Synthesis of 3-methoxy-quinoxalin-2-ones from methyl trimethoxyacetate and phenylenediamines

Article abstract of DOI:10.1016/j.tetlet.2009.11.017

Treatment of phenylenediamines with methyl trimethoxyacetate led to the formation of 3-methoxy-quinoxalin-2-ones with the assistance of lanthanide-based Lewis acids.

Full text of DOI:10.1016/j.tetlet.2009.11.017

Tetrahedron Letters 51 (2010) 337–339
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Tetrahedron Letters
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Synthesis of 3-methoxy-quinoxalin-2-ones from methyl trimethoxyacetate
and phenylenediamines
a,*
a
b
a
Jennifer D. Venable , David E. Kindrachuk , Matthew L. Peterson , James P. Edwards
a
Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA
TransForm Pharmaceuticals, Inc., 29 Hartwell Avenue, Lexington, MA, USA
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Treatment of phenylenediamines with methyl trimethoxyacetate led to the formation of 3-methoxy-qui-
noxalin-2-ones with the assistance of lanthanide-based Lewis acids.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 19 October 2009
Revised 4 November 2009
Accepted 5 November 2009
Available online 11 November 2009
During the course of our research, we became interested in syn-
thesizing structurally diverse examples of benzimidazole-2-car-
boxylic esters. However, there are relatively few efficient ways to
construct this simple chemotype. One method is a two-step proce-
dure involving the formation of 2-trichloromethylbenzimidazoles
O
NH2
N
O
RO
RO OR
R = Me, Et
neat
OR
100 ºC
X
X
OR
X = O, NH2
X = O, NH
1
Scheme 1. Synthesis of benzimidazole carboxylic esters.3
followed by hydrolysis with an alcoholic solvent. The desired ester
oxidation state of the 2-position can also be achieved via formation
of a 2-hydroxymethyl benzimidazole followed by oxidation with
2
KMnO
4
to obtain the corresponding carboxylic acid. However,
yields can be quite variable using this procedure. We were intri-
gued by the literature report of a one-pot synthesis of benzoxaz-
ole and benzimidazole-2-carboxylates from the direct
condensation of 2,2,2-trialkoxyacetates with 1,2-aminophenols or
O
O
3
a) pyridine, CH3OH
H3CO
Cl
Et O, 0 ºC - rt
OCH3
2
OCH3
H CO
H CO Cl
3
OCH3
3
b) pyrrolidine
vac. distill
1
2
1
,2-phenylenediamines, respectively (Scheme 1).
Commercially available 2,2-dichloro-2-methoxy methyl ester
1) was treated with methanol and pyridine followed by a vacuum
Scheme 2. Formation of methyl trimethoxyacetate (2).
(
distillation to afford the desired methyl trimethoxyacetate (2) in
good yields (Scheme 2).4
However, direct condensation of 2 with 2,3-diaminotoluene,
under the cited conditions, afforded a complex reaction mixture.
Table 1
Optimization of the synthesis for quioxalin-2-ones
3
In order to optimize the reaction conditions, a small solvent screen
was initiated (Table 1, entries 1–5). All reactions were performed
at reflux. It was found that by using toluene as a solvent with
NH2
NH2
O
N
OCH3
O
conditions
H CO
3
OCH3
N
H
8
H CO OCH3
3
4
equiv 2 gave 24% yield of a major product (Table 1, entry 5). Since
CH3
CH3
all spectral analysis of this product was consistent with the desired
benzimidazole 2-carboxylate, a variety of substituted 1,2-benzen-
ediamines were subjected to the reaction conditions. Surprisingly,
when utilizing 4-trifluoromethyl-1,2-phenylenediamine, a mixture
of isomeric products was obtained. This result called into question
our initial assignment of the benzimidazole 2-carboxylate struc-
ture. We thus considered the possibility that the actual products
2
Entry
Solventa
THF
1,4-Dioxane
MeOH
Promoter
Equiv 2
h
% Yield 8
1
2
3
4
5
6
7
8
—
—
—
—
4
4
4
4
4
2
2
2
24
24
24
24
24
24
4
—
—
—
—
24
35
63
72
DMF
Toluene
Toluene
Toluene
Toluene
—
1 equiv pTsOH
10 mol % Sc(OTf)
10 mol % Yb(OTf)
3
3
4
*
Corresponding author.
E-mail address: jvenable@its.jnj.com (J.D. Venable).
a
All reactions performed at 0.4 M.
0
040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.017

3
38
J. D. Venable et al. / Tetrahedron Letters 51 (2010) 337–339
R1
R2
N
OCH3
F3C
F3C
NH2
NH2
N
O
2
2
X
N
H
O
N
H
OCH3
1
2
4
3
3
a) R = CF , R = H
3
b) R1 = H , R = CF3
2
NaOH
BBr3
H
F3C
N
O
F3C
N
O
O
N
H
5
OH
N
H
6
Scheme 3. Formation of quinoxalin-2-ones 3a, 3b.
of the condensation were the isomeric quinoxalin-2-ones 3a and
tube. After 4 h under these conditions, 63% and 72% of the desired
quinoxalin-2-one product 8 could be isolated, respectively.
3
b (Scheme 3).
Additionally, if the putative benzimidazole 4 had formed, it
This reaction could be expanded to include a variety of substit-
uents around the arene ring (Fig. 2). For 3-substituted 1,2-pheny-
lenediamines, only a single regioisomeric product was obtained
(7–9). Presumably the first intermediate is oxonium ion formation
of 2 resulting in the loss of methanol. This can then condense with
the least sterically hindered amine to give an imine intermediate.
Finally, intramolecular cyclization of the more hindered amine,
preferentially with the pendant ester, would give rise to the
isolated quinoxalin-2-one products as a single isomer. The
should hydrolyze to the corresponding carboxylic acid 5 when trea-
ted with sodium hydroxide, however, only starting material was
recovered when subjected to strongly basic conditions (Scheme 3).
Interestingly, treatment of the isolated isomeric mixture with boron
tribromide afforded the known quinoxalin-dione 6 as a single prod-
uct giving chemical proof of structures 3a and 3b.
After scanning the materials that had been synthesized thus far
for crystallinity, we were able to determine the X-ray crystal struc-
ture of the product obtained from the condensation of 3-chloro-5-
trifluoromethylphenylene diamine and 2. The structure was deter-
mined to be the quinoxalin-2-one 7 instead of the anticipated
benzimidazole carboxylate (Fig. 1).
With this discovery, we set out to further optimize the reaction
conditions for the formation of the 6,6-sytem. Using toluene as the
solvent, we examined the effect Bronsted and Lewis acids had on
the reaction rate and outcome. Treatment of 2,3-diaminotoluene
with 2 equiv of 2 in refluxing toluene (Dean–Stark) for 12 h gave
the product 8 in 35% yield. The best results were obtained by run-
ning the reaction in the presence of catalytic quantities (10 mol %)
of either scandium or ytterbium triflate for 4 h at 110 °C in a sealed
2
(2 eq.)
N
OCH3
NH2
NH2
10% Yb(OTf)3
R
R
Toluene, 100 ºC
N
H
O
F3C
N
OCH3
6
7
6%
2%
7
8
9
N
H
O
Cl
N
OCH3
O
N
H
CH3
NO2
N
OCH3
O
44%
52%
N
H
N
OCH3
O
1
1
0
1
N
H
Cl
Cl
N
OCH3
O
7
8%
N
H
Cl
N
OCH3
N
OCH3
O
6
1
2%
.5:1
1
2a, 12b
N
H
O
Cl
N
H
F3C
N
OCH3
N
OCH3
O
3
a, 3b
6
1%
Figure 1. Ortep diagram (50% ellipsoids for non-hydrogen atoms) of the two
crystallographically unique molecules in the asymmetric unit from the X-ray crystal
structure of 7. Atom names and the numbering scheme employed are shown. Short
contacts between heavy atoms are indicated by dashed lines.
1.1:1
N
H
O
F3C
N
H
Figure 2. 3-Methoxyquinoxalin-2-ones 3, 7–12.

J. D. Venable et al. / Tetrahedron Letters 51 (2010) 337–339
339
symmetrical 1,2-phenylenediamine and 4,5-dichloro-1,2-phenyl-
References and notes
enediamine gave the corresponding quinoxalin-ones 10 and 11 in
good yields. As previously seen when steric bulk is removed from
the ortho position, mixtures of regioisomers are obtained as dem-
onstrated by utilizing 4-chloro (12a and 12b) or 4-trifluoromethyl
1
.
(a) Garuti, L.; Marinella, R.; De Clercq, E. Bioorg. Med. Chem. Lett. 2002, 12, 2707;
b) Young, J. R.; Huang, S. X.; Walsh, T. F.; Wyvratt, M. J., Jr.; Yang, Y. T.;
Yudkovitz, J. B.; Cui, J.; Mount, G. R.; Ren, R. N.; Wu, T.-J.; Shen, X.; Lyons, K. A.;
Mao, A.-H.; Carlin, J. R.; Karanam, B. V.; Vincent, S. H.; Cheng, K.; Goulet, M. T.
Bioorg. Med. Chem. Lett. 2002, 12, 827.
(a) Copeland, R. A.; Day, A. R. J. Am. Chem. Soc. 1943, 65, 1072; (b) Orjales, A.;
Alonso-Cires, L.; Lopez-Tudanca, P.; Tapia, I.; Mosquera, R.; Labeaga, L. Eur. J.
Med. Chem. 1999, 34, 415.
(
(3a and 3b) phenylenediamine under the reaction conditions to
2
.
give a mixture of isomeric products which can be separated by sil-
ica gel chromatography. Structural confirmation of the individual
isomers were determined by NOE correlation.
3. (a) Musser, J. H.; Bailey, H. T. T. Synth. Commun. 1984, 14, 947; for other
examples see: Fouchard, D. M. D.; Tillekeratne, L. M. V.; Hudson, R. A. J. Org.
Chem. 2004, 69, 2626; (b) Boger, D. L.; Schmitt, H. W.; Fink, B. E.; Hedrick, M. P. J.
Org. Chem. 2001, 66, 6654.
4. (a) Jones, R. G. J. Am. Chem. Soc. 1951, 73, 5168; (b) Kantlehner, W.;
Kapassakalidis, J. J.; Maier, T. Liebigs Ann. 1980, 9, 1448; (c) Kantlehner, W.;
Dinkeldein, U.; Bredereck, H. Liebigs Ann. 1979, 9, 1346.
In conclusion, a new one-step method for synthesizing differen-
3
tiated quinoxalin-2-ones has been developed utilizing Yb(OTf) as
5
a Lewis acid catalyst. The 3-methoxy substituent provides a han-
dle for further functionalization of these molecules.
5.
Typical experimental conditions for the synthesis of 3-methoxy-qyinoxalin-2-ones:
3-Methoxy-8-methyl-1H-quinoxalin-2-one (8): mixture of 2,3-diamino
toluene (0.20 g, 1.64 mmol, 1.0 equiv), methyl trimethoxyacetate (1.07 g,
.54 mmol, 2.0 equiv), and ytterbium triflate (0.10 g, 0.16 mmol, 0.10 equiv) in
Acknowledgments
A
6
Theauthorsthank JiejunWuforassistancewith compoundstruc-
tural determination and John Keith for editing the manuscript.
toluene (4 mL, 0.4 M) was heated at 100 °C for 4 h in a sealed tube. The reaction
was cooled, and the precipitate was collected by vacuum filtration. After
washing with hot ethyl acetate (2 Â 10 mL), the precipitate was dried in vacuo
to afford 0.22 g (72%) of 3-methoxy-8-methyl-1H-quinoxalin-2-one. 1H NMR
Supplementary data
(
400 MHz, CDCl
3
): 11.34 (br s, 1H), 7.25 (d, J = 7.8 Hz, 1H), 7.12 (m, 2H), 4.14 (s,
3H), 2.59 (s, 3H).
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.11.017.