One-Pot Synthesis of Quinoxalinones via Tandem Nitrosation/Cyclization of N-Aryl Cyanoacetamides

Article abstract of DOI:10.1021/acs.joc.7b01930

A new one-pot strategy for the synthesis of quinoxalin-2-ones from the tandem nitrosation/cyclization reaction of N-aryl cyanoacetamides with tert-butyl nitrite has been developed. The dehydrogenative N-incorporation is achieved through a sequence of nitrosation, tautomerization, and cyclization, affording quinoxalin-2-ones in moderate to good yields with good functional group tolerance.

Full text of DOI:10.1021/acs.joc.7b01930

Subscriber access provided by UNIVERSITY OF THE SUNSHINE COAST
Note
One-Pot Synthesis of Quinoxalinones via Tandem
Nitrosation/Cyclization of N-Aryl Cyanoacetamides
Fang Wang, Bo-Lun Hu, Lizhi Liu, Hai-Yong Tu, and Xing-Guo Zhang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01930 • Publication Date (Web): 28 Sep 2017
Downloaded from http://pubs.acs.org on September 28, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 15
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
One-Pot Synthesis of Quinoxalinones via Tandem
Nitrosation/Cyclization of N-Aryl Cyanoacetamides
Fang Wang,† BoꢀLun Hu,† Lizhi Liu,*,‡ HaiꢀYong Tu† and XingꢀGuo Zhang*,†
†College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, China
‡Guangzhou Center for Disease Control and Prevention, Guangzhou 51440, China
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
* Eꢀmail: pearms12@126.com; zxg@wzu.edu.cn.
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
Abstract
A new oneꢀpot strategy for the synthesis of quinoxalinꢀ2ꢀones from the tandem nitrosation/cyclization
reaction of Nꢀaryl cyanoacetamides with tertꢀbutyl nitrite has been developed. The dehydrogenative Nꢀ
incorporation is achieved through a sequence of nitrosation, tautomerization and cyclization, affording
quinoxalinꢀ2ꢀones in moderate to good yields with good functional group tolerance.
Quinoxalinones are important heterocyclic scaffolds which display a wide range of biological and
medicinal properties including antithrombotic and antitumor activity,1 and are also employed as kinases
inhibitors, antimicrobial agents and benzodiazepine receptor agonist.2 Accordingly, many versatile
methods have been developed for the construction of quinoxalinones,3 but most of them focus on the
condensation of oꢀphenylenediamine with 1,2ꢀdicarbonyls or their equivalents.3g, 4 Recently, the radical
cyclization of 2ꢀazidoꢀNꢀphenylacetamides has also been found to be an effective approach for their
preparation (Scheme 1, eq 1).5 In 2010, Bao reported a copperꢀcatalyzed double amination of 2ꢀhaloꢀNꢀ
(2ꢀhalophenyl)ꢀacetamides with TsNH2 for the synthesis of quinoxalinꢀ2ꢀones (eq 2).6 In 2015, Yu
group developed a strategy for the synthesis of quinoxalinꢀ2ꢀones from visible lightꢀinduced radical
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 15
cyclization of Nꢀchloroimines (eq 3).7 Despite the significance of these methods, the general and
efficient approach for constructing quinoxalinones is desirable, especially using a oneꢀpot strategy from
readily available materials. Herein, we wish to report a oneꢀpot synthesis strategy of 3ꢀcyanoꢀ
quinoxalinꢀ2ꢀones via sequential nitrosation/cyclization reaction of Nꢀaryl cyanoacetamides using tertꢀ
butyl nitrite as nitrogen source (eq 4).
1
2
3
4
5
6
7
8
9
Scheme 1. Construction of Quinoxalinones
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
We began our studies by testing the reaction between 2ꢀcyanoꢀNꢀmethylꢀNꢀphenylacetamide (1a)8
and TBN (the nitrogen source) to optimize the reaction conditions (Table 1). Firstly, substrate 1a was
reacted with 5 equiv of TBN and 2 equiv of Cs2CO3 in DMF at 100 oC for 6 h, giving the target product
2a in 12% yield and its oxide 3a in 19% yield (entry 1). To enhance the reaction yield, several solvents
were examined, including dioxane, toluene and MeCN (entries 2ꢀ4). MeCN was found to give the best
results. Subsequently, a variety of bases, such as Li2CO3, K2CO3, NaHCO3, and CsOAc were
investigated, but all were less effective than Cs2CO3 (entries 5ꢀ8). Inspired by some of our previous
work,9 5 equiv of HOAc was added into the reaction, and we found that products 2a and 3a were
isolated in 45% and 34% yield, respectively (entry 9). Only 14% yield was obtained when the reaction
was conducted in 5 equiv of HOAc without Cs2CO3 (entry 10), which implied that the acidity of buffer
solution Cs2CO3/AcOH played as a crucial role in the cyclization reaction. Consistent with this
hypothesis, only trace amount of product was observed when a stronger acid (CF3COOH) was used
(entry 11). To inhibit the hydrolysis of amide, 100 mg 4 Å molecular sieve was added into the reaction.
We were pleased to find that the product 2a was isolated in 39% yield, accompanied by 52% of its oxide
3a (entry 12). We supposed that product 3a was produced from the oxidation of 2a by excessive TBN,
and could be converted back to product 2a through a simple reduction process. As expected, without
ACS Paragon Plus Environment

Page 3 of 15
The Journal of Organic Chemistry
further separation, the mixture of 2a and oxide 3a could be easily reduced by a solution of Na2S2O4 in
ethyl alcohol and water to afford quinoxalinone 2a as a sole product in 85% yield (entry 13). Lower
yield was observed when the reaction was carried out in the presence of 4 equiv of TBN or 4 equiv of
HOAc (entries 14 and 15).
1
2
3
4
5
6
7
8
9
Table 1. Screening of Optimal Reaction Conditionsa
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
isolated yield (%)
entry
base
additive
solvent
2a
3a
1
Cs2CO3
ꢀ
DMF
12
19
2
3
Cs2CO3
Cs2CO3
Cs2CO3
Li2CO3
K2CO3
NaHCO3
CsOAc
Cs2CO3
ꢀ
ꢀ
dioxane
toluene
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
16
trace
41
13
16
22
trace
17
17
24
34
trace
0
4
ꢀ
ꢀ
5
26
6
ꢀ
24
7
ꢀ
23
8
ꢀ
28
9
HOAc
HOAc
CF3CO2H
HOAc
HOAc
HOAc
HOAc
45
10
11
12b
13b,c
14b,c,d
15b,c,e
14
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
trace
39
52
0
85
67
0
78
0
aReaction conditions: 1a (0.2 mmol), tꢀBuONO (1.0 mmol), base (2.0 equiv) and
additive (5.0 equiv) in solvent (1 mL) under air atmosphere at 100 °C for 6 h. b4
c
Å MS (100 mg) was added. After reaction finished, a solution of Na2S2O4 (0.7
mmol) in ethyl alcohol (2 mL) and water (4 mL) was added, then stirred at 90 °C
for 2 h. d4.0 equiv tꢀBuONO. e4.0 equiv HOAc.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 15
1
2
3
4
Scheme 2. Variation of Nꢀaryl Cyanoacetamidea
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
CN
O
Me
N
CN
O
N
CN
O
Me
N
N
N
Me
Me
Me
2b, 64%
2a, 85%
2c, 51%
Et
N
CN
N
CN
N
CN
N
O
N
O
N
O
Me
Me
Me
2f, 65%
2d, 60%
2e, 70%
MeO
N
CN
F
N
CN
EtO
Br
N
CN
N
O
N
O
N
O
Me
Me
Me
2g, 62%
2h, 48%
2i, 40%
Cl
N
CN
F3C
N
CN
N
CN
N
O
N
O
N
O
Me
2j, 76%
Me
Me
2k, 53%
2l, 71%
N
CN
Ac
N
CN
N
CN
O
N
O
N
O
N
Et
Me
Ph
2n, 47%
2m, 64%
2o, 43%
N
CN
N
CN
N
N
CN
N
N
O
N
O
O
Bn
Me
n-Bu
2p, 51%
2q, 70%
2r, 23%
aReaction conditions: 1 (0.2 mmol), tꢀBuONO (1.0 mmol), Cs2CO3 (2.0 equiv), 100 mg 4 Å MS and
HOAc (5.0 equiv) in MeCN (1 mL) under air atmosphere at 100 °C for 6 h. Then, a solution of Na2S2O4
(0.7 mmol) in ethyl alcohol (2 mL) and water (4 mL) was added and stirred under air atmosphere at 90
°C for 2 h, isolated yield.
ACS Paragon Plus Environment

Page 5 of 15
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Having established the optimal conditions for this tandem reaction, we proceeded to explore the
substrate scope by testing the reaction of a wide variety of Nꢀaryl cyanoacetamides with TBN (Scheme
2). Firstly, the substitution effect on the aromatic ring was examined. The results disclosed that both
electronꢀwithdrawing group and electronꢀdonating group in the metaꢀ or paraꢀ position of aryl moiety
were suitable and afforded the corresponding products in moderate to good yields. For example, metaꢀ
tolyl substituted acetamide 1b provided the product 2b in 64% yield, and paraꢀtolyl substituted
cyanoacetamide 1c gave the product 2c in 51% yield. NꢀAryl cyanoacetamides bearing ethyl, propyl,
tertꢀbutyl, methoxy or ethoxy afforded products 2dꢀh in 48ꢀ70% yields. In the case of halide substrates,
fluorinated, chlorinated and brominated Nꢀphenyl cyanoacetamides afforded the products 2iꢀk in 40ꢀ
76% yields. Moreover, the cyanoacetamides with strong electronꢀwithdrawing group were also suitable
substrates under standard reaction conditions. For example, trifluoromethyl and acetyl substituted
phenyl cyanoacetamides provided 2l, m in 71 and 64% yields, respectively. Subsequently, a number of
substituents on the Nꢀsubstituted moiety were examined. We were pleased to find that Nꢀdiphenyl, ethyl,
nꢀbutyl and benzyl substituted cyanoacetamides afforded corresponding products 2nꢀq in moderate to
good yields (43ꢀ70%). Interestingly, the reaction of nitrogenꢀcontaining heterocyclic compound 1r
proceeded smoothly to give pyrido[3,4ꢀb]pyrazinꢀ2ꢀone 2r, albeit in a low yield (23%).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To illustrate the applicability of this reaction, further transformation of product 2a was investigated as
showed in Scheme 3. 1ꢀMethylꢀ1,2ꢀdihydroquinoxalinꢀ2ꢀoneꢀ3ꢀcarboxamide 4 was isolated in 67%
yield when product 2a was treated with 10 mol% Cu(OAc)2 and 3 equiv NEt2OH in H2O at 60 °C for 12
h.10 This result demonstrated that 3ꢀcyanoꢀquinoxalinꢀ2ꢀones could be easily transformed to
quinoxalinoneꢀ3ꢀcarboxamides, which exhibit a wide range of physicochemical properties, biological
and medicinal properties including antibacterial and antiallergic activity.11 Furthermore, in the presence
of 5 equiv NaBH4, product 2a was reduced to 1ꢀmethylꢀ3,4ꢀdihydroquinoxalinꢀ2(1H)ꢀone 5 in 74%
yield, which has been reported to possess pharmaceutical and biological activity.12
Scheme 3. Synthetic Applications of 2a
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 15
In order to probe the mechanism of this sequential nitrosation/cyclization, several control experiments
were conducted as shown in Scheme 4. The reaction of substrate 1a with TBN was performed under the
standard conditions by adding 6.0 equiv of 2,2,6,6ꢀtetramethylpiperidine oxide (TEMPO), a radical
scavenger (Scheme 4, eq 1). The reaction were suppressed, neither the product 2a nor its oxide 3a could
be detected. These results indicated that the reaction might be involved a free radical process.
Furthermore, Nꢀhydroxyꢀ2ꢀ(methyl(phenyl)amino)ꢀ2ꢀoxoacetimidoyl cyanide 68 was performed with
TBN under the optimal conditions. As expected, the desired product 2a was isolated in 79% yield (eq 2),
suggesting that oxime 6 might be a key intermediate for the cyclization in the tandem reaction.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4. Control Experiments
Scheme 5. Possible Mechanism
On the basis of the present results and related precedents,9b, 13 a plausible mechanism for the
nitrosation/cyclization of Nꢀaryl cyanoacetamide is presented in Scheme 5. Initially, ⋅NO radical and
ACS Paragon Plus Environment

Page 7 of 15
The Journal of Organic Chemistry
tertꢀbutoxy radical is generated from the decomposition of tertꢀbutyl nitrite. Then, the hydrogen
abstraction of tertꢀbutoxy radical with cyanoacetamide 1a affords alkyl radical intermediate A.13c
Subsequently, intermediate A reacts with the ⋅NO radical to give intermediate B, which is further
converted to oxime 6 via tautomerization in Cs2CO3/AcOH buffer solution. Finally, the acidic
dehydration of key intermediate oxime 6 in the presence of HOAc leads to the desired product 2a.9a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In summary, we have developed a convenient and efficient method for the synthesis of
quinoxalinꢀ2ꢀones via oneꢀpot tandem nitrosation/cyclization of Nꢀaryl cyanoacetamides. A variety
of Nꢀaryl cyanoacetamides underwent the nitrosation/cyclization reaction with tertꢀbutyl nitrite
successfully to afford the corresponding quinoxalinꢀ2ꢀones in moderate to good yields. Compared to
traditional nitrosation with NaNO2 and strong acid, this reaction applied TBN as the nitroso group
source in the absence of strong acid, which provided a new route for the nitrosation of some acidꢀ
sensitive substrates.
Experimental Section
General Information:
1
13
Chemicals were either purchased or purified by standard techniques. H NMR and C NMR spectra
were measured on a 500 MHz spectrometer (500 MHz for 1H and 125 MHz for 13C), using DMSOꢀd6 as
the solvent with tetramethylsilane (TMS) as an internal standard at room temperature. Chemical shifts
are given in δ relative to TMS, and the coupling constants J are given in hertz. Highꢀresolution mass
spectra were recorded on an ESIꢀQꢀTOF mass spectrometer. All reactions under air atmosphere were
conducted using standard Schlenk techniques. Melting points were measured on an X4 melting point
apparatus and were uncorrected. Column chromatography was performed using EM silica gel 60 (300ꢀ
400 mesh).
General Procedure for the Synthesis of Cyanoacetanilides 1:
To a stirred suspension of cyanoacetic acid (550 mg, 6.5 mmol) in dichloromethane (25 mL) was
added oxalyl chloride (0.52 mL, 6 mmol) followed by three drops of DMF at 0 °C. The reaction mixture
was stirred at rt for 3 h. To this solution was added a solution of anilines (5 mmol) in dichloromethane
(20 mL) followed by triethylamine (1.74 mL, 12.5 mmol) at 0 °C. The reaction mixture was stirred for
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 15
12ꢀ24 h and then washed with water (10 mL) and 1 N HCl (10 mL). The organic layer was dried over
Na2SO4 and evaporated to afford a crude solid, which was purified by column chromatography on silica
gel (petroleum ether/ethyl acetate, v/v) to afford pure Cyanoacetanilides 1.8
1
2
3
4
5
6
7
8
9
General Procedure for the Synthesis of Quinoxalin-2-ones 2:
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Cyanoacetanilides 1 (0.2 mmol), TBN (103 mg, 1.0 mmol), Cs2CO3 (130.4 mg, 0.4 mmol), HOAc
(60 mg, 1.0 mmol), and 4 Å MS (100 mg) in MeCN (1 mL) was added to a flameꢀdried Schlenk tube
with a magnetic stirring bar. The reaction mixture was stirred at 100 °C for 6 h. Then, Na2S2O4 (120 mg,
0.7 mmol) in ethyl alcohol (2 mL) and water (4 mL) was added to this solution. The reaction mixture
was stirred at 90 °C for a further 2 h under air atmosphere. After the reaction equilibrium, the reaction
mixture was poured into ethyl acetate, which was washed with saturated NaHCO3 (2 x 10 mL) and brine
(1 x 10 mL). After the aqueous layer was extracted with ethyl acetate, the organic layer was collected,
dried over anhydrous MgSO4, and evaporated under vacuum. The residue was purified by column
chromatography on silica gel (petroleum ether/ethyl acetate, v/v) to afford the desired products.
Procedure for the Synthesis of 1-Methyl-1, 2-dihydroquinoxalin-2-one-3-carboxamide 4:
To a flameꢀdried Schlenk tube with a magnetic stirring bar were charged 3ꢀCyanoꢀ1ꢀmethylꢀ1,2ꢀ
dihydroquinoxalinꢀ2ꢀone 2a (37 mg, 0.2 mmol), Cu(OAc)2 (3.62 mg, 10 mol%), NEt2OH (53.4 mg, 3
equiv) in H2O (2 mL). The reaction mixture was stirred at 60 °C for 12 h. After the reaction equilibrium,
the mixture was poured into ethyl acetate, which was washed with brine (2 x 10 mL). After the
combined organic layer was extracted with ethyl acetate, dried over anhydrous MgSO4 and evaporated
under vacuum. The residue was purified by column chromatography on silica gel (petroleum ether
/ethyl acetate, v/v) to afford the desired product 4 in 67% yield.
Procedure for the Synthesis of 1-Methyl-3,4-dihydroquinoxalin-2(1H)-one 5:
NaBH4 (38 mg, 5 equiv) was added to a solution of 2a (37mg, 0.2 mmol) in dry THF (1 mL) at room
temperature. The reaction mixture was stirred at 50 °C for 1 hour. After the removal of solvent, the
ACS Paragon Plus Environment

Page 9 of 15
The Journal of Organic Chemistry
product was purified by column chromatography on silica gel (petroleum ether /ethyl acetate, v/v) to
1
2
3
afford the desired product 5 in 74% yield.
4
5
Procedure for the Synthesis of N-Hydroxy-2-(methyl(phenyl)amino)-2-oxoacetimidoyl Cyanide 6:
To solution of cyanoacetanilide 1a (348 mg, 2.0 mmol) in THF (7.0 mL) was added sodium hydride
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(96 mg, 60% dispersion in mineral oil, 2.4 mmol). The reaction mixture was stirred at 35 °C for 1 h.
Then TBN (515 mg, 5.0 mmol) was added dropwise and the reaction mixture was stirred at 60 °C until
complete consumption of the starting material as detected by TLC or GCꢀMS analysis Then, after the
removal of solvent, the product was purified by column chromatography on silica gel (petroleum ether
/ethyl acetate, v/v) to afford the desired product 6 in 34% yield.8
3ꢀCyanoꢀ1ꢀmethylꢀ1,2ꢀdihydroquinoxalinꢀ2ꢀone (2a)5c: Purification by column chromatography on
silica gel (petroleum ether/ ethyl acetate = 2:1, v/v) affords the title compound as a yellow solid (31.5
1
mg, 85% yield), mp 153ꢀ155 °C (uncorrected); H NMR (500 MHz, DMSOꢀd6) δ 7.89 (d, J = 8.0 Hz,
1H), 7.83ꢀ7.80 (m, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.49ꢀ7.46 (m, 1H), 3.63 (s, 3H); 13C NMR (125 MHz,
DMSOꢀd6) δ 153.0, 134.6, 134.3, 133.7, 132.4, 130.8, 124.6, 115.5, 115.0, 29.6; LRMS (EI, 70 eV) m/z
(%): 185 (M+, 100), 156 (72), 130 (47); HRMS (ESI) calcd for C10H7N3ONa+ ([M + Na]+) 208.0481,
found 208.0471.
3ꢀCyanoꢀ1,7ꢀdimethylꢀ1,2ꢀdihydroquinoxalinꢀ2ꢀone (2b): Purification by column chromatography on
silica gel (petroleum ether/ ethyl acetate = 3:1, v/v) affords the title compound as a yellow solid (25.5
mg, 64% yield), mp 178ꢀ180 °C (uncorrected); 1H NMR (500 MHz, DMSOꢀd6) δ 7.75 (d, J = 8.0 Hz,
1H), 7.47 (s, 1H), 7.28 (d, J = 8.0 Hz, 1H), 3.58 (s, 3H), 2.48 (s, 3H); 13C NMR (125 MHz, DMSOꢀd6) δ
153.2, 146.2, 134.4, 132.0, 130.9, 130.5, 126.1, 115.4, 115.2, 29.6, 22.0; LRMS (EI, 70 eV) m/z (%):
199 (M+, 100), 170 (78), 156 (27); HRMS (ESI) calcd for C11H9N3ONa+ ([M + Na]+) 222.0638, found
222.0642.
3ꢀCyanoꢀ1,6ꢀdimethylꢀ1,2ꢀdihydroquinoxalinꢀ2ꢀone (2c): Purification by column chromatography on
silica gel (petroleum ether/ ethyl acetate = 3:1, v/v) affords the title compound as a yellow solid (20.3
1
mg, 51% yield), mp 174ꢀ176 °C (uncorrected); H NMR (500 MHz, DMSOꢀd6) δ 7.69 (s, 1H), 7.65 (d,
J = 8.5 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 3.60 (s, 3H), 2.39 (s, 3H). 13C NMR (125 MHz, DMSOꢀd6) δ
152.9, 135.9, 134.3, 133.4, 132.4, 132.3, 130.0, 115.3, 115.1, 29.6, 20.0; LRMS (EI, 70 eV) m/z (%):
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 15
199 (M+, 100), 170 (70), 156 (27); HRMS (ESI) calcd for C11H9N3ONa+ ([M + Na]+) 222.0638, found
222.0644.
1
2
3
4
5
6
7
3ꢀCyanoꢀ6ꢀethylꢀ1ꢀmethylꢀ1,2ꢀdihydroquinoxalinꢀ2ꢀone (2d): Purification by column chromatography
on silica gel (petroleum ether/ ethyl acetate = 4:1, v/v) affords the title compound as a yellow solid (25.6
8
9
1
mg, 60% yield), mp 166ꢀ168 °C (uncorrected); H NMR (500 MHz, DMSOꢀd6) δ 7.66 (d, J = 8.5 Hz,
2H), 7.55 (d, J = 8.5 Hz, 1H), 3.58 (s, 3H), 2.68 (q, J = 7.5 Hz, 2H), 1.18 (t, J = 7.5 Hz, 3H); 13C NMR
(125 MHz, DMSOꢀd6) δ 152.9, 140.5, 134.9, 133.3, 132.45, 132.41, 128.8, 115.4, 115.0, 29.6, 27.0,
15.3; LRMS (EI, 70 eV) m/z (%): 213 (M+, 51), 198 (100); HRMS (ESI) calcd for C12H11N3ONa+ ([M +
Na]+) 236.0794, found 236.0791.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3ꢀCyanoꢀ1ꢀmethylꢀ6ꢀpropylꢀ1,2ꢀdihydroquinoxalinꢀ2ꢀone (2e): Purification by column chromatography
on silica gel (petroleum ether/ ethyl acetate = 4:1, v/v) affords the title compound as a yellow solid (31.8
mg, 70% yield), mp 141ꢀ143 °C (uncorrected); 1H NMR (500 MHz, DMSOꢀd6) δ 7.62 (d, J = 9.0 Hz,
2H), 7.53 (d, J = 9.0 Hz, 1H), 3.56 (s, 3H), 2.61 (t, J = 7.5 Hz, 2H), 1.61ꢀ1.53 (m, 2H), 0.84 (t, J = 7.5
Hz, 3H); 13C NMR (125 MHz, DMSOꢀd6) δ 152.9, 138.9, 135.3, 133.3, 132.5, 132.4, 129.5, 115.3,
115.0, 35.9, 29.5, 23.8, 13.4; LRMS (EI, 70 eV) m/z (%): 227 (M+, 63), 201 (100), 171 (40); HRMS
(ESI) calcd for C13H14N3O+ ([M + H]+) 228.1131, found 228.1137.
3ꢀCyanoꢀ1ꢀmethylꢀ6ꢀ(tertꢀbutyl)ꢀ1,2ꢀdihydroquinoxalinꢀ2ꢀone
(2f):
Purification
by
column
chromatography on silica gel (petroleum ether/ ethyl acetate = 4:1, v/v) affords the title compound as a
1
yellow solid (31.4 mg, 65% yield), mp 182ꢀ184 °C (uncorrected); H NMR (500 MHz, DMSOꢀd6) δ
13
7.87 (d, J = 9.0 Hz, 1H), 7.77 (s, 1H), 7.56 (d, J = 9.0 Hz, 1H), 3.58 (s, 3H), 1.29 (s, 9H); C NMR
(125 MHz, DMSOꢀd6) δ 152.9, 147.4, 133.3, 132.6, 132.22, 132.16, 126.4, 115.3, 115.0, 34.2, 30.8,
29.6; LRMS (EI, 70 eV) m/z (%): 241 (M+, 17), 226 (100), 198 (18); HRMS (ESI) calcd for
C14H15N3ONa+ ([M + Na]+) 264.1107, found 264.1116.
3ꢀCyanoꢀ1ꢀmethylꢀ6ꢀmethoxyꢀ1,2ꢀdihydroquinoxalinꢀ2ꢀone
(2g):
Purification
by
column
chromatography on silica gel (petroleum ether/ ethyl acetate = 2:1, v/v) affords the title compound as a
1
yellow solid (26.7 mg, 62% yield), mp 171ꢀ173 °C (uncorrected); H NMR (500 MHz, DMSOꢀd6) δ
7.51 (d, J = 9.0 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H), 7.30 (s, 1H), 3.75 (s, 3H), 3.53(s, 3H); 13C NMR (125
MHz, DMSOꢀd6) δ 156.1, 152.7, 133.6, 133.2, 129.0, 124.2, 116.7, 115.1, 111.4, 56.0, 29.9; LRMS (EI,
70 eV) m/z (%): 215 (M+, 100), 200 (44), 172 (52); HRMS (ESI) calcd for C11H9N3O2Na+ ([M + Na]+)
238.0587, found 238.0593.
ACS Paragon Plus Environment

Page 11 of 15
The Journal of Organic Chemistry
3ꢀCyanoꢀ6ꢀethoxyꢀ1ꢀmethylꢀ1,2ꢀdihydroquinoxalinꢀ2ꢀone (2h): Purification by column chromatography
1
2
3
4
5
on silica gel (petroleum ether/ ethyl acetate = 3:1, v/v) affords the title compound as a yellow solid (22.0
1
mg, 48% yield), mp 162ꢀ164 °C (uncorrected); H NMR (500 MHz, DMSOꢀd6) δ 7.53 (d, J = 9.5 Hz,
1H), 7.38 (d, J = 9.5 Hz, 1H), 7.30 (s, 1H), 4.06 (q, J = 7.0 Hz, 2H), 3.57 (s, 3H), 1.32 (t, J = 7.0 Hz,
6
7
8
9
13
3H); C NMR (125 MHz, DMSOꢀd6) δ 155.2, 152.5, 133.4, 133.1, 128.7, 124.3, 116.4, 114.9, 111.9,
64.0, 29.7, 14.4; LRMS (EI, 70 eV) m/z (%): 229 (M+, 100), 214 (37), 186 (40); HRMS (ESI) calcd for
C12H11N3O2Na+ ([M + Na]+) 252.0743, found 252.0751.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3ꢀCyanoꢀ6ꢀfluoroꢀ1ꢀmethylꢀ1,2ꢀdihydroquinoxalinꢀ2ꢀone (2i): Purification by column chromatography
on silica gel (petroleum ether/ ethyl acetate = 3:1, v/v) affords the title compound as a yellow solid (16.3
1
mg, 40% yield), mp 177ꢀ179 °C (uncorrected); H NMR (500 MHz, DMSOꢀd6) δ 7.75ꢀ7.73 (m, 1H),
13
7.70ꢀ7.64 (m, 2H), 3.58 (s, 3H); C NMR (125 MHz, DMSOꢀd6) δ 158.3 (d, JC−F = 241.8 Hz), 152.7,
135.1, 132.7, 131.4, 122.4 (d, JC−F = 24.1 Hz), 117.4, 115.4 (d, JC−F = 22.6 Hz), 114.7, 29.9; LRMS (EI,
70 eV) m/z (%): 203 (M+, 100), 174 (78), 148 (21); HRMS (ESI) calcd for C10H7FN3O+ ([M + H]+)
204.0568, found 204.0571.
3ꢀCyanoꢀ6ꢀchloroꢀ1ꢀmethylꢀ1,2ꢀdihydroquinoxalinꢀ2ꢀone (2j): Purification by column chromatography
on silica gel (petroleum ether/ ethyl acetate = 3:1, v/v) affords the title compound as a yellow solid (33.3
1
mg, 76% yield), mp 171ꢀ181 °C (uncorrected); H NMR (500 MHz, DMSOꢀd6) δ 7.97 (s, 1H), 7.81 (d,
J = 9.0 Hz, 1H), 7.65 (d, J = 9.0 Hz, 1H), 3.58 (s, 3H); 13C NMR (125 MHz, DMSOꢀd6) δ 152.8, 135.2,
134.0, 133.4, 132.8, 129.3, 128.6, 117.4, 114.7, 29.9; LRMS (EI, 70 eV) m/z (%): 219 (M+, 100), 190
(53), 164 (18); HRMS (ESI) calcd for C10H6ClN3ONa+ ([M + Na]+) 242.0092, found 242.0088.
6ꢀBromoꢀ3ꢀcyanoꢀ1ꢀmethylꢀ1,2ꢀdihydroquinoxalinꢀ2ꢀone (2k): Purification by column chromatography
on silica gel (petroleum ether/ ethyl acetate = 3:1, v/v) affords the title compound as a yellow solid (27.9
1
mg, 53% yield), mp 184ꢀ186 °C (uncorrected); H NMR (500 MHz, DMSOꢀd6) δ 8.11 (s, 1H), 7.93 (d,
J = 9.0 Hz, 1H), 7.59 (d, J = 9.0 Hz, 1H), 3.58 (s, 3H); 13C NMR (125 MHz, DMSOꢀd6) δ 152.7, 142.1,
136.6, 133.8, 133.1, 132.3, 117.6, 116.2, 114.6, 29.8; LRMS (EI, 70 eV) m/z (%): 262 (M+, 100), 234
(33), 155 (29); HRMS (ESI) calcd for C10H7BrN3O+ ([M + H]+) 263.9767, found 263.9783.
3ꢀCyanoꢀ1ꢀmethylꢀ6ꢀ(trifluoromethyl)ꢀ1,2ꢀdihydroquinoxalinꢀ2ꢀone (2l): Purification by column
chromatography on silica gel (petroleum ether/ ethyl acetate = 4:1, v/v) affords the title compound as a
1
yellow solid (35.9 mg, 71% yield), mp 195ꢀ197 °C (uncorrected); H NMR (500 MHz, DMSOꢀd6) δ
8.24 (s, 1H), 8.70 (d, J = 9.0 Hz, 1H), 7.81 (d, J = 9.0 Hz, 1H), 3.61 (s, 3H); 13C NMR (125 MHz,
DMSOꢀd6) δ 153.0, 137.0, 135.9, 131.6, 130.1, 127.9, 124.6 (q, JC−F = 33.0 Hz), 123.6 (q, JC−F = 271.0
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 15
Hz), 117.1, 114.6, 30.0; LRMS (EI, 70 eV) m/z (%): 253 (M+, 100), 227 (55), 198 (25); HRMS (ESI)
calcd for C11H6F3N3ONa+ ([M + Na]+) 276.0355, found 276.0372.
1
2
3
4
5
6
7
6ꢀAcetylꢀ3ꢀcyanoꢀ1ꢀmethylꢀ1,2ꢀdihydroquinoxalinꢀ2ꢀone (2m): Purification by column chromatography
on silica gel (petroleum ether/ ethyl acetate = 2:1, v/v) affords the title compound as a yellow solid (29.1
8
9
1
mg, 64% yield), mp 189ꢀ191 °C (uncorrected); H NMR (500 MHz, DMSOꢀd6) δ 8.43 (s, 1H), 8.24 (d,
J = 9.0 Hz, 1H), 7.73 (d, J = 9.0 Hz, 1H), 3.63 (s, 3H), 2.63 (s, 3H); 13C NMR (125 MHz, DMSOꢀd6) δ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
196.2, 153.0, 137.4, 134.9, 132.8, 132.7, 131.7, 131.3, 116.0, 114.6, 29.9, 26.7; LRMS (EI, 70 eV) m/z
+
(%): 227 (M+, 37), 212 (100); HRMS (ESI) calcd for C12H10N3O2 ([M + H]+) 228.0768, found
228.0769.
3ꢀCyanoꢀ1ꢀphenylꢀ1,2ꢀdihydroquinoxalinꢀ2ꢀone (2n): Purification by column chromatography on silica
gel (petroleum ether/ ethyl acetate = 4:1, v/v) affords the title compound as a yellow solid (23.2 mg,
1
47% yield), mp 198ꢀ200 °C (uncorrected); H NMR (500 MHz, DMSOꢀd6) δ 7.92 (d, J = 8.0 Hz, 1H),
7.63ꢀ7.56 (m, 4H), 7.42ꢀ7.36 (m, 3H), 6.58 (d, J = 8.0 Hz, 1H); 13C NMR (125 MHz, DMSOꢀd6) δ
152.7, 135.2, 134.9, 134.8, 134.3, 132.4, 130.6, 130.3, 129.9, 128.2, 124.6, 115.8, 114.9; LRMS (EI, 70
eV) m/z (%): 247 (M+, 100), 77 (54); HRMS (ESI) calcd for C15H9N3ONa+ ([M + Na]+) 270.0638,
found 270.0636.
1ꢀEthylꢀ3ꢀcyanoꢀ1,2ꢀdihydroquinoxalinꢀ2ꢀone (2o): Purification by column chromatography on silica
gel (petroleum ether/ ethyl acetate = 4:1, v/v) affords the title compound as a yellow solid (17.1 mg,
1
43% yield), mp 166ꢀ168 °C (uncorrected); H NMR (500 MHz, DMSOꢀd6) δ 7.74 (d, J = 8.0 Hz, 1H),
7.68ꢀ7.65 (m, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.33ꢀ7.30 (m, 1H), 4.10 (q, J = 7.0 Hz, 2H), 1.08 (t, J = 7.0
Hz, 3H); 13C NMR (125 MHz, DMSOꢀd6) δ 152.6, 134.8, 133.7, 133.3, 132.7, 131.1, 124.6, 115.3,
115.0, 37.8, 12.2; LRMS (EI, 70 eV) m/z (%): 199 (M+, 85), 187 (82), 143 (100); HRMS (ESI) calcd for
C11H9N3ONa+ ([M + Na]+) 222.0638, found 222.0641.
1ꢀButylꢀ3ꢀcyanoꢀ3,4ꢀdihydroquinoxalinꢀ2ꢀone (2p): Purification by column chromatography on silica
gel (petroleum ether/ ethyl acetate = 4:1, v/v) affords the title compound as a yellow solid (23.2 mg,
1
51% yield), mp 183ꢀ185 °C (uncorrected); H NMR (500 MHz, DMSOꢀd6) δ 7.89 (d, J = 8.0 Hz, 1H),
7.82ꢀ7.78 (m, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.47ꢀ7.44 (m, 1H), 4.20 (t, J = 8.0 Hz, 2H), 1.63ꢀ1.57 (m,
2H), 1.40ꢀ1.35 (m, 2H), 0.89 (t, J = 8.0 Hz, 3H); 13C NMR (125 MHz, DMSOꢀd6) δ 152.7, 134.6, 133.7,
133.5, 132.6, 131.0, 124.5, 115.4, 114.9, 42.2, 28.8, 19.5, 13.6; LRMS (EI, 70 eV) m/z (%): 227 (M+,
100), 185 (92), 171 (94); HRMS (ESI) calcd for C13H14N3O+ ([M + H]+) 228.1131, found 228.1136.
ACS Paragon Plus Environment

Page 13 of 15
The Journal of Organic Chemistry
1ꢀBenzylꢀ3ꢀcyanoꢀ1,2ꢀdihydroquinoxalinꢀ2ꢀone (2q)5c: Purification by column chromatography on silica
1
2
3
4
5
gel (petroleum ether/ ethyl acetate = 4:1, v/v) affords the title compound as a yellow solid (36.6 mg,
1
70% yield), mp 169ꢀ171 °C (uncorrected); H NMR (500 MHz, DMSOꢀd6) δ 7.88 (d, J = 8.0 Hz, 1H),
7.67ꢀ7.64 (m, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.40ꢀ7.37 (m, 1H), 7.29ꢀ7.24 (m, 4H), 7.21ꢀ7.18 (m, 1H),
5.45 (s, 2H); 13C NMR (125 MHz, DMSOꢀd6) δ 153.2, 134.9, 134.4, 134.3, 133.5, 132.6, 130.9, 128.7,
127.5, 126.9, 124.7, 115.7, 114.9, 45.6; LRMS (EI, 70 eV) m/z (%): 261 (M+, 24), 91 (100), 65 (13);
HRMS (ESI) calcd for C16H11N3ONa+ ([M + Na]+) 284.0794, found 284.0797.
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3ꢀCyanoꢀ1ꢀmethylꢀ1,2ꢀdihydropyrido[3,4ꢀb]pyrazineꢀ2ꢀone
(2r):
Purification
by
column
chromatography on silica gel (petroleum ether/ ethyl acetate = 5:1, v/v) affords the title compound as a
yellow solid (8.6 mg, 23% yield), mp 151ꢀ153 °C (uncorrected); 1H NMR (500 MHz, DMSOꢀd6) δ 9.05
(s, 1H), 8.73 (d, J = 6.0 Hz, 1H), 7.65 (d, J = 6.0 Hz, 1H), 3.58 (s, 3H); 13C NMR (125 MHz, DMSOꢀd6)
δ 153.2, 152.3, 151.9, 139.5, 135.6, 128.7, 114.5, 109.7, 29.4; HRMS (ESI) calcd for C9H7N4O+ ([M +
H]+) 187.0614, found 187.0625.
3ꢀCyanoꢀ1ꢀmethylꢀ1,2ꢀdihydroquinoxalinꢀ2ꢀone 4ꢀOxide (3a)8: Purification by column chromatography
on silica gel (petroleum ether/ ethyl acetate = 2:1, v/v) affords the title compound as a yellow solid (20.9
1
mg, 52% yield), mp 213ꢀ215 °C (uncorrected); H NMR (500 MHz, DMSOꢀd6) δ 8.14 (d, J = 8.0 Hz,
1H), 7.87ꢀ7.84 (m, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.46ꢀ7.43 (m, 1H), 3.58 (s, 3H); 13C NMR (125 MHz,
DMSOꢀd6) δ 155.4, 136.3, 134.9, 131.5, 125.4, 120.6, 117.5, 117.1, 112.2, 30.2; LRMS (EI, 70 eV) m/z
(%): 201 (M+, 100).
1ꢀMethylꢀ1,2ꢀdihydroquinoxalinꢀ2ꢀoneꢀ3ꢀcarboxamide (4)14: Purification by column chromatography on
silica gel (ethyl acetate) affords the title compound as a pale yellow solid (27.2 mg, 67% yield), mp 172ꢀ
1
174 °C (uncorrected); H NMR (500 MHz, DMSOꢀd6) δ 8.16 (s, 1H), 7.82 (d, J = 7.5 Hz, 1H), 7.79 (s,
1H), 7.69ꢀ7.65 (m, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.40ꢀ7.37 (m, 1H), 3.60 (s, 3H); 13C NMR (125 MHz,
DMSOꢀd6) δ 165.1, 152.9, 151.6, 133.7, 131.8, 131.5, 129.9, 124.0, 115.0, 29.1; HRMS (ESI) calcd for
+
C10H10N3O2 ([M + H]+) 204.0768, found 204.0768.
1ꢀMethylꢀ3,4ꢀdihydroquinoxalinꢀ2(1H)ꢀone (5): Purification by column chromatography on silica gel
(petroleum ether/ ethyl acetate = 3:1, v/v) affords the title compound as a pale yellow oil (23.8 mg, 74%
1
yield); H NMR (500 MHz, DMSOꢀd6) δ 6.87 (d, J = 8.0 Hz, 1H), 6.79ꢀ6.76 (m, 1H), 6.67ꢀ6.63 (m,
2H), 5.95 (s, 1H), 3.70 (s, 2H), 3.16 (s, 3H); 13C NMR (125 MHz, DMSOꢀd6) δ 165.3, 136.7, 128.6,
123.1, 118.2, 114.7, 113.6, 46.8, 28.1; LRMS (EI, 70 eV) m/z (%): 162 (M+, 64), 133 (100), 92 (17);
HRMS (ESI) calcd for C9H10N2ONa+ ([M + Na]+) 185.0685, found 185.0684.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 15
NꢀHydroxyꢀ2ꢀ(methyl(phenyl)amino)ꢀ2ꢀoxoacetimidoyl Cyanide (6)8: Purification by column
1
2
3
4
5
chromatography on silica gel (petroleum ether/ ethyl acetate = 2:1, v/v) affords the title compound as a
1
white solid (138.0 mg, 34% yield), mp 154ꢀ156 °C (uncorrected); H NMR (500 MHz, DMSOꢀd6) δ
13
14.14 (s, 1H), 7.45ꢀ7.42 (m, 2H), 7.35ꢀ7.34 (m, 3H), 3.36 (s, 3H); C NMR (125 MHz, DMSOꢀd6) δ
6
7
8
9
158.5, 142.7, 129.6, 127.69, 127.65, 126.9, 108.8, 38.1; HRMS (ESI) calcd for C10H9N3O2Na+ ([M +
Na]+) 226.0587, found 226.0590.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Acknowledgment. We thank the National Natural Science Foundation of China (No. 21272177) and
Natural Science Foundation of Zhejiang Province (No. LR15B020002) for financial support.
1
13
Supporting Information Available: Copies of H and C NMR spectra for product 2aꢀ2r, 3a, 4, 5
and 6. This material is available free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Ries, U. J.; Priepke, H. W. M.; Hauel, N. H.; Handschuh, S.; Mihm, G.; Stassen, J. M.; Wienen,
W.; Nar, H. Bioorg. Med. Chem. Lett. 2003, 13, 2297−2302. (b) Carta, A.; Sanna, P.; Gherardini, L.;
Usai, D.; Zanetti, S. Farmaco. 2001, 56, 933−938. (c) Galal, S. A.; Khairat, S. H. M.; Ragab, F. A. F.;
Abdelsamie, A. S.; Ali, M. M.; Soliman, S. M.; Mortier, J.; Wolber, G.; Diwani, H. El. Eur. J. Med.
Chem. 2014, 86, 122−132. (d) Willardsen, J. A.; Dudley, D. A.; Cody, W. L.; Chi, L.; McClanahan, T.
B.; Mertz, T. E.; Potoczak, R. E.; Narasimhan, L. S.; Holland, D. R.; Rapundalo, S. T.; Edmunds, J. J. J.
Med. Chem. 2004, 47, 4089−4099.
(2) (a) Lawrence, D. S.; Copper, J. E.; Smith, C. D. J. Med. Chem. 2001, 44, 594−601. (b) Tung, C.ꢀL.;
Sun, C.ꢀM. Tetrahedron. Lett. 2004, 45, 1159−1162. (c) Weïwer, 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.
(3) For selected examples: (a) Dhole, S.; Selvaraju, M.; Maiti, B.; Chanda, K.; Sun, C.ꢀM. ACS Comb.
Sci. 2015, 17, 310−316. (b) Chen, D.; Bao, W. Adv. Synth. Catal. 2010, 352, 955−960. (c) Tanimori, S.;
Kashiwagi, H.; Nishimura, T.; Kirihata, M. Adv. Synth. Catal. 2010, 352, 2531−2537. (d) Zhou, Y.; Ji,
X.; Liu, G.; Zhang, D.; Zhao, L.; Jiang, H.; Liu, H. Adv. Synth. Catal. 2010, 352, 1711−1717. (e) Lai, J.ꢀ
J.; Salunke, D. B.; Sun, C.ꢀM. Org. Lett. 2010, 12, 2174−2177. (f) Luo, X.; Chenard, E.; Martens, P.;
Cheng, Y.ꢀX.; Tomaszewski, M. J. Org. Lett. 2010, 12, 3574−3577. (g) Mtiraoui, H.; Renault, K.;
Sanselme, M.; Msaddek, M.; Renard, P.ꢀY.; Sabot, C. Org. Biomol. Chem. 2017, 15, 3060−3068.
(4) (a) Bekerman, D. G.; Abasolo, M. I.; Fernández, B. M. J. Heterocycl. Chem. 1992, 29, 129−133. (b)
Eller, G. A.; Datterl, B.; Holzer, W. J. Heterocycl. Chem. 2007, 44, 1139−1141. (c) Gris, J.; Glisoni, R.;
Fabian, L.; Fernández, B.; Moglioni, A. G. Tetrahedron. Lett. 2008, 49, 1053−1056. (d) Ballini, R.;
ACS Paragon Plus Environment

Page 15 of 15
The Journal of Organic Chemistry
Gabrielli, S.; Palmieri, A. Synlett. 2009, 965−967. (e) Kleme, R.; Bentz, C.; Zukowski, T.; Schefzig, L.;
Lentz, D.; Reissing, H.ꢀU.; Zimmer, R. Synthesis, 2016, 48, 1491−1501.
1
2
3
(5) (a) Bencivenni, G.; Lanza, T.; Leardini, R.; Minozzi, M.; Nanni, D.; Spagnolo, P.; Zanardi, G. J.
Org. Chem. 2008, 73, 4721−4724. (b) Li, Z.ꢀS.; Wang, W.ꢀX.; Yang, J.ꢀD.; Wu, Y.ꢀW.; Zhang, W. Org.
Lett. 2013, 15, 3820−3823. (c) Yang, T.; Zhu, H.; Yu, W., Org. Biomol. Chem., 2016, 14, 3376–3384.
(6) Chen, D.; Wang, Z.; Bao, W. J. Org. Chem. 2010, 75, 5768−5771.
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(7) Li, D.; Ma, H.; Yu, W. Adv. Synth. Catal. 2015, 357, 3696−3702.
(8) Kobayashi, Y.; Kuroda, M.; Toba, N.; Okada, M.; Tanaka, R.; Kimachi, T. Org. Lett. 2011, 13,
6280−6283.
(9) (a) Yang, Z.ꢀJ.; Liu, C.ꢀZ.; Hu, B.ꢀL.; Deng, C.ꢀL.; Zhang, X.ꢀG. Chem. Commun. 2014, 50,
14554−14557. (b) Wang, F.; Zhang, T.; Tu, H.ꢀY.; Zhang, X.ꢀG. J. Org. Chem. 2017, 82, 5475−5480.
(10) Chu, J.ꢀJ.; Hu, B.ꢀL.; Liao, Z.ꢀY.; Zhang, X.ꢀG. J. Org. Chem. 2016, 81, 8647−8652.
(11) (a) Matsui, K. Osaka City Medical Journal. 2001, 47, 1−9. (b) MarquésꢀGallego, P.; Gamizꢀ
Gonzalez, M. A.; ForteaꢀPérez, F. R.; Lutz, M.; Spek, A. L.; Pevec, A.; Kozlevčar, B.; Reedijk, J.
Dalton Trans. 2010, 39, 5152−5158. (c) Elina, A. S.; Musatova, I. S.; Peresleni, E. M.; Padeiskaya, E. N.
Chemistry of Heterocyclic Compounds, 1976, 12, 239−244. (d) Ager, I. R.; Barnes, A. C.; Danswan, G.
F.; Hairsine, P. W.; Kay, D. P.; Kennewell, P. D.; Matharu, S. S.; Miller, P.; Robson, P.; Rowlands, D.
A.; Tully, W. R.; Westwood, R. J. Med. Chem. 1988, 31, 1098−1115.
(12) (a) Smil, D. V.; Manku, S.; Chantigny, Y. A.; Leit, S.; Wahhab, A.; Deziel, R.; Yan, T. P.; Fournel,
M.; Maroun, C.; Li, Z.; Lemieux, A.ꢀM.; Nicolescu, A.; Rahil, J.; Besterman, J. M.; Lefebvre, S.;
Panetta, A. Bioorg. Med. Chem. Lett. 2009, 19, 688 – 692. (b) Mahaney, P. E.; Webb, M. B.; Ye, F.;
Sabatucci, J. P.; Steffan, R. J.; Chadwick, C. C; Harnish, D. C.; Trybulski, E. J.; Bioorg. Med. Chem.
2006, 14, 3455 – 3466. (c) Su, D.ꢀS.; Markowitz, M. K.; DiPardo, R. M.; Murphy, K. L.; Harrell, C. M.;
OMalley, S. S.; Ransom, R. W.; Chang, R. S. L.; Ha, S.; Hess, F. J.; Pettibone, D. J. J. Am. Chem. Soc.
2003, 125, 7516 – 7517.
(13) (a) Hirabayashi, T.; Sakaguchi, S.; Ishii, Y. Angew. Chem., Int. Ed. 2004, 43, 1120−1123. (b)
Prateeptongkum, S.; Jovel, I.; Jackstell, R.; Vogl, N.; Weckbecker, C.; Beller, M. Chem. Commun.
2009, 1990−1992. (c) Chen, F.; Huang, X.; Li, X.; Shen, T.; Zou, M.; Jiao, N. Angew. Chem., Int. Ed.
2014, 53, 10495−10499. (d) Shu, Z.; Ye, Y.; Deng, Y.; Zhang, Y.; Wang, J. Angew. Chem., Int. Ed.
2013, 52, 10573−10576. (e) Shen, T.; Yuan, Y.; Jiao, N. Chem. Commun. 2014, 50, 554−556.
(14) King, F. E.; ClarkꢀLewis, J. W. J. Chem. Soc. 1953, 172−177.
ACS Paragon Plus Environment