Manganese(I)-Catalyzed Sustainable Synthesis of Quinoxaline and Quinazoline Derivatives with the Liberation of Dihydrogen

Article abstract of DOI:10.1021/acs.joc.0c00561

Direct synthesis of N-heterocycles via the acceptorless dehydrogenative coupling is very challenging and scarcely reported under 3d transition-metal catalysis. Here, we have developed an efficient Mn(I)-catalyzed sustainable synthesis of various quinoxalines from 1,2-diaminobenzenes and 1,2-diols via the acceptorless dehydrogenative coupling reaction. Further, this strategy was successfully applied for the unprecedented synthesis of quinazolines by the reaction of 2-aminobenzyl alcohol with primary amides. The present protocol provides an atom-economical and sustainable route for the synthesis of various quinoxaline and quinazoline derivatives by employing an earth-abundant manganese salt and simple phosphine-free NNN-tridentate ligand.

Full text of DOI:10.1021/acs.joc.0c00561

Subscriber access provided by Uppsala universitetsbibliotek
Article
Manganese(I)-Catalyzed Sustainable Synthesis of Quinoxaline
and Quinazoline Derivatives with the Liberation of Dihydrogen
Akash Mondal, Manoj K. Sahoo, Murugan Subaramanian, and Ekambaram Balaraman
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00561 • Publication Date (Web): 13 May 2020
Downloaded from pubs.acs.org on May 13, 2020
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 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 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.
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 39
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Manganese(I)-Catalyzed Sustainable Synthesis of Quinoxaline and
Quinazoline Derivatives with the Liberation of Dihydrogen
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
Akash Mondal, Manoj Kumar Sahoo, Murugan Subaramanian, and Ekambaram Balaraman*
Department of Chemistry, Indian Institute of Science Education and Research (IISER) Tirupati,
Tirupati – 517507, India. E-mail: eb.raman@iisertirupati.ac.in
ABSTRACT: Direct synthesis of N-heterocycles via the acceptorless dehydrogenative
coupling (ADC) is very challenging and scarcely reported under 3d-transition metal catalysis.
Here we have developed an efficient Mn(I)-catalyzed sustainable synthesis of various
quinoxalines from 1,2-diaminobenzenes and 1,2-diols via the acceptorless dehydrogenative
coupling reaction. Further, this strategy was successfully applied for the unprecedented
synthesis of quinazolines by the reaction of 2-aminobenzyl alcohol with primary amides. The
present protocol provides an atom-economical and sustainable route for the synthesis of various
quinoxaline and quinazoline derivatives by employing an earth-abundant manganese salt and
simple phosphine-free NNN-tridentate ligand.
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 39
1
2
3
4
INTRODUCTION
5
6
7
8
Nitrogen-containing heteroaromatics such as quinoxalines and quinazolines are a class
of heterocyclic motifs that are commonly found as the core structural skeletons in
bioactive natural products and many pharmaceuticals (Figure 1).1-3 They also play a
significant role as starting materials for the drug discovery process.3 Thus, the
development of new catalytic approaches to the sustainable synthesis of these N-
heterocycles from simple and abundant starting materials has attracted great interest.4
Of late, significant contribution has been made towards the direct synthesis of N-
heteroaromatics under precious metal catalysis via the ADC and the hydrogen auto-
transfer (HA) protocols.5-6 In recent years, there has been a rapid development of non-
precious metal catalysts for innovative organic synthesis, and this has emerged as a key
technology for a more sustainable production of fine chemicals and pharmaceuticals.7
Indeed, direct synthesis of N-heterocycles via the acceptorless dehydrogenative
coupling (ADC) is very challenging and scarcely reported under 3d-transition metal
catalysis.8-9
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
Figure 1. Pharmaceutically Active Compounds Containing Quinoxaline and Quinazoline
Motif (Selected Examples)
2
ACS Paragon Plus Environment

Page 3 of 39
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Among the 3d-transition metals, iron and manganese have the unique features of being
non‐toxic and environmentally benign. Of late, manganese complexes have been
effectively applied to synthesize different N-heterocycles via ADC/HA strategy.10-12 For
the first time, Milstein and co-workers reported the acceptorless dehydrogenative
coupling (ADC) of amines and primary alcohols to give aldimines catalyzed by a
molecularly defined PNP-Mn(I) complex.10b The research group of Kirchner reported
an Mn-catalyzed quinoline synthesis from amino alcohols and secondary alcohols, and
pyrimidine synthesis from amidines, secondary alcohols and primary alcohols (Scheme
1).12d Recently, the research group of Kempe reported a manganese catalyzed direct
synthesis of pyrimidine by the reaction of benzamidine with alcohols.12e Subsequently,
the synthesis of pyrroles by the reaction of 1,2-amino alcohols with secondary alcohols
under the ADC has been reported by the same group.12f An elegant base-switchable
approach to amines or imines from the reaction of anilines with alcohols was also
reported.11e Notably, most of the catalysts used in the ADC reactions possess electron-
rich phosphine ligands. Despite the tremendous success of phosphine ligands in
homogeneous catalysis, their preparation is often non-trivial, needing multi-step
syntheses, and requiring handling under an inert atmosphere etc. As a result, the
phosphine ligands are expensive and can be challenging to make on a large scale,
thereby hindering sustainable development. In continuation of our efforts towards
phosphine-ligand free non-noble metal catalysis,9c, 10f-10h, 13 we have reported the N-
alkylation of anilines using a catalytic amount of commercially available Mn(CO)5Br
and NNN-ligand (L12) via the HA strategy.10f Inspired by this results, herein we report
a manganese catalyzed sustainable synthesis of quinoxaline, and unprecedented Mn-
catalyzed direct synthesis of quinazolines via the ADC of 2-aminobenzyl alcohol with
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
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 39
1
2
3
4
5
6
benzamides. These tandem dehydrogenative annulation reactions operate under mild,
benign conditions and produce only H2 and H2O as by-products.
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 1. Mn(I)-Catalyzed Synthesis of N-Heteroaromatics via the ADC and N-
Alkylation of Amines
Manganese catalyzed a) quinoline and pyrimidine synthesis developed by Kirchner and co-
workers; b) pyrrole synthesis by Kempe and co-workers; c) Mn(CO)5Br catalyzed N-alkylation
of anilines using alcohols as alkylating agent; d) The Mn(I)/L12 catalyzed quinoxaline and
quinazoline synthesis disclosed herein. R1, R2 = H, alkyl or aryl; R3 = alkyl or aryl.
RESULT AND DISCUSSION
To explore the [Mn]-catalyzed acceptorless dehydrogenative annulation reaction, 1,2-
diaminobenzene (1a) and 1-phenyl-1,2-ethanediol (2a) were chosen as the model substrates.
4
ACS Paragon Plus Environment

Page 5 of 39
The Journal of Organic Chemistry
1
2
3
4
5
6
We have carefully screened various [Mn]-catalysts, ligands, bases solvents, and reaction
temperature (Table-1).14 After systematic studies, a catalytic amount of [Mn]/L12 (2 mol% of
7
8
9
Mn(CO)5Br and 3 mol% of L12), and 40 mol% of KOtBu in toluene at 130 C C (oil-bath
temperature) was found to be optimal condition for this transformation and gave the desired
product 3a in 83% isolated yield (Table 1, entry 1). The necessity of each compounds were
studied systematically under standard conditions. It was observed that under the present Mn-
catalytic conditions the ligand L15 (two methylene-bridged PNP) gave the expected product
(quinoxaline, 3a) in 85% yield and showed a similar reactivity as compared with the present
phosphine-free NNN ligand system (L12).11d
o
o
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
Table 1. Optimization of Reaction Conditionsa
Conversion of
Yield of
Entry Variation from initial conditions
1a (%)b
3a (%)c
1.
2.
3.
4.
5.
6.
7.
8.
9.
No variation
No Mn(CO)5Br
93
trace
trace
trace
38
83
nd
nd
nd
21
51
61
60
nd
No base
In absence of ligand L12
80 oC instead of 130 oC
Decane instead of toluene
1,4-dioxane instead of toluene
24 h instead of 36 h
64
70
82
Mn(acac)3 as a [Mn] source
trace
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 39
1
2
3
4
5
6
7
8
9
10.
11.
12.
13.
14.
15.
16.
Cp*Mn(CO)3 as a [Mn] source
trace
56
nd
48
53
38
16d
76
61
LiOtBu instead of KOtBu
NaOtBu instead of KOtBu
KOH instead of KOtBu
Potassium salt of ligand L12
0.35 equiv of KOtBu
67
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
50
24
85
0.25 equiv of KOtBu
78
aReaction conditions: Substrate 1a (0.50 mmol), 2a (0.50 mmol), cat.[Mn] (2.0 mol%), ligand
o
o
L12 (3.0 mol%), base (0.20 mmol), solvent (3 mL), argon atmosphere, 130 C C (oil-bath
temperature) for 36 h. bConversion of 1a based on GC using m-xylene as an internal standard.
cIsolated yield. dNo additional base is used. nd = not detected.
Notably, under optimized reaction conditions such as in the absence of [Mn]-catalyst, base or
ligand no formation of product (3a) was observed, and both the unreacted reactants were
6
ACS Paragon Plus Environment

Page 7 of 39
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
recovered from the reaction mixture (Table 1, entries 2-4). From various solvents screened,
toluene was found to be the most suitable solvent for this tandem annulation reaction (Table 1,
entries 1 and 6-7). Performing the reaction at 80 oC dramatically reduced the observed yield of
3a (Table 1, entry 5). Lowering in the yield of 3a (68%) was observed when the reaction was
conducted for 24 h (Table 1, entry 8). Among the various [Mn]-catalysts screened for the
present ADC reaction, a freshly prepared Mn(CO)5Br was found to possess superior catalytic
activity, and gave a maximum yield of 3a (Table 1, entries 1, 9-10). Similarly, KOtBu was
found to be optimal base for this transformation and gave the maximum yield of 3a under the
optimal reaction conditions (Table 1, entries 1, 11-12). Thus, changing the base from KOtBu
to either of LiOtBu, Cs2CO3, Na2CO3, KOH resulted in lower yield of the desired product
(~40%). A potassium salt of the ligand L12 showed less reactivity under standard reaction
conditions (Table 1, entry 14). A maximum yield of quinoxaline (Table 1, entries 1, 15-16)
was observed by applying 40 mol% of KOtBu. Recently, a potential role of base in the Mn-
catalyzed (de)hydrogenation catalysis was emphasized by the research group of Kempe.15
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
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 39
1
2
3
4
Table 2. ADC of 1,2-Diols with 1,2-Diaminobenzene: Direct Synthesis of Quinoxalinesa,b
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
aReaction conditions: Substrate 1 (0.50 mmol), 2 (0.50 mmol), Mn(CO)5Br (2.0 mol%), ligand
o
o
L12 (3.0 mol%), KOtBu (0.2 mmol), toluene (3 mL), argon atmosphere, 130 C C (oil-bath
temperature) for 36 h. bIsolated yield. cA mixture of two isomeric quinoxaline derivatives were
observed.
Under the optimal reaction conditions, we have explored the scope of the present [Mn]-
catalyzed ADC strategy for the direct synthesis of diverse quinoxalines (3). Several 1,2-
diaminobenzene derivatives (1) and 1,2-diols (2) were subjected under the catalytic
8
ACS Paragon Plus Environment

Page 9 of 39
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
acceptorless dehydrogenative cyclization conditions. As shown in Table 2, the present
annulation strategy exhibits a wide substrate scope and gave various quinoxaline derivatives16
in very good yields (up to 83%). The reaction of 1,2-diaminobenzene with an equivalent
amount of 1-phenyl-1,2-ethanediol yielded 83% of 2-phenylquinoxaline 3a under the optimal
conditions. Gratifyingly, acyclic aliphatic 1,2-diols underwent annulation reaction smoothly
with 1,2-diaminobenzene, and gave the corresponding 2-substituted quinoxalines in good
yields (Table 2, products 3b-3e). However, the reaction of 1,2-diaminobenzene with
cyclohexane-1,2-diol gave 3f in 56% isolated yield. Notably, methyl substituted 1,2-
diaminobenzenes showed similar reactivity as like 1a (R1 = H) and gave a mixture of two
isomeric quinoxaline derivatives upon treatment with various 1,2-diols under the optimal
conditions. When 4-methyl-1,2-diaminobenzene (1b: R1 = 4-Me) reacted with 1-phenyl-1,2-
ethanediol gave 79% of product 3g. Similarly, 1b reacted with propane-1,2-diol to give
quinoxaline 3h in 56% isolated yield. The reaction of 1b with other aliphatic 1,2-diols gave the
corresponding annulated products in moderate to good yields (Table 2, products 3i-3k).
Interestingly, upon reaction of 4,5-dimethyl-1,2-diaminobenzene (1c: R1 = 4,5-dimethyl) with
various acyclic, aliphatic 1,2-diols and cyclohexane-1,2-diol gave the corresponding
quinoxalines up to 82% yields (Table 2, products 3l-3p). To our delight, some of the acyclic
aliphatic 1,2-diols also underwent acceptorless dehydrogenative annulation reaction with 1,2-
diaminobenzene and gave the desired quinoxaline derivatives in moderate yields (3q-3s). Next
to further study the scope of the reaction, different 1,2-diaminobenzenes having both electron-
withdrawing and halo-substituted groups have been investigated. Thus, the ADC of 1,2-
diphenylethane-1,2-diol with the 1,2-diaminobenzenes possessing both electron-donating (1t)
and halo-substituted groups (1u and 1v) in the aromatic nucleus proceeded well and offered
the desired quinoxaline derivatives (3t-3v) in moderate to good yields (up to 77%). Notably,
dichloro-substituted vicinal diol reacted smoothly with 1,2-diaminobenzene under the
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
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 39
1
2
3
4
5
6
7
8
9
optimized reaction conditions and gave the corresponding quinoxaline derivative (3w) in 80%
isolated yield. To demonstrate the practical utility of the present Mn-catalyzed direct synthesis
of quinoxaline derivatives (3a and 3v) a larger scale synthesis has been performed.
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 2. Proposed Mechanism for the Synthesis of Quinoxaline
To our delight, we have qualitatively analysed the formation of molecular hydrogen as well as
the dehydrogenated carbonyl compound (proven by GC). The amount of liberated H2 was also
determined.14 The catalytic reaction under oxygen atm failed to yield the desired product. These
results proved that the reaction proceeds via acceptorless dehydrogenative coupling. A base
promoted cyclization of 1,2-dicarbonyl compound (generated via dehydrogeative pathway)
with 1,2-diaminobenzene was carried. This experimental result confirms that the cyclization
(condensation) step is promoted by base and the effect of Mn-metal catalyst in the cyclization
step is negligible. Thus, the dehydrogenative annulation of 1,2-diols with 1,2-diaminobenzenes
for the synthesis quinoxalines operates by the initial dehydrogenation of the primary alcoholic
group of the 1,2-diol system. Next, a condensation reaction of 1,2-diaminobenzene with the
carbonyl moiety (I) leads to the intermediate II followed by the formation of III via the
acceptorless dehydrogenation. Finally, an intramolecular condensation reaction of III leads to
the formation of quinoxaline (3) as the final product (Scheme 2).
10
ACS Paragon Plus Environment

Page 11 of 39
The Journal of Organic Chemistry
1
2
3
4
5
6
Table 3. ADC of 2-Aminobenzyl Alcohol with Benzamides: Direct Synthesis of
Quinazolinesa,b
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
aReaction conditions: Substrate 4 (0.50 mmol), 5a (0.50 mmol), Mn(CO)5Br (2.0 mol%),
ligand L12 (3.0 mol%), KOtBu (0.20 mmol), toluene (3 mL), argon atmosphere, 130 oC oC (oil-
bath temperature) for 36 h. bIsolated yield.
Next, we have explored the sustainable synthesis of quinazolines derivatives17 by using the
same catalytic system. All the reaction parameters and components were studied carefully.
Thus, treatment of 2-aminobenzyl alcohol (4) with benzamide (5a: R = Ph) gave 2-
phenylquinazoline (6a) in 81% isolated yield under the standard reaction conditions. Further,
the reaction of 4 with different substituted benzamides gave the corresponding quinazolines in
excellent yields without significant variation in the yields of the products. This clearly suggests
that electronically biased substituent groups present on aromatic ring of benzamide have
negligible effects in the annulation reaction. Notably, the amino alcohol 4 effectively reacted
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 39
1
2
3
4
5
6
7
8
9
with various halo-substituted benzamides and gave the corresponding quinazolines in 60% to
76% isolated yields without any dehalogenation reaction (Table 3, products 6b, 6d-6f).
Similarly, electronically rich benzamides with 3-methyl (5c), and 4-methoxy (5g) groups
enabled the corresponding products in 71% and 80% isolated yields, respectively. Interestingly,
heteroaromatic benzamide 5h reacted with 4 to give pyridinyl substituted quinazoline 6h in
66% isolated yield. To our delight, the aliphatic primary amides 5i and 5j underwent
dehydogenative annulation smoothly with 4 under our optimal conditions and gave the
expected aliphatic substituted quinazolines 6i and 6j in 64% and 68% isolated yields,
respectively. Other aliphatic primary amides 5K and 5l also showed a similar activity and
yielded the expected quinazoline derivatives in moderate yields. Notably, benzamides
containing electron withdrawing groups (5n and 5o) didn’t yield the product under our Mn-
catalyzed conditions. Also trans-cinnamamide (5m) didn’t show any reactivity towards the
formation of 6m.
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 3. Control Experiments: Direct Synthesis of Quinazoline
aStandard conditions: Starting material(s) (0.50 mmol), Mn(CO)5Br (2.0 mol%), ligand L12
o
o
(3.0 mol%), KOtBu (0.20 mmol), toluene (3 mL), argon atmosphere, 130 C C (oil-bath
temperature) for 36 h.
12
ACS Paragon Plus Environment

Page 13 of 39
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
The active NNN-[Mn] complex (IV) derived from ligand L12 was detected in high resolution
mass spectrometry (HRMS);14 and attempts to isolate the NNN-[Mn] complex (I) is under
process in our laboratory. Pleasingly, the formation of molecular hydrogen was qualitatively
analyzed on gas chromatography (GC) under the standard reaction of 4 and 5a; however, in the
absence of benzamide 5a, 2-aminobenzaldehyde (7) was detected with the formation of H2 gas.
The reaction of 4 with 5a under standard reaction conditions in the presence of 1.0 equivalent
of Bu4NBr (known to stabilize nanoparticles),18 resulted a slightly lowering in the yield (79%)
of 6a. Moreover, addition of excess mercury to the reaction mixture under optimal conditions
didn’t affect the yield of 6a (81%). Thus, the mercury test and the reaction in presence of
Bu4NBr clearly suggest that this reaction is completely homogeneous in nature. When the
reaction was performed in the presence of a radical scavenger TEMPO (2 equiv.), didn’t affect
the yield of the product which certainly ruled out the possibility of single electron transfer
pathway (SET). Notably, 2-aminobenzyl alcohol underwent dehydrogenation under Mn-
catalytic conditions and yielded 2-aminobenzaldehyde (20% GC yield) after 12 h along with
the formation of H2 gas. The dehydrative condensation of 2-aminobenzaldehyde with
benzamide has been mediated by KOtBu. Indeed, in the absence base no product formation
(6a) was observed (Scheme 3). After careful examination of the effect of other ligands under
our standard reaction conditions, it has been observed that the presence NH moiety in the ligand
is very important and plays crucial role in the catalytic reaction. Based on observations from
these control experiments, here we propose a possible reaction pathway for the direct synthesis
of quinazoline as shown in Scheme 4.
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
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 39
1
2
3
4
Scheme 4. A Plausible Mechanism: Synthesis of Quinazoline under Mn-Catalysis.
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
Initially, in the presence of potassium tert-butoxide the Mn-salt Mn(CO)5Br and the ligand L12
upon coordination produces the active Mn-catalyst (IV). Then the O-H bond activation of 2-
aminobenzyl alcohol (4) by a complex IV via the metal-ligand cooperation (MLC) leads to the
intermediate V. The intermediate V undergoes β-H elimination and thus generating 2-
aminobenzaldehyde (7) and the intermediate VI. Next, 2-aminobenzaldehyde (7) couples with
primary amide (5a) leads to quinazoline via the elimination of water molecules. Finally,
dihydrogen liberation from the intermediate VI via the MLC regenerates the active Mn-catalyst
IV.
CONCLUSIONS
In conclusion, we have developed an earth-abundant manganese(I)-catalyzed direct synthesis
of quinoxaline and quinazoline derivatives via the ADC of 1,2-diols with 1,2-diaminobenzene,
and the ADC of 2-aminobenzyl alcohol with benzamides, respectively. The present tandem
dehydrogenative annulation reactions utilize simple and abundantly available chemicals, and
14
ACS Paragon Plus Environment

Page 15 of 39
The Journal of Organic Chemistry
1
2
3
4
5
6
proceed in the absence of any oxidants and produce water and molecular hydrogen as by-
products.
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
EXPERIMENTAL SECTION
1. General Information. All catalytic experiments were carried out using standard Schlenk
techniques. Unless otherwise stated reaction were conducted in flame-dried glassware under
an atmosphere of nitrogen and commercially obtained reagent were used as received. All
solvents were reagent grade or better. Toluene was refluxed over sodium/benzophenone,
followed by distilled under argon atmosphere and stored over sodium. Chemicals used in
catalysis reactions were used without additional purification. Thin layer chromatography
(TLC) was performed using silica gel precoated aluminium foil which was visualized with
visualized with UV light at 254 nm or under iodine. Column chromatography was performed
with SiO2 (Silicycle Siliaflash F60 (230-400 mesh). 1H NMR (500, 400, 200 MHz), 13C NMR
(126, 101, 50 MHz) spectra were recorded on the NMR spectrometer. Deuterated chloroform
was used as the solvent, and chemical shift values (δ) are reported in parts per million relatives
to the residual signals of this solvent [δ 7.27 for H (chloroform-d), δ 77.0 for 13C{1H}
1
(chloroform-d). Abbreviations used in the NMR follow-up experiments: s, singlet; d, doublet;
dd, doublet of doublet; t, triplet; tt, triplet of triplet; td, triplet of doublet; q, quartet; br, broad;
m, multiplet. GC analysis was carried out using a HP-5 column (30 m, 0.25 mm, 0.25μ). Mass
spectra were obtained on a GCMS-QP 5000 instruments with ionization voltages of 70 eV.
High resolution mass spectra (HRMS) were obtained on a High-resolution mass spectra
(HRMS) were obtained by fast atom bombardment (FAB) using a double focusing magnetic
sector mass spectrometer and electron impact (EI) ionization technique (magnetic sector-
electric sector double focusing mass analyzer).
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 39
1
2
3
4
5
6
7
8
9
2A. General Procedure for the Mn-Catalyzed Synthesis of Quinoxaline via the ADC of
1,2-Diols with 1,2-Diaminobenzene: To a 15 mL oven dried seal tube, substrate 1 (0.50
mmol.), 2 (0.50 mmol.), potassium tert-butoxide (0.20 mmol), Mn(CO)5Br (2.0 mol%), ligand
L12 (3.0 mol%), and 3 mL dry toluene were added under a continuous flow of argon gas. After
addition of solvent, the colour of the reaction mixture becomes dark green. Then the reaction
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
o
tube was placed on a preheated oil-bath temperature maintained at 130 C with constant
stirring. After 36 h, the reaction tube was allowed to cool down to room temperature. The
reaction mixture was subjected to GC and GC-MS analysis and consumption of 1,2-
phenylenediamine was determined from GC using m-xylene as the internal standard. The
combined crude reaction mixture was evaporated and pure product was obtained after silica gel
column chromatographic purification using a mixture of petroleum ether and EtOAc as eluent
(9:1 ratio).
2B. General Procedure for the Mn-Catalyzed Synthesis of Quinazolines via the ADC of
2-Aminobenzyl Alcohol with Benzamides: To a 15 mL oven dried seal tube, substrate 1 (0.50
mmol.), 2 (0.50 mmol.), potassium tert-butoxide (0.20 mmol), Mn(CO)5Br (2.0 mol%), ligand
L12 (3.0 mol%), and 3 mL dry toluene were added under a continuous flow of argon gas. After
addition of solvent, the colour of the reaction mixture becomes dark green. Then the reaction
o
tube was placed on a preheated oil-bath temperature maintained at 130 C with constant
stirring. After 36 h, the reaction tube was allowed to cool down to room temperature. The
reaction mixture was subjected to GC and GC-MS analysis and consumption of benzamide was
determined from GC using m-xylene as the internal standard. The combined crude reaction
mixture was evaporated and pure product was obtained after silica gel column chromatographic
purification using a mixture of petroleum ether and EtOAc as eluent (9:1 ratio).
16
ACS Paragon Plus Environment

Page 17 of 39
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2C. Procedure for Large-scale Synthesis of Quinoxalines (3a and 3v): To demonstrate the
practical utility of the present Mn-catalyzed direct synthesis of quinoxaline derivatives a larger
scale synthesis has been performed.
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 a 100 mL oven dried seal tube, 1,2-diaminobenzene (5.0 mmol), 1,2-diol (5.20 mmol),
potassium tert-butoxide (2 mmol), Mn(CO)5Br (2.0 mol%), ligand L12 (3.0 mol%), and 20 mL
dry toluene were added under a continuous flow of argon gas. Then, the reaction tube was
placed on a preheated oil-bath temperature maintained at 130 oC with constant stirring. After
48 h, the reaction mixture was cooled to room temperature and chloroform was added to dilute
the mixture. Then it was filtered through celite and filtrate was concentrated under reduced
pressure. The crude residue was purified further by silica gel (230-400 mesh) column
chromatography using a mixture of petroleum ether and EtOAc as eluent (9:1 ratio). Yield of
3a is (785 mg, 76%) and 3v (1.42 g, 81%).
3. Characterization Data of Compounds:
2-Phenylquinoxaline (3a)12a
The title compound was synthesized according to the general procedure described in section
2A. The product was purified using silica gel (230-400 mesh) column chromatography using a
mixture of petroleum ether/EtOAc (Rf = 0.75) as an eluent. White solid (86 mg, 83%); 1H NMR
(200 MHz, CDCl3): δ 9.33 (s, 1H), 8.04-8.27 (m, 4H), 7.67-7.91 (m, 2H), 7.42-7.66 (m, 3H);
13C{1H} NMR (50 MHz, CDCl3): δ 151.2, 142.7, 141.6, 140.9, 136.1, 129.6, 129.5, 128.8,
128.5, 126.9 ppm; HRMS (ESI) m/z calculated for C14H11N2 [M+H]+ 207.0917; found
207.0925.
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 39
1
2
3
4
2-Ethylquinoxaline (3b)12a
5
6
7
8
The title compound was synthesized according to the general procedure described in section
2A. The product was purified using silica gel (230-400 mesh) column chromatography using a
mixture of petroleum ether/EtOAc (Rf = 0.70) as an eluent. Colorless liquid (51 mg, 65%); 1H
NMR (200 MHz, CDCl3): δ 8.75 (s, 1H), 8.13-7.93 (m, 2H), 7.79-7.61 (m, 2H), 3.05 (q, J =
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
13
7.63 Hz, 2H), 1.43 (t, J = 7.63 Hz, 3H); C{1H} NMR (50 MHz, CDCl3): δ 158.5, 145.6,
142.2, 141.3, 130.0, 129.2, 129.0, 128.9, 29.7, 13.5 ppm; HRMS (ESI) m/z calculated for
C10H11N2 [M+H]+ 159.0917; found 159.0917.
2-Propylquinoxaline (3c) 16
b
The title compound was synthesized according to the general procedure described in section
2A. The product was purified using silica gel (230-400 mesh) column chromatography using a
mixture of petroleum ether/EtOAc (Rf = 0.70) as an eluent. Colorless liquid (63 mg, 73%); 1H
NMR (200 MHz, CDCl3): δ 8.68 (s, 1H), 8.09-7.94 (m, 2H), 7.75-7.59 (m, 2H), 2.94 (t, J =
7.58 Hz, 2H), 1.94-1.64 (m, 3H), 0.98 (t, J = 7.33 Hz, 3H); 13C{1H} NMR (50 MHz, CDCl3):
δ 157.4, 145.8, 141.2, 129.9, 129.1, 128.9, 128.8, 38.3, 22.8, 13.9 ppm; HRMS (ESI) m/z
calculated for C11H13N2 [M+H]+ 173.1073; found 173.1077.
2-Butylquinoxaline (3d)12a
The title compound was synthesized according to the general procedure described in section
2A. The product was purified using silica gel (230-400 mesh) column chromatography using a
mixture of petroleum ether/EtOAc (Rf = 0.75) as an eluent. Colourless liquid (60 mg, 64%); 1H
NMR (200 MHz, CDCl3): δ 8.67 (s, 1H), 8.16-7.84 (br s, 2H), 7.80-7.50 (br s, 2H), 2.94 (t, J
= 7.58 Hz, 2H), 1.91-1.63 (m, 2H), 1.58-1.23 (m, 2H), 0.90 (t, J = 7.33 Hz, 3H); 13C{1H} NMR
(50 MHz, CDCl3): δ 157.7, 145.8, 142.2, 141.1, 129.8, 129.4, 129.1, 128.8, 36.2, 31.6, 22.5,
13.8 ppm; HRMS (ESI) m/z calculated for C12H15N2 [M+H]+ 187.1230; found 187.1233.
18
ACS Paragon Plus Environment

Page 19 of 39
The Journal of Organic Chemistry
1
2
3
4
2-Hexylquinoxaline (3e)16d
5
6
7
8
The title compound was synthesized according to the general procedure described in section
2A. The product was purified using silica gel (230-400 mesh) column chromatography using a
mixture of petroleum ether/EtOAc (Rf = 0.77) as an eluent. Pale yellow liquid (71 mg, 66%);
1H NMR (200 MHz, CDCl3): δ 8.67 (s, 1H), 8.08-7.89 (m, 2H), 7.75-7.55 (m, 2H), 2.94 (t, J =
7.71 Hz, 2H), 1.89-1.61 (m, 2H), 1.48-1.04 (br. s, 7H), 0.81 (t, J = 6.57 Hz, 3H); 13C{1H} NMR
(50 MHz, CDCl3): δ 157.7, 145.8, 142.2, 141.1, 136.1, 129.8, 129.1, 128.8, 36.5, 31.6, 29.5,
29.1, 22.5, 14.0 ppm; HRMS (ESI) m/z calculated for C14H19N2 [M+H]+ 215.1543; found
215.1548.
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
1,2,3,4-Tetrahydrophenazine (3f)10d
The title compound was synthesized according to the general procedure described in section
2A. The product was purified using silica gel (230-400 mesh) column chromatography using a
1
mixture of petroleum ether/EtOAc (Rf = 0.77) as an eluent. Brown solid (52 mg, 56%); H
NMR (200 MHz, CDCl3): 8.10-7.88 (m, 2H), 7.77-7.59 (m, 2H), 3.27-3.03(m, 4H), 2.05 (quint,
J = 3.16 Hz, 4H); 13C{1H} NMR (50 MHz, CDCl3): δ 154.1, 141.2, 141.2, 128.8, 128.3, 33.2,
22.8 ppm; HRMS (ESI) m/z calculated for C12H13N2 [M+H]+ 185.1073; found 185.1080.
Isolated as a mixture of isomers 7-Methyl-2-phenylquinoxaline (3g) and 6-Methyl-2-
phenylquinoxaline (3g’)16b
The title compound was synthesized according to the general procedure described in section
2A. The product was purified using silica gel (230-400 mesh) column chromatography using a
mixture of petroleum ether/EtOAc (Rf = 0.75) as an eluent. White solid (87 mg, 79%); 1H NMR
(200 MHz, CDCl3): δ 9.28 (d, J = 5.05 Hz, 1H), 8.29-8.13 (m, 2H), 8.11-7.85 (m, 2H), 7.69-
13
7.44 (m, 4H), 2.62 (s, 3H); C{1H} NMR (50 MHz, CDCl3): δ 143.2, 142.4, 140.8, 132.6,
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 39
1
2
3
4
5
6
131.8, 130.0, 129.9, 129.1, 128.6, 128.4, 127.5, 127.4, 21.8 ppm; HRMS (ESI) m/z calculated
for C15H13N2 [M+H]+ 221.1073; found 221.1082.
7
8
9
Isolated as
a
mixture of isomers 2,7-Dimethylquinoxaline (3h) and 2,6-
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
Dimethylquinoxaline (3h’)12a
The title compound was synthesized according to the general procedure described in section
2A. The product was purified using silica gel (230-400 mesh) column chromatography using a
1
mixture of petroleum ether/EtOAc (Rf = 0.75) as an eluent. Yellow solid (44 mg, 56%); H
NMR (200 MHz, CDCl3): δ 8.69 (d, J = 12.97 Hz, 1H), 8.00-7.7 (m, 2H), 7.61-7.49 (m, 1H),
13
2.74 (s, 3H), 2.59 (s, 3H); C{1H} NMR (50 MHz, CDCl3): δ 153.6, 152.7, 145.8, 145.0.6,
140.9, 140.5, 139.2, 132.2, 131.1, 128.6, 128.0, 127.5, 22.5, 22.4, 21.8, 21.6 ppm; HRMS (ESI)
m/z calculated for C10H11N2 [M+H]+ 159.0917; found 159.0917.
Isolated as a mixture of isomers 2-Propyl-7-methylquinoxaline (3i) and 2-Propyl-6-
methylquinoxaline (3i’)
The title compound was synthesized according to the general procedure described in section
2A. The product was purified using silica gel (230-400 mesh) column chromatography using a
mixture of petroleum ether/EtOAc (Rf = 0.74) as an eluent. White solid (52 mg, 57%); 1H NMR
(200 MHz, CDCl3): δ 8.85-8.53 (m, 1H), 8.05-7.70 (m, 2H), 7.66-7.43 (m, 1H), 2.97 (t, J =
7.96 Hz, 2H), 2.58 (s, 3H), 2.01-1.70 (m, 2H), 1.15-0.93 (m, 3H); C{1H} NMR (50 MHz,
13
CDCl3): δ 157.3, 156.4, 145.6, 144.8, 142.2, 141.2, 140.3, 139.6, 139.2, 132.1, 131.0, 128.6,
128.3, 127.9, 127.7, 38.3, 22.8, 21.7, 21.6, 13.8 ppm; HRMS (ESI) m/z calculated for C12H13N2
[M+H]+ 187.1230; found 187.1229.
20
ACS Paragon Plus Environment

Page 21 of 39
The Journal of Organic Chemistry
1
2
3
4
5
6
Isolated as a mixture of isomers 2-Butyl-7-methylquinoxaline (3j) 2-Butyl-6-
methylquinoxaline (3j’)12a
7
8
9
The title compound was synthesized according to the general procedure described in section
2A. The product was purified using silica gel (230-400 mesh) column chromatography using a
mixture of petroleum ether/EtOAc (Rf = 0.75) as an eluent. Pale green liquid (75 mg, 75%); 1H
NMR (200 MHz, CDCl3): δ 8.60 (d, J = 5.05 Hz, 1H), 7.79-7.67 (m, 2H), 7.61-7.39 (m, 1H),
2.91 (t, J = 7.58 Hz, 2H), 2.50 (s, 3H), 1.74 (quint, J = 7.83 Hz, 2H), 1.53-1.25 (m, 2H), 0.89
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
13
(t, J = 7.20 Hz, 3H); C{1H} NMR (50 MHz, CDCl3): δ 157.5, 156.6, 145.6, 144.8, 140.3,
139.2, 132.1, 128.6, 128.2, 127.9, 127.7, 36.1, 31.6, 22.5, 21.7, 21.6, 13.8 ppm; HRMS (ESI)
m/z calculated for C13H17N2 [M+H]+ 201.1386; found 201.1390.
Isolated as a mixture of isomers 2-Hexyl-7-methylquinoxaline (3k) and 2-Hexyl-6-
methylquinoxaline (3k’)
The title compound was synthesized according to the general procedure described in section
2A. The product was purified using silica gel (230-400 mesh) column chromatography using a
mixture of petroleum ether/EtOAc (Rf = 0.76) as an eluent. White solid (69 mg, 60%); 1H NMR
(200 MHz, CDCl3): δ 8.89-8.51 (m, 1H), 8.12-7.74 (m, 2H), 7.67-7.39 (m, 1H), 2.99 (t, J =
7.96 Hz, 2H), 2.58 (s, 3H), 1.98-1.67 (br. s, 2H), 1.57-1.11 (br. s, 6H), 1.09-0.77 (br. s, 3H);
13C{1H} NMR (50 MHz, CDCl3): δ 157.5, 156.6, 145.6, 144.8, 141.2, 140.3, 139.1, 132.0,
131.0, 128.6, 128.3, 127.9, 127.7, 36.4, 36.3, 31.5, 29.5, 29.0, 22.4, 21.7, 21.6, 13.9 ppm;
HRMS (ESI) m/z calculated for C15H21N2 [M+H]+ 229.1699; found 229.1699.
6,7-Dimethyl-2-phenylquinoxaline (3l)16b
The title compound was synthesized according to the general procedure described in section
2A. The product was purified using silica gel (230-400 mesh) column chromatography using a
mixture of petroleum ether/EtOAc (Rf = 0.77) as an eluent. White solid (96 mg, 82%); 1H NMR
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 39
1
2
3
4
5
6
7
8
9
(200 MHz, CDCl3): δ 9.15 (s, 1H), 8.23-8.01 (m, 2H), 7.82 (d, J = 10.48 Hz, 2H), 7.59-7.33
(m, 3H), 2.45 (s, 6H); 13C{1H} NMR (50 MHz, CDCl3): δ 151.0, 142.4, 140.8, 140.5, 137.1,
129.8, 129.0, 128.6, 128.1, 127.3, 20.3 ppm; HRMS (ESI) m/z calculated for C16H15N2 [M+H]+
235.1230; found 235.1234.
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
2-Ethyl-6,7-dimethylquinoxaline (3m)9h
The title compound was synthesized according to the general procedure described in section
2A. The product was purified using silica gel (230-400 mesh) column chromatography using a
1
mixture of petroleum ether/EtOAc (Rf = 0.77) as an eluent. Brown solid (61 mg, 65%); H
NMR (200 MHz, CDCl3): δ 8.58 (s, 1H), 7.72 (d, J = 3.66 Hz, 2H), 2.94 (q, J = 7.58 Hz, 2H),
2.41 (s, 6H), 1.35 (t, J = 7.71 Hz, 3H); 13C{1H} NMR (50 MHz, CDCl3): δ 155.2, 142.3, 138.8,
138.1, 137.9, 137.0, 125.9, 125.7, 27.2, 18.1, 17.9, 11.2 ppm; HRMS (ESI) m/z calculated for
C12H15N2 [M+H]+ 187.1230; found 187.1233.
2-Butyl-6,7-dimethylquinoxaline (3n)16b
The title compound was synthesized according to the general procedure described in section
2A. The product was purified using silica gel (230-400 mesh) column chromatography using a
mixture of petroleum ether/EtOAc (Rf = 0.75) as an eluent. Pale green liquid (77 mg, 72%); 1H
NMR (200 MHz, CDCl3): δ 8.55 (s, 1H), 7.705 (d, J = 3.16 Hz, 2H), 2.89 (t, J = 7.58 Hz, 2H),
2.39 (s, 6H), 1.87-1.61 (m, 2H), 1.49-1.22 (m, 2H), 0.88 (t, J = 7.20 Hz, 3H); 13C{1H} NMR
(50 MHz, CDCl3): δ 156.6, 144.8, 141.1, 140.3, 140.1, 139.1, 128.1, 127.9, 36.1, 31.7, 22.5,
20.1, 13.8 ppm; HRMS (ESI) m/z calculated for C14H19N2 [M+H]+ 215.1543; found 215.1548.
2-Hexyl-6,7-dimethylquinoxaline (3o)
The title compound was synthesized according to the general procedure described in section
2A. The product was purified using silica gel (230-400 mesh) column chromatography using a
mixture of petroleum ether/EtOAc (Rf = 0.75) as an eluent. Pale green liquid (70 mg, 58%); 1H
22
ACS Paragon Plus Environment

Page 23 of 39
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
NMR (200 MHz, CDCl3): δ 8.56 (s, 1H), 7.725 (d, J = 3.28 Hz, 2H), 2.90 (t, J = 7.96 Hz, 2H),
2.41 (s, 6H), 1.86-1.68 (m, 2H), 1.46-1.08 (m, 7H), 0.81 (t, J = 6.82 Hz, 3H); 13C{1H} NMR
(50 MHz, CDCl3): δ 156.7, 144.8, 141.1, 140.3, 140.1, 139.2, 128.1, 127.9, 36.4, 31.6, 29.6,
29.1, 22.5, 20.3, 20.2, 14.0 ppm; HRMS (ESI) m/z calculated for C16H23N2 [M+H]+ 243.1856;
found 243.1861.
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
7,8-Dimethyl-1,2,3,4-tetrahydrophenazine (3p)16c
The title compound was synthesized according to the general procedure described in section
2A. The product was purified using silica gel (230-400 mesh) column chromatography using a
mixture of petroleum ether/EtOAc (Rf = 0.78) as an eluent. Colorless liquid (53 mg, 50%); 1H
NMR (200 MHz, CDCl3): δ 7.18 (d, J = 3.25 Hz, 2H), 2.22 (s, 4H), 2.11 (s, 4H), 1.55 (s, 5H);
13C{1H} NMR (50 MHz, CDCl3): δ 155.2, 142.3, 138.8, 137.9, 137.0, 125.9, 125.7, 27.3, 18.1,
11.3 ppm; HRMS (ESI) m/z calculated for C14H17N2 [M+H]+ 213.1383; found 213.1386.
Quinoxaline (3q)12a
The title compound was synthesized according to the general procedure described in section
2A. The product was purified using silica gel (230-400 mesh) column chromatography using a
mixture of petroleum ether/EtOAc (Rf = 0.70) as an eluent. Black solid (26 mg, 40%); 1H NMR
(400 MHz, CDCl3): δ 8.83 (s, 2H), 8.22-7.99 (m, 2H), 7.85-7.56 (m, 2H); 13C{1H} NMR (101
MHz, CDCl3): δ 144.7, 142.7, 129.8, 129.2 ppm; HRMS (ESI) m/z calculated for C8H7N2
[M+H]+ 131.0604; found 131.0605.
2-Methylquinoxaline (3r)16b
The title compound was synthesized according to the general procedure described in section
2A. The product was purified using silica gel (230-400 mesh) column chromatography using a
mixture of petroleum ether/EtOAc (Rf = 0.73) as an eluent. Orange-red liquid (47 mg, 65%);
1H NMR (400 MHz, CDCl3): δ 8.73 (s, 1H), 8.12-7.97 (m, 2H), 7.70 (ddd, J = 9.9, 8.0, 1.6 Hz,
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 39
1
2
3
4
2H), 2.76 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ 153.6, 145.8, 141.9, 140.8, 129.8,
5
6
129.0, 128.7, 128.5, 22.4 ppm.
7
8
9
2,3-Dimethylquinoxaline (3s)16b
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
The title compound was synthesized according to the general procedure described in section
2A. The product was purified using silica gel (230-400 mesh) column chromatography using a
mixture of petroleum ether/EtOAc (Rf = 0.73) as an eluent. White solid (34 mg, 43%); 1H NMR
13
(400 MHz, CDCl3): δ = 7.95-7.93 (m, 2H), 7.63-7.61 (m, 2H), 2.68 (s, 6H); C{1H} NMR
(101 MHz, CDCl3): δ 153.3, 140.9, 128.7, 128.2, 23.0 ppm; HRMS (ESI) m/z calculated for
C10H11N2 [M+H]+ 159.0917; found 159.0916.
6-nitro-2,3-diphenylquinoxaline (3t)12c
The title compound was synthesized according to the general procedure described in section
2A. The product was purified using silica gel (230-400 mesh) column chromatography using a
1
mixture of petroleum ether/EtOAc (Rf = 0.66) as an eluent. Yellow solid (101 mg, 62%). H
NMR (600 MHz, CDCl3) δ 9.10 (d, J = 2.28 Hz, 1H), 8.55 - 8.53 (m, 1H), 8.31(d, J = 9.12 Hz,
13
1H), 7.60 - 7.57 (m, 4H), 7.46 - 7.44 (m, 2H), 7.41 - 7.38 (m, 4H) ppm. C{1H} NMR (151
MHz, CDCl3) δ 156.26, 155.63, 147.77, 143.51, 139.89, 137.99, 137.93, 130.70, 129.84,
129.76, 129.74, 129.60, 128.42, 125.56, 123.25.
6-bromo-2,3-diphenylquinoxaline (3u)12c
The title compound was synthesized according to the general procedure described in section
2A. The product was purified using silica gel (230-400 mesh) column chromatography using a
1
mixture of petroleum ether/EtOAc (Rf = 0.61) as an eluent. White solid (131 mg, 73%). H
NMR (600 MHz, CDCl3) δ 8.38 (d, J = 2.21 Hz, 1H), 8.05 (d, J = 8.88 Hz, 1H), 7.86 - 7.84
13
(m, 1H), 7.54 - 7.53 (m, 4H), 7.41 - 7.39 (m, 2H), 7.37 - 7.35 (m, 4H) ppm. C{1H} NMR
24
ACS Paragon Plus Environment

Page 25 of 39
The Journal of Organic Chemistry
1
2
3
4
(151 MHz, CDCl3) δ 154.14, 153.66, 141.66, 139.85, 138.61, 138.51, 133.42, 131.37, 130.42,
5
6
129.77, 129.70, 129.06, 128.99, 128.27, 128.25, 123.76.
7
8
9
6,7-dichloro-2,3-diphenylquinoxaline (3v)12c
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
The title compound was synthesized according to the general procedure described in section
2A. The product was purified using silica gel (230-400 mesh) column chromatography using a
1
mixture of petroleum ether/EtOAc (Rf = 0.65) as an eluent. Brown solid (135 mg, 77%). H
NMR (600 MHz, CDCl3) δ 8.31 (s, 2H), 7.53 - 7.52 (m, 4H), 7.43 - 7.40 (m, 2H), 7.38 - 7.36
13
(m, 4H) ppm. C{1H} NMR (151 MHz, CDCl3) δ 154.44, 139.89, 138.32, 134.38, 129.75,
129.74, 129.26, 128.33.
2,3-bis(2-chlorophenyl)quinoxaline (3w)12c
The title compound was synthesized according to the general procedure described in section
2A. The product was purified using silica gel (230-400 mesh) column chromatography using a
mixture of petroleum ether/EtOAc (Rf = 0.60) as an eluent. Brown solid (140 mg, 80%). 1H
NMR (600 MHz, CDCl3) δ 8.27 - 8.25 (m, 2H), 7.88 - 7.86 (m, 2H), 7.40 (s, 2H), 7.34 - 7.33
(m, 2H), 7.29 (s, 2H), 7.28 - 7.24 (m, 2H) ppm. 13C{1H} NMR (151 MHz, CDCl3) δ 152.57,
141.13, 137.11, 132.87, 131.14, 130.53, 130.07, 129.47, 129.31, 126.34.
2-Phenylquinazoline (6a)16b
The title compound was synthesized according to the general procedure described in section
2B. The product was purified using silica gel (230-400 mesh) column chromatography using a
mixture of petroleum ether/EtOAc (Rf = 0.75) as an eluent. White solid (84 mg, 81%); 1H NMR
(200 MHz, CDCl3): δ 9.48 (s, 1H), 8.74-8.54 (m, 2H), 8.28-8.08 (m, 1H), 8.08 -7.81 (m, 2H),
7.69-7.59-(m, 1H), 7.58 -7.47 (m, 3H); 13C{1H} NMR (50 MHz, CDCl3): δ 161.1, 160.6, 150.8,
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 39
1
2
3
4
5
6
138.1, 134.2, 130.7, 128.7, 128.6, 127.3, 127.2, 123.7 ppm; HRMS (ESI) m/z calculated for
C14H11N2 [M+H]+ 207.0917; found 207.0922.
7
8
9
2-(2-Bromophenyl)quinazoline (6b)17i
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
The title compound was synthesized according to the general procedure described in section
2B. The product was purified using silica gel (230-400 mesh) column chromatography using a
mixture of petroleum ether/EtOAc (Rf = 0.76) as an eluent. White solid (86 mg, 60%); 1H NMR
(200 MHz, CDCl3): δ 9.46 (s, 1H), 8.65-8.57 (m, 2H), 8.09 (d, J = 8.7 Hz, 1H), 7.96-7.85 (m,
2H), 7.65-7.46 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ 161.0, 160.4, 150.7, 137.9, 134.1,
130.5, 128.6, 128.5, 127.2, 127.1, 123.5 ppm; HRMS (ESI) m/z calculated for C14H9N2Br [M]
283.9944; found 284.1448.
2-(m-Tolyl)quinazoline (6c)17b
The title compound was synthesized according to the general procedure described in section
2B. The product was purified using silica gel (230-400 mesh) column chromatography using a
mixture of petroleum ether/EtOAc (Rf = 0.75) as an eluent. Pale green liquid (73 mg, 66%); 1H
NMR (200 MHz, CDCl3): δ 9.50-9.36 (m, 1H), 8.45-8.28 (m, 2H), 8.15-8.00 (m, 1H), 7.97-
13
7.77 (m, 2H), 7.65-7.49 (m, 1H), 7.46-7.21 (m, 2H), 2.42 (s, 3H); C{1H} NMR (50 MHz,
CDCl3): δ 161.2, 160.4, 150.7, 138.3, 137.9, 134.1, 131.4, 129.1, 128.6, 127.2, 127.1, 125.8,
123.6, 21.5 ppm; HRMS (ESI) m/z calculated for C15H13N2 [M+H]+ 221.1073; found
221.1079.
2-(4-Chlorophenyl)quinazoline (6d)17a
The title compound was synthesized according to the general procedure described in section
2B. The product was purified using silica gel (230-400 mesh) column chromatography using a
mixture of petroleum ether/EtOAc (Rf = 0.74) as an eluent. White solid (83 mg, 69%); 1H NMR
(200 MHz, CDCl3): δ 9.41 (s, 1H), 8.57 (d, J = 8.3 Hz, 2H), 8.06 (d, J = 8.7 Hz, 1H), 7.96-7.83
26
ACS Paragon Plus Environment

Page 27 of 39
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(m, 2H), 7.60 (t, J = 7.6 Hz, 1H), 7.50 (d, J = 8.3 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3):
δ 160.3, 159.8, 150.5, 136.7, 136.4, 134.1, 129.8, 128.7, 128.4, 127.3, 127.0, 123.4 ppm;
HRMS (ESI) m/z calculated for C14H10N2Cl [M+H]+ 241.0527; found 241.0528.
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
2-(4-Bromophenyl)quinazoline (6e)17b
The title compound was synthesized according to the general procedure described in section
2B. The product was purified using silica gel (230-400 mesh) column chromatography using a
1
mixture of petroleum ether/EtOAc (Rf = 0.76) as an eluent. White solid (108 mg, 76%); H
NMR (200 MHz, CDCl3): δ 9.44 (s, 1H), 8.53-8.45 (m, 2H), 8.06 (d, J = 7.8 Hz, 1H), 7.98-
13
7.58 (m, 2H), 7.70-7.58 (m, 3H); C{1H} NMR (100 MHz, CDCl3): δ 160.5, 160.0, 150.6,
136.9, 134.2, 131.7, 130.1, 128.5,127.5, 127.1, 125.3, 123.6 ppm; HRMS (ESI) m/z calculated
for C14H9N2Br [M]+ 285.0022; found 285.0015.
2-(4-Iodophenyl)quinazoline (6f)17b
The title compound was synthesized according to the general procedure described in section
2B. The product was purified using silica gel (230-400 mesh) column chromatography using a
1
mixture of petroleum ether/EtOAc (Rf = 0.77) as an eluent. White solid (120 mg, 72%); H
NMR (200 MHz, CDCl3): δ 9.44 (s, 1H), 8.35 (d, J = 8.2 Hz, 1H), 8.06 (d, J = 8.7 Hz, 1H),
7.97-7.81 (m, 4H), 7.67-7.47 (m, 2H); 13C{1H} NMR (50 MHz, CDCl3): δ 160.2, 159.9, 150.3,
137.4, 137.2, 133.9, 130.2, 129.9, 128.3, 128.2, 127.2, 126.8, 123.3, 97.4 ppm; HRMS (ESI)
m/z calculated for C14H10N2I [M+H]+ 332.9883; found 332.9870.
2-(4-Methoxyphenyl)quinazoline (6g)17a
The title compound was synthesized according to the general procedure described in section
2B. The product was purified using silica gel (230-400 mesh) column chromatography using a
1
mixture of petroleum ether/EtOAc (Rf = 0.63) as an eluent. Brown liquid (83 mg, 70%); H
NMR (200 MHz, CDCl3): δ 9.46-9.25 (m, 1H), 8.60-8.41 (m, 2H), 7.97 (dd, J = 0.8, 8.4 Hz,
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 39
1
2
3
4
5
6
7
8
9
1H), 7.88-7.72 (m, 2H), 7.59-7.40 (m, 1H), 7.04-6.90 (m, 2H), 3.83 (s, 3H); 13C{1H} NMR (50
MHz, CDCl3): δ 161.8, 160.8, 160.4, 150.8, 134.0, 130.7, 130.2, 128.4, 127.1, 126.8, 123.3,
114.0, 55.4 ppm; HRMS (ESI) m/z calculated for C15H13ON2 [M+H]+ 237.1022; found
237.1027.
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
2-(Pyridin-4-yl)quinazoline (6h)17b
The title compound was synthesized according to the general procedure described in section
2B. The product was purified using silica gel (230-400 mesh) column chromatography using a
mixture of petroleum ether/EtOAc (Rf = 0.55) as an eluent. White solid (68 mg, 66%); 1H NMR
(200 MHz, CDCl3): δ 9.35 (s, 1H), 8.31-8.08 (m, 4H), 7.86-7.73 (m, 2H), 7.67-7.49 (m, 3H);
13C{1H} NMR (50 MHz, CDCl3): δ 151.7, 143.3, 142.2, 141.5, 136.7, 130.2, 130.1, 129.5,
129.4, 129.1, 127.5 ppm; HRMS (ESI) m/z calculated for C13H10N3 [M+H]+ 208.0869; found
208.0869.
2-(tert-butyl)quinazoline (6i)17b
The title compound was synthesized according to the general procedure described in section
2B. The product was purified using silica gel (230-400 mesh) column chromatography using a
1
mixture of petroleum ether/EtOAc (Rf = 0.85) as an eluent. Green liquid (60 mg, 64%); H
NMR (200 MHz, CDCl3): δ 9.30 (s, 1H), 8.05-7.71 (m, 3H), 7.63-7.40 (m, 1H), 1.45 (s, 9H);
13C{1H} NMR (50 MHz, CDCl3): δ 159.9, 133.5, 128.3, 126.8, 126.7, 122.8, 39.5, 29.6 ppm;
HRMS (ESI) m/z calculated for C12H15N2 [M+H]+ 187.1230; found 187.1233.
2-cyclohexylquinazoline (6j)17h
The title compound was synthesized according to the general procedure described in section
2B. The product was purified using silica gel (230-400 mesh) column chromatography using a
mixture of petroleum ether/EtOAc (Rf = 0.79) as an eluent. White solid (72 mg, 68%); 1H NMR
(200 MHz, CDCl3): δ 9.37 (s, 1H), 8.00 (d, J = 8.5 Hz, 1H), 7.89 (t, J = 7.9 Hz, 2H), 7.60 (t, J
= 7.3 Hz, 1H), 3.26-2.97 (m, 1H), 2.11 (d, J = 12.82 Hz, 2H), 1.92 (d, J = 12.82 Hz, 2H), 1.87-
28
ACS Paragon Plus Environment

Page 29 of 39
The Journal of Organic Chemistry
1
2
3
4
13
1.73 (m, 3H), 1.58-1.31 (m, 4H); C{1H} NMR (50 MHz, CDCl3): δ 170.9, 160.3, 150.4,
5
6
7
8
133.8, 128.0, 127.0, 126.8, 123.2, 47.9, 31.9, 26.3, 26.0 ppm; HRMS (ESI) m/z calculated for
C14H18N2 [M+H]+ 213.1386; found 213.1386.
9
2-Pentylquinazoline (6k)17g
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
The title compound was synthesized according to the general procedure described in section
2B. The product was purified using silica gel (230-400 mesh) column chromatography using a
1
mixture of petroleum ether/EtOAc (Rf = 0.76) as an eluent. Yellow solid (58 mg, 58%); H
NMR (400 MHz, CDCl3): δ 9.35 (s, 1H), 7.95-8.06 (m, 1H), 7.81-7.94 (m, 2H), 7.59 (td, J =
7.5, 1.0 Hz, 1H), 3.05-3.20 (m, 2H), 1.84-2.00 (m, 3H), 1.31-1.49 (m, 4H), 0.84-0.98 (m, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 167.9, 160.4, 150.4, 134.0, 127.9, 127.1, 126.9, 123.1,
40.0, 31.8, 28.8, 22.6, 14.1 ppm; HRMS (ESI) m/z calculated for C13H17N2 [M+H]+ 201.1386;
found 201.1382.
2-Isopropylquinazoline (6l)17f
The title compound was synthesized according to the general procedure described in section
2B. The product was purified using silica gel (230-400 mesh) column chromatography using a
mixture of petroleum ether/EtOAc (Rf = 0.76) as an eluent. Colourless liquid (53 mg, 61%); 1H
NMR (400 MHz, CDCl3): δ 9.37 (s, 1H), 7.99 (dd, J = 8.3, 0.7 Hz, 1H), 7.82-7.94 (m, 2H),
7.59 (td, J = 7.5, 1.0 Hz, 1H), 3.39 (quin, J = 6.9 Hz, 1H), 1.45 (d, J = 6.9 Hz, 6H); 13C{1H}
NMR (101 MHz, CDCl3): δ 171.7, 160.5, 150.3, 133.8, 128.0, 127.0, 126.8, 123.2, 38.0, 21.8
ppm; HRMS (ESI) m/z calculated for C11H13N2 [M+H]+ 173.1073; found 173.1068.
■ ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at
DOI:
29
ACS Paragon Plus Environment