4:1 ratio of regioisomers; both sets of signals are
listed.
HRMS (ESI): m/z [M + H]+ calcd for C16H15N2O2: 267.1134; found:
267.1128.
7-Methoxy-3-(2-thienyl)quinoxalin-2-one (8i)12
HRMS (ESI): m/z [M + H]+ calcd for C16H15N2O2: 267.1134; found:
The ketimine formation required 48 h and the cyclization required 72 h.
267.1128.
Yield: 2.51 g (90%); light yellow solid; mp 246–247 °C (dec.).
IR (ATR): 1658, 1615, 1259, 1181, 818 cm–1
.
7-Methoxy-3-(4-methoxyphenyl)quinoxalin-2-one (8f)
1H NMR (400 MHz, DMSO-d6): δ = 12.58 (s, 1 H), 8.40 (d, J = 1.2 Hz, 1
H), 7.82–7.83 (m, 1 H), 7.68 (d, J = 9.2 Hz, 1 H), 7.20–7.23 (m, 1 H),
6.93 (dd, J = 2.8, 8.8 Hz, 1 H), 6.80 (d, J = 2.8 Hz, 1 H), 3.84 (s, 3 H).
Isolated as a 9.0:1 ratio of regioisomers; only signals of the major re-
gioisomer are listed.
The ketimine formation required 18 h and the cyclization required 23
h. The final solids required an additional slurry wash in 5.2 mL/g
MTBE to remove residual 4-chloroaniline.
Yield: 1.81 g (80%); yellow solid; mp 230–231 °C.
IR (ATR): 1666, 1286, 1170, 1026, 827 cm–1
.
13C NMR (100 MHz, DMSO-d6): δ = 160.4, 155.7, 153.6, 153.0, 145.7,
139.3, 139.1, 133.0, 132.6, 132.1, 131.3, 130.9, 130.2, 129.5, 128.0,
127.9, 126.8, 125.7, 119.5, 116.2, 112.5, 109.2, 97.6, 55.6, 55.6. Isolat-
ed as a 9.0:1 ratio of regioisomers; both sets of signals are listed.
HRMS (ESI): m/z [M + H]+ calcd for C13H11N2O2S: 259.0541; found:
259.0536.
1H NMR (400 MHz, DMSO-d6): δ = 12.39 (s, 1 H), 8.35 (d, J = 9.2 Hz, 2
H), 7.71 (d, J = 8.8 Hz, 1 H), 7.02 (d, J = 8.8 Hz, 2 H), 6.92 (dd, J = 2.8, 9.2
Hz, 1 H), 6.78 (d, J = 2.4 Hz, 1 H), 3.83–3.84 (m, 6 H). Isolated as an
8.0:1 ratio of regioisomers; only signals of the major regioisomer are
listed.
13C NMR (100 MHz, DMSO-d6): δ = 161.0, 160.6, 160.3, 155.5, 154.9,
154.3, 149.6, 133.3, 132.7, 131.0, 130.6, 129.8, 128.5, 128.4, 128.3,
127.0, 126.0, 119.2, 115.8, 113.2, 112.1, 109.8, 97.3, 55.6, 55.3, 55.2.
Isolated as an 8.0:1 ratio of regioisomers; both sets of signals are list-
ed.
Acknowledgment
The authors are grateful for the guidance and support from Mark
Scott, Erica Tiong, and Johann Chan in completing this work.
HRMS (ESI): m/z [M + H]+ calcd for C16H15N2O3: 283.1083; found:
283.1077.
Supporting Information
3-[4-(Dimethylamino)phenyl]-7-methoxy-quinoxalin-2-one (8g)
Supporting information for this article is available online at
The ketimine formation required 41 h and the cyclization required 72 h.
https://doi.org/10.1055/s-0037-1609345.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

J
H. V. Huynh et al.
Paper
Synthesis
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