Synthesis of 5,6-dihydrodibenzo[b,h][1,6]naphthyridines via copper bromide catalyzed intramolecular [4 + 2] hetero-Diels-Alder reactions

Article abstract of DOI:10.1021/acs.joc.5b02669

A highly efficient synthesis of 5,6-dihydrodibenzo[b,h][1,6]naphthyridines was achieved by reaction between 2-(N-propargylamino)benzaldehydes and arylamines in the presence of CuBr₂. The in situ generated electron-deficient heterodienes bearing a tethered alkyne partner underwent an intramolecular inverse electron-demand hetero-Diels-Alder reaction followed by air oxidation to furnish the products in high yields. This reaction tolerated a large number of substituents to afford diverse products under mild conditions. This strategy was also successfully extended to the synthesis of 12,13-dihydro-6H-benzo[h]chromeno[3,4-b][1,6]naphthyridin-6-ones starting from 3-amino-2H-chromen-2-one, again in high yields.

Full text of DOI:10.1021/acs.joc.5b02669

Subscriber access provided by ORTA DOGU TEKNIK UNIVERSITESI KUTUPHANESI
Article
Synthesis of 5,6-Dihydrodibenzo[b,h][1,6]naphthyridines via Copper
Bromide-Catalyzed Intramolecular [4+2] Hetero-Diels-Alder Reactions
Isravel Muthukrishnan, Perumal Vinoth, Thavaraj Vivekanand, Subbiah
Nagarajan, C. Uma Maheswari, J. Carlos Menéndez, and Vellaisamy Sridharan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02669 • Publication Date (Web): 22 Dec 2015
Downloaded from http://pubs.acs.org on December 24, 2015
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 27
The Journal of Organic Chemistry
1
2
3
4
Synthesis of 5,6-Dihydrodibenzo[b,h][1,6]naphthyridines via Copper Bromide-Catalyzed
5
6
Intramolecular [4+2] Hetero-Diels-Alder Reactions†
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
Isravel Muthukrishnan,a Perumal Vinoth,a Thavaraj Vivekanand,a Subbiah Nagarajan,a C. Uma
Maheswari,a J. Carlos Menéndezb and Vellaisamy Sridharan*a
aOrganic Synthesis Group, Department of Chemistry, School of Chemical and Biotechnology, SASTRA University,
Thanjavur 613401, Tamil Nadu, India. E-mail: vsridharan@scbt.sastra.edu, vesridharan@gmail.com
bDepartamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, 28040
Madrid, Spain.
† Dedicated to Professor Shanmugam Muthusubramanian on the occasion of his retirement
GRAPHICAL ABSTRACT
R2
R3
Ts
N
Ts
N
R2
CuBr2
N
R2
R1
R1
Ts
24 examples
(up to 89%)
N
[4 + 2]
(10 mol%)
CHO
NH2
+
N
Toluene
Ts
R1
N
O
N
O
2 examples
(up to 79%)
R1
ABSTRACT
A highly efficient synthesis of 5,6-dihydrodibenzo[b,h][1,6]naphthyridines was achieved by the
reaction between 2-(N-propargylamino)benzaldehydes and arylamines in the presence of CuBr2.
The in situ generated electron-deficient heterodienes bearing a tethered alkyne partner underwent
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 27
1
2
3
4
5
6
7
8
9
intramolecular inverse electron-demand hetero Diels-Alder reaction (IEDDA) followed by air
oxidation to furnish the products in high yields. This reaction tolerated a large number of
substituents to afford diverse products under mild conditions. This strategy was also successfully
extended to the synthesis of 12,13-dihydro-6H-benzo[h]chromeno[3,4-b][1,6]naphthyridin-6-
ones starting from 3-amino-2H-chromen-2-one, again in high yields.
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
INTRODUCTION
The inverse electron-demand hetero Diels-Alder reaction (IEDDA) between electron-deficient
heterodienes (benzylidene anilines) and electron-rich dienophiles, generally known as the
Povarov reaction, is a versatile transformation to access tetrahydroquinoline derivatives.1,2 These
reactions are normally catalyzed by metal Lewis acids by coordinating with the 1,3-heterodiene
nitrogen to further increase its electron-deficiency and thus minimize the LUMO energy of the
heterodiene to trigger the cycloaddition.3 During the past two decades, a large number of chiral
catalysts were also developed to obtain chiral tetrahydroquinolines, including natural products.4
This powerful reaction was further extended to obtain polyheterocyclic compounds by means of
intramolecular versions starting from heterodienes bearing a tethered alkene partner.5 Although
the majority of this kind of IEDDA reactions involved the use of olefins as the dienophiles and
thus afforded tetrahydroquinolines, a considerable effort has been devoted to the direct synthesis
of quinolines by using alkynes as dienophiles.6 The [4+2] cycloaddition between in situ
generated benzylidene anilines and alkynes for the direct access to quinolines can be catalyzed
by a number of acidic catalysts including triflic acid, SnCl2, Fe(OTf)3, Ga(OTf)3, Sc(OTf)3,
Cu(OTf)2, molecular iodine, HClO4-modified montmorillonite, K-10 under microwave
irradiation, potassium dodecatungstocobaltate trihydrate and CuI/La(OTf)3 in ionic liquid,
2
ACS Paragon Plus Environment

Page 3 of 27
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
among others (Scheme 1a). Likewise, intramolecular [4+2] Povarov-type cycloaddition with
tethered alkyne dienophiles have also been explored to access polycyclic heterocyclic
compounds, normally restricted to the easily accessible salicylaldehyde-derived aryl aldehydes.7
[1,6]-Naphthyridines and their benz-fused analogs dibenzo[b,h][1,6]naphthyridines are
biologically significant molecules and exhibit numerous pharmacological activities. Thus,
members of this class of polycyclic compounds act as potential inhibitors of telomere
maintenance,8 topoisomerase I9 and FGF receptor-1 tyrosine kinase.10 Besides, 8-substituted-
[1,6]naphthyridines exhibit HIV-1 integrase inhibitory activity and cytotoxicity against cancer
cells.11 Furthermore, dibenzo[b,h][1,6]naphthyridines are known for their florescence properties;
for instance, the 2-acetylaminobenzaldehyde-derived dibenzo[b,h][1,6]naphthyridines have
found application in fluorescent DNA labelling.12 Despite the significance of
dibenzo[b,h][1,6]naphthyridines in biology, only a limited number of reports deal with the direct
synthesis of these compounds. The main methodologies developed with this purpose include the
silica-gel catalyzed, three-component reaction between 2-hydroxyacetophenone, aryl aldehydes
and malononitrile,13 the neat reaction between 4-chloro-2-methylquinoline and aminoketones14
and a few others.15 Recently, Wang and co-workers reported the synthesis of
dibenzo[b,h][1,6]naphthyridines involving the Sc(OTf)3-catalyzed cascade reaction between o-
aminoacetophenone with methanamine in moderate to good yields (Scheme 1b).16 A one-pot
synthesis of these compounds starting from 2-acetylaminobenzaldehydes was also reported
(Scheme 1c).12 Notwithstanding these few reports, no efficient, general methods are available to
access these significant compounds.
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 27
1
2
3
4
5
6
7
8
9
In view of the unique biological and fluorescence properties of dibenzo[b,h][1,6]naphthyridines
and the scarcity available procedures, development of simple and efficient protocols for their
synthesis from readily available starting materials is highly desirable. In this context, we
envisaged an intramolecular [4+2] cycloaddition between the in situ generated benzylidene
anilines derived from 2-aminoarylaldehydes bearing a tethered alkyne partner and arylamines to
afford the title compounds (Scheme 1d). The proposed route involves initial cycloaddition
followed by spontaneous dehydrogenation. To the best of our knowledge, the envisioned
intramolecular Povarov-type [4+2] cycloaddition-oxidation strategy has not been reported for the
synthesis of dibenzo[b,h][1,6]naphthyridines. Furthermore, owing to the lack of access to 2-(N-
propargylamino)benzaldehydes, the synthetic utility of these compounds has not been well
explored.17
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
4
ACS Paragon Plus Environment

Page 5 of 27
The Journal of Organic Chemistry
1
2
3
(a) [4 + 2] Cycloaddition of benzylidene anilines and alkynes
4
5
6
7
R3
R3
N
R3
1. [4+2]
2. [O]
R1
Ref. 6
R1
+
R1
R2
N
R2
R2
8
NH2
OHC
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
(b) Wang and co-workers (Ref. 16 )
R2 CH3
R1
O
HN
Sc(OTf)3
CH3
R1
R2CH2NH2
2
+
N
NH2
R1
(c) Okuma and co-workers (Ref. 12)
R
O
N
CHO
NaOH
+
2
H3C
R
N
NHAc
(d) This work: Synthesis of 5,6-dihydrodibenzo[b,h][1,6]naphthyridines via intramolecular [4+2] cycloaddition
Ts
N
R2
R2
R2
N
R1
R3
R3
Ts
Ts
N
N
CuBr2
CHO
[4+2]
+
N
NH2
R3
R1
R1
Scheme 1. One-pot access to quinolines and dibenzo[b,h][1,6]naphthyridines
RESULTS AND DISCUSSION
To explore the possibility of our planned synthesis, our initial efforts were directed to the
identification of a suitable catalytic system and reaction conditions. The required precursor 2-(N-
tosyl-N-propargylamino)benzaldehyde 1a was synthesized in a few straightforward steps starting
from 2-aminobenzyl alcohol. With a properly tethered alkyne dienophile partner, we studied the
intramolecular [4+2] cycloaddition, combining 1a with p-anisidine 2a in the presence of a
variety of catalysts under diverse reaction conditions (Table 1). At the outset, we investigated the
role of Lewis acids including CAN, InCl3, BiCl3 and Sc(OTf)3 to trigger the cycloaddition in
o
acetonitrile at 25 C. Use of 10 mol % of these catalysts did not afford the product 3a; instead,
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 27
1
2
3
4
formation of the intermediate imine A was observed from the crude 1H-NMR spectra in all cases.
5
6
o
To our delight, elevation of temperature to 80 C triggered the [4+2] cycloaddition-oxidation
7
8
9
sequence furnishing the product dibenzo[b,h][1,6]naphthyridine 3a in moderate yields (entries 1
to 8). However, in all the tested Lewis acids, the reactions were fairly slow and, even after 24 h,
some unreacted intermediate imine was observed. InCl3 and Sc(OTf)3 were superior, yielding
75% and 67% of the product, respectively (entries 4 and 8). On the other hand, change of
solvents did not significantly improve the yield (entries 9 to 12). Encouraged by these
preliminary results, we subsequently moved to copper salts as catalysts. Gratifyingly, switching
the catalyst to CuCl (10 mol%) increased the rate of the reaction remarkably affording 80% of
the product in just one-hour reaction time at 25 oC. Indeed, 5 mol% of the catalyst was sufficient
to allow complete conversion and to yield 81% of the product in toluene (entries 13 and 14). In
order to improve the isolated yield and to avoid the byproducts of decomposition, we carried out
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
the reaction at 5 C, but only imine formation was noticed with traces of the product 3a (entry
15). A subsequent solvent screening revealed that acetonitrile, dioxane, DCM, DCE, ethanol and
THF were inefficient to improve the yield (entries 16-23). Among the other tested cuprous
halides, CuI failed to afford the product and CuBr yielded 56% of 3a in 1h (entries 24 and 25).
On the other hand, the last copper halide to be tested CuBr2 (10 mol%) was the most efficient one
in terms of yield providing 88% of the isolated product. Although the reaction time was 20
hours, the reaction was clean and no side products or decomposition was observed (entry 26).
The reaction time was reduced to 12 hours with 30 mol% of the catalyst, and Cu(OAc)2 was
inefficient (entries 27 and 28). The reaction was also carried out in the presence 10 mol% of
CuCl2 and a comparable yield with CuCl was obtained albeit in longer reaction time (entry 29).
6
ACS Paragon Plus Environment

Page 7 of 27
The Journal of Organic Chemistry
1
2
3
4
5
6
Finally, we settled on CuBr2 (10 mol%) as the catalyst and toluene as the solvent for subsequent
studies due to the high yield and neatness of the reaction.
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
Table 1. Optimization of reaction conditionsa
Ts
N
Ts
Ts
OMe
Catalyst
Solvent
N
CHO
N
1a
+
N
N
Reaction
Conditions
OMe
OMe
3a
A
H2N
2a
Entry Catalyst
mol% Solvent
Temp.
(oC)
25
80
25
80
25
80
25
80
80
80
80
80
25
25
5
25
25
25
25
25
25
25
25
25
25
25
25
25
25
Reaction Yield of
time (h)
24
24
24
24
24
24
24
24
24
24
24
24
1
3a (%)b
c
1
CAN
10
10
10
10
10
10
10
10
10
10
10
10
10
5
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
Toluene
DCE
-
2
CAN
58d
c
3
InCl3
-
4
InCl3
75d
c
5
6
7
8
BiCl3
BiCl3
Sc(OTf)3
Sc(OTf)3
InCl3
-
61d
c
-
67d
70d
61d
71d
65d
80
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26f
27
28
29
InCl3
Sc(OTf)3
Sc(OTf)3
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuI
CuBr
CuBr2
CuBr2
Cu(OAc)2
CuCl2
Toluene
DCE
Toluene
Toluene
Toluene
MeCN
MeCN
Dioxane
Dioxane
EtOH
1
6
81
5
5
traced
traced
65
24
6
24
1
24
1
20
5
20
20
5
23d
52
c
-
DCM
63
5
DCE
1
68
5
THF
24
24
1
20
12
12
8
traced
c
10
10
10
30
10
10
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
-
56e
88
89
22e
82
aAll reactions were carried out with 1a (0.5 mmol) and 2a (0.5 mmol) with catalyst in 3 mL toluene. b Isolated yield.
cOnly imine A formation was observed. d Unreacted imine A was noticed in the crude H NMR spectra. e No imine
1
or unreacted aldehyde was present. f Optimized reaction conditions.
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 27
1
2
3
4
5
6
7
8
9
Next we turned our attention to study the scope and limitations of the methodology and the
results are summarized in Table 2. The starting 2-(N-tosyl-N-propargylamino)benzaldehydes 1a-
e were synthesized from the corresponding 2-aminobenzyl alcohols using the literature
procedure.18 With the necessary starting materials in hand, our initial studies focused on the
utilization of diverse arylamines 2 combining with aldehyde 1a for the cycloaddition-oxidation
sequence to obtain the corresponding dibenzo[b,h][1,6]naphthyridines 3. As shown in entries 1
to 10 in Table 2, the reaction tolerated well a variety of substituents including methyl, methoxy,
chloro, bromo, dimethyl (2,4- and 3,5-) and dichloro (2,4-) groups. Irrespectively of the
electronic nature of the substituents, the reactions were completed between 16 to 24 hours and an
average of 80% yield was obtained. The nature of the substituents helps in the formation of
intermediate imine A (with or without catalyst) and once the imine is formed, the Lewis acids
triggered the intramolecular [4+2] reaction, where the substituents played no significant role. In
order to further test the functional group tolerance, we employed o-aminophenol as the substrate.
Interestingly, the reaction proceeded well to yield 75% of product 3j with no traces of a
benzoxazole-type side product (entry 10). Compound 3j is an important molecule that contains
the biologically significant 8-hydroxyquinoline scaffold.19
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
Additionally, treatment of bromoaldehyde 1b with a set of arylamines bearing methyl, methoxy
and chloro-substituents furnished the respective dibenzo[b,h][1,6]naphthyridines 3k-3n in high
yields (entries 11 to 14). In all cases, the maximum reaction time was 20 h and the highest yield
of 85% was obtained in the case of the 4-methoxy substituted compound 3n. In order to increase
the structural diversity accessible by this methodology, we investigated the reactivity of the
terminal phenyl-substituted alkyne derivatives 1d and 1e. In contrast to terminal alkynes, these
8
ACS Paragon Plus Environment

Page 9 of 27
The Journal of Organic Chemistry
1
2
3
4
substrates were reluctant to undergo the intramolecular cycloaddition under the optimized
5
6
o
conditions. Only traces of the product formation were observed at 25 C together with the
7
8
9
o
intermediate imines A. Nonetheless, increase of the reaction temperature to 70 C triggered 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
reaction to afford the desired products, again in good yields (entries 15 to 18). The fluoro-
substituted derivative was also synthesized with comparable yield (entry 18). The electron rich
dimethoxy-substituted aldehyde 1c was also reacted with arylamines under optimized conditions
yielding 79-82% of the products (entries 19 and 20). Finally, 1-naphthylamine was tested to
obtain the pentacyclic derivatives 3u and 3v. Although these reactions afforded the products
under ambient temperature, the reactions were very slow and complete conversion was achieved
only at 70 oC, affording 73-86% of isolated products.
Table 2. Scope and limitations of the methodology: Synthesis of dibenzo[b,h][1,6]naphthyridines 3a
R2
R2
Ts
N
R2
CuBr2
(10 mol%)
R3
R3
Ts
Ts
H2N
N
N
[4+2]
R1
+
R3
Toluene, 25 oC
(73-89%)
N
N
CHO
1
2
R1
R1
A
3a-v
Entry
Product 3
Reaction Yield Entry
time (h)
(%)b
Product 3
Reaction Yield
time (h)
(%)b
R4
Ts
R3
R2
N
Ts
R3
N
N
R1
N
3a-j
R2
R1
3o-r
1
3a: R1 = R2 = H, R3 = OMe, R4
20
88
15
3o: R1 = H, R2 = R3 = Me
24c
24c
78
= H
2
3
3b: R1 = R2 = R3 = R4 = H
3c: R1 = R2 = H, R3 = Me, R4 =
H
20
16
83
76
16
17
3p: R1 = Br, R2 = R3 = Me
83
82
3q: R1 = Br, R2 = OMe, R3 = 20c
H
4
5
6
3d: R1 = Me, R2 = H, R3 = Me,
R4 = H
16
82
74
79
18
3r: R1 = Br, R2 = H, R3 = F
24c
89
3e: R1 = H, R2 = Me, R3 = H, R4 16
= Me
Ts
R2
N
3f: R1 = OMe, R2 = R3 = R4 = H 24
N
R1
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 27
1
2
3
4
5
6
7
8
9
7
8
3g: R1 = R2 = H, R3 = Cl, R4 =
20
77
80
H
3h: R1 = Cl, R2 = H, R3 = Cl, R4 20
= H
9
10
3i: R1 = R2 = H, R3 = Br, R4 = H 20
78
75
19
20
3s: R1 = H, R2 = F
3t: R1 = Et, R2 = H
Ts
N
12
16
82
79
3j: R1 = OH, R2 = R3 = R4 = H
24
Ts
R2
N
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
N
R1
R1
R1
Br
3k-n
3k: R1 = R2 = H
3l: R1 = R2 = Me
3u-v
11
12
13
14
20
16
20
20
82
84
80
85
21
22
3u: R1 = H
20c
16c
86
73
3v: R1 = OMe
3m: R1 = H, R2 = Cl
3n: R1 = H, R2 = OMe
Ts
N
Ph
Ts
N
Ts
N
Ts
N
Ph
Ts
N
H3CO
H3CO
CHO
Br
CHO
CHO
Br
CHO
CHO
1d
1b
1c
1e
1a
a Reaction conditions: unless otherwise noted, all reactions were carried out with 1 (0.5 mmol) and 2 (0.5 mmol) in
the presence of CuBr2 (10 mol%) in 3 mL toluene at 25 C. Isolated yield. The reactions were carried out at 70
oC.
o
b
c
In addition to simple arylamines, the reactivity of p-phenylenediamine with aldehyde 1a was also
investigated (Scheme 2). Initially, we employed the optimized conditions with a 1:0.5 ratio of the
aldehyde and diamine in toluene. Unexpectedly, no product formation was observed even after
24 h and only traces of the intermediate imine was noticed. However, increase of the reaction
temperature afforded 51% of the heptacyclic compound 4. Further efforts to improve the yield of
the product by changing the mole ratio of the reactants and the use of CuCl as catalyst were
unsuccessful.
Ts
N
2
CuBr2
(10 mol%)
N
Ts
CHO
1a
N
N
Toluene,
70 oC, 16 h
(51%)
Ts
N
+
NH2
4
H2N
Scheme 2. Synthesis of bis-dibenzo[b,h][1,6]naphthyridine 4
10
ACS Paragon Plus Environment

Page 11 of 27
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Finally, to further validate the protocol, we envisioned to synthesize 12,13-dihydro-6H-
benzo[h]chromeno[3,4-b][1,6]naphthyridin-6-ones 6 from readily available 3-amino-2H-
chromen-2-one 5, since coumarin and its derivatives are among the most significant heterocyclic
scaffolds of wide biological interest.20 The reaction between aldehydes 1a and 1b, and 3-amino-
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
2H-chromen-2-one
5
in the presence of CuBr2 furnished benzo[h]chromeno[3,4-
b][1,6]naphthyridin-6-ones 6 albeit in moderate yields. Change of catalyst to CuCl improved the
yield significantly under similar experimental conditions furnishing the products 6a and 6b in
74% and 79% respectively (Table 3).
Table 3. Synthesis of 12,13-dihydro-6H-benzo[h]chromeno[3,4-b][1,6]naphthyridin-6-ones 6a
Ts
N
Ts
Catalyst
(10 mol%)
R1
CHO
N
1
+
O
Toluene,
70 oC
N
O
NH2
O
R1
O
6a: R1 = H
6b: R1 = Br
5
Entry
Compound
CuBr2 (10 mol%)
CuCl (10 mol%
Reaction
time (h)
24
Yield
Reaction
time (h)
12
Yield
(%)b
60
(%)b
74
1
2
6a
6b
24
63
12
79
a Reaction conditions: all reactions were carried out with 1 (0.5 mmol) and 5 (0.5 mmol) in the presence of catalyst
(10 mol%) in 3 mL toluene at 70 oC. b Isolated yield.
The mechanism for the synthesis of dibenzo[b,h][1,6]naphthyridines 3 involves the initial
formation of imine A, which was confirmed in several occasions during the optimization
process, followed by Povarov-type intramolecular [4+2] cycloaddition catalyzed by CuBr2. The
21
activation of the heterodiene is attributed to the Lewis acidity of CuBr2 to trigger the addition
of the tethered alkyne to the heterodiene to furnish tetrahydrodibenzo[b,h][1,6]naphthyridines C
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 27
1
2
3
4
5
6
through the intermediacy of species B. Subsequent air oxidation under the experimental
conditions yielded products 3 (Scheme 3).
7
8
9
R2
R2
R3
R3
H
Ts
Ts
N
R2
Ts
N
N
H2N
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
CuBr2
-H2O
[4+2]
R1
+
N
R3
N
CHO
CuBr2
R1
CuBr2
1
2
R1
A
B
-CuBr2
R2
R2
N
R3
R3
Ts
Ts
N
N
air
oxidation
N
H
R1
R1
3
C
Scheme 3. Proposed mechanism
CONCLUSION
In conclusion, we have developed a simple and efficient method for the synthesis of 5,6-
dihydrodibenzo[b,h][1,6]naphthyridines from inexpensive and readily available starting
materials and catalysts under mild conditions. The CuBr2-catalyzed reaction between 2-(N-
propargylamino)benzaldehydes and arylamines afforded the products via intramolecular [4+2]
cycloaddition between the in situ generated heterodiene and tethered alkyne dienophile. This
methodology allows direct access to the products by generating two nitrogen heterocycles in a
single operation besides its other significant features including high yield, simple operation and
high atom economy. This protocol was also extended to the synthesis of 12,13-dihydro-6H-
benzo[h]chromeno[3,4-b][1,6]naphthyridin-6-ones in good yields.
12
ACS Paragon Plus Environment

Page 13 of 27
The Journal of Organic Chemistry
1
2
3
4
EXPERIMENTAL SECTION
5
6
7
8
General Information. All reagents and solvents were purchased from commercial
suppliers and used without further purification. The reactions were monitored by thin-
layer chromatography visualized by UV detection or using p-anisaldehyde stain or
molecular iodine. Melting points were recorded on a melting point apparatus in capillaries
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
13
and are uncorrected. H- and C-NMR spectra were recorded in CDCl3 or DMSO-d6 at
1
13
room temperature in a spectrometer operating at 300 MHz for H and 75 MHz for C.
Chemical shifts (δ) are expressed in ppm using TMS as internal standard and coupling
constants (J) are given in Hz. Infrared (IR) spectra were obtained in a FTIR spectrometer
with a diamond ATR accessory for solid and liquid samples, requiring no sample
preparation and the major frequencies were reported in cm-1. Elemental analyses were
determined by using a CHNS combustion microanalyzer.
General procedure for the synthesis of compounds 3, 4 and 6.
To a stirred solution of 2-(N-propargylamino)benzaldehydes 1 (0.5 mmol) and arylamines
2 or 3-amino-2H-chromen-2-one 5 (0.5 mmol) in toluene (3 mL) was added CuBr2 or CuCl
o
o
(10 mol%) and stirring was continued at 25 C or 70 C for the time periods given in
Tables 2 and 3. After completion of the reaction, as indicated by TLC, the reaction
mixture was diluted with dichloromethane (15 mL), washed with water (10 mL) and brine
solution (10 mL). The organic layer was dried over anhyd. Na2SO4 and the solvent was
removed under reduced pressure. The crude was purified through flash silica gel column
chromatography using petroleum ether: ethyl acetate as eluent (90:10 to 60:40, v/v).
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 27
1
2
3
4
Characterization data for compounds 3, 4 and 6.
5
6
9-Methoxy-5-tosyl-5,6-dihydrodibenzo[b,h][1,6]naphthyridine (3a). Colourless solid; mp:
7
8
9
o
183-185 C; yield: 184 mg, 88%; IR (neat) 2980.5, 2945.0, 1620.2, 1596.7, 1494.6, 1345.5,
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
1226.8, 1160.1, 1064.4 cm-1; H NMR (300 MHz, CDCl3): δ 1.81 (s, 3H), 3.92 (s, 3H), 4.99 (s,
2H), 6.53 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 2.7 Hz, 1H), 6.96 (d, J = 8.4 Hz, 2H), 7.26 (dd, J =
9.0, 2.7 Hz, 1H), 7.38-7.50 (m, 2H), 7.58 (s, 1H), 7.78 (dd, J = 7.8, 1.2 Hz, 1H), 7.84 (d, J = 9.3
Hz, 1H), 8.26 (dd, J = 7.5, 2.1 Hz, 1H); 13C NMR (75 MHz, CDCl3)*: δ 20.9, 49.7, 55.6, 104.6,
122.1, 125.0, 125.6, 127.2, 127.8, 128.3, 128.6, 130.1, 130.6, 130.8, 131.0, 134.3, 137.9, 143.6,
143.7, 147.1,157.9. Anal Calcd for C24H20N2O3S: C, 69.21; H, 4.84; N, 6.73. Found: C, 68.96;
H, 4.88; N, 6.98. *One aromatic carbon is merged with others.
o
5-Tosyl-5,6-dihydrodibenzo[b,h][1,6]naphthyridine (3b). Colourless solid; mp: 174-177 C;
yield: 160 mg, 83%; IR (neat) 3033.6, 1596.8, 1449.4, 1343.0, 1161.5, 1061.1 cm-1; H NMR
1
(300 MHz, CDCl3): δ 1.80 (s, 3H), 5.07 (s, 2H), 6.56 (d, J = 8.1 Hz, 2H), 7.03 (d, J = 8.1 Hz,
2H), 7.46-7.59 (m, 3H), 7.67 (td, J = 8.4, 1.2 Hz, 1H), 7.72 (s, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.85
(dd, J = 7.8, 0.9 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 8.38 (dd, J = 7.8, 1.8 Hz, 1H); 13C NMR (75
MHz, CDCl3)*: δ 20.9, 49.7, 124.6, 126.0, 126.6, 127.1, 127.2, 127.8, 127.9, 128.6, 129.2,
129.4, 130.6, 132.2, 134.4, 138.4, 143.7, 147.7, 149.5. Anal Calcd for C23H18N2O2S: C, 71.48;
H, 4.69; N, 7.25. Found: C, 71.16; H, 4.68; N, 7.38. *Two aromatic carbons are merged with
others.
9-Methyl-5-tosyl-5,6-dihydrodibenzo[b,h][1,6]naphthyridine (3c). Brown solid; mp: 179-181
oC; yield: 152 mg, 76%; IR (neat) 3027.0, 2920.0, 1597.8, 1491.7, 1348.3, 1161.1, 1064.5 cm-1;
1H NMR (300 MHz, CDCl3): δ 1.74 (s, 3H), 2.47 (s, 3H), 4.96 (s, 2H), 6.49 (d, J = 8.4 Hz, 2H),
6.94 (d, J = 8.4 Hz, 2H), 7.36-7.48 (m, 4H), 7.54 (s, 1H), 7.75 (dd, J = 7.8, 1.2 Hz, 1H), 7.80 (d,
14
ACS Paragon Plus Environment

Page 15 of 27
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
J = 9.3 Hz, 1H), 8.27 (dd, J = 7.5, 1.5 Hz, 1H); 13C NMR (75 MHz, CDCl3)*: δ 20.9, 21.6, 49.7,
124.6, 125.8, 125.9, 127.2, 127.3, 127.8, 128.6, 128.9, 130.4, 130.8, 131.5, 131.7, 134.4, 136.6,
138.2, 143.6, 146.3, 148.6. Anal Calcd for C24H20N2O2S: C, 71.98; H, 5.03; N, 6.99. Found: C,
71.67; H, 5.10; N, 7.01. *One aromatic carbon is merged with others.
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
9,11-Dimethyl-5-tosyl-5,6-dihydrodibenzo[b,h][1,6]naphthyridine (3d). Colourless solid; mp:
o
184-186 C; yield: 170 mg, 82%; IR (neat) 3044.5, 2905.6, 1594.6, 1488.7, 1350.6, 1166.2,
1081.5 cm-1; 1H NMR (300 MHz, CDCl3): δ 1.79 (s, 3H), 2.44 (s, 3H), 2.67 (s, 3H), 4.98 (s, 2H),
6.48 (d, J = 8.1 Hz, 2H), 6.93 (d, J = 8.1 Hz, 2H), 7.26 (s, 1H), 7.29 (s, 1H), 7.37-7.48 (m, 2H),
7.52 (s, 1H), 7.75 (d, J = 7.5 Hz, 1H), 8.34 (dd, J = 7.5, 1.8 Hz, 1H); 13C NMR (75 MHz,
CDCl3): δ 17.6, 20.8, 21.6, 49.7, 123.9, 124.1, 125.9, 127.2, 127.3, 127.5, 127.6, 128.5, 130.0,
131.4, 131.5, 131.7, 134.3, 136.1, 136.9, 138.1, 143.5, 145.2, 147.1. Anal Calcd for
C25H22N2O2S: C, 72.44; H, 5.35; N, 6.76. Found: C, 72.17; H, 5.39; N, 6.93.
8,10-Dimethyl-5-tosyl-5,6-dihydrodibenzo[b,h][1,6]naphthyridine (3e). Colourless solid; mp:
o
159-160 C; yield: 153 mg, 74%; IR (neat) 3035.3, 2898.7, 1596.3, 1459.8, 1340.6, 1160.8,
1051.3 cm-1; 1H NMR (300 MHz, CDCl3): δ 1.74 (s, 3H), 2.42 (s, 3H), 2.55 (s, 3H), 4.98 (s, 2H),
6.49 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 7.10 (s, 1H), 7.41 (td, J = 7.2, 1.5 Hz, 1H),
7.45 (td, J = 8.1, 1.5 Hz, 1H), 7.57 (s, 1H), 7.70 (s, 1H), 7.75 (dd, J = 7.8, 1.2 Hz, 1H), 8.29 (dd,
J = 7.8, 1.8 Hz, 1H); 13C NMR (75 MHz, CDCl3)*: δ 18.5, 20.9, 21.7, 49.9, 123.3, 124.6, 125.9,
126.4, 127.2, 127.7, 128.6, 128.7, 129.4, 130.4, 130.6, 133.5, 134.7, 138.3, 139.3, 143.7, 148.2,
148.9. Anal Calcd for C25H22N2O2S: C, 72.44; H, 5.35; N, 6.76. Found: C, 72.09; H, 5.38; N,
6.91. *One aromatic carbon is merged with others.
11-Methoxy-5-tosyl-5,6-dihydrodibenzo[b,h][1,6]naphthyridine (3f). Colourless solid; mp:
o
179-180 C; yield: 165 mg, 79%; IR (neat) 2918.5, 1598.4, 1558.0, 1488.3, 1345.9, 1161.9,
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 27
1
2
3
4
5
6
7
8
9
1067.0 cm-1; 1H NMR (300 MHz, CDCl3): δ 1.81 (s, 3H), 4.06 (s, 3H), 5.05 (s, 2H), 6.63 (d, J =
8.1 Hz, 2H), 7.00 (d, 7.5 Hz, 1H), 7.10 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 7.5 Hz, 1H), 7.42 (t, J =
7.8 Hz, 1H), 7.43-7.56 (m, 2H), 7.65 (s, 1H), 7.82 (d, J = 7.5 Hz, 1H), 8.46 (dd, J = 7.5, 1.8 Hz,
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
1H); C NMR (75 MHz, CDCl3): δ 20.8, 49.5, 56.1, 107.8, 119.0, 125.2, 126.4, 126.9, 127.2,
127.6, 127.7, 128.4, 128.8, 130.3, 130.5, 132.3, 134.8, 138.2, 139.5, 143.8, 148.5, 155.3. Anal
Calcd for C24H20N2O3S: C, 69.21; H, 4.84; N, 6.73. Found: C, 68.91; H, 4.94; N, 6.84.
9-Chloro-5-tosyl-5,6-dihydrodibenzo[b,h][1,6]naphthyridine (3g). Colourless solid; mp: 182-
185 C; yield: 162 mg, 77%; IR (neat) 3039.7, 1598.3, 1482.9, 1349.9, 1165.2, 1063.4 cm-1; H
NMR (300 MHz, CDCl3): δ 1.85 (s, 3H), 5.04 (s, 2H), 6.59 (d, J = 8.1 Hz, 2H), 7.01 (d, J = 8.1
Hz, 2H), 7.47 (td, J = 7.5, 0.9 Hz, 1H), 7.53-7.61 (m, 2H), 7.63 (s, 1H), 7.69 (d, J = 2.1 Hz, 1H),
7.83 (d, J = 8.1 Hz, 1H), 7.92 (d, J = 9.0 Hz, 1H), 8.34 (dd, J = 7.8, 1.5 Hz, 1H); 13C NMR (75
MHz, CDCl3)*: δ 20.9, 49.6, 125.7, 126.0, 127.2, 127.7, 127.8, 127.9, 129.7, 130.2, 130.3,
130.7, 130.9, 131.2, 132.2, 134.3, 138.4, 143.8, 145.9, 149.8. Anal Calcd for C23H17ClN2O2S: C,
65.63; H, 4.07; N, 6.66. Found: C, 65.29; H, 4.05; N, 6.70. *One aromatic carbon is merged with
others.
o
1
9,11-Dichloro-5-tosyl-5,6-dihydrodibenzo[b,h][1,6]naphthyridine (3h). Colourless solid; mp
o
243-246 C; yield: 182 mg, 80%; IR (neat) 3065.8, 2919.3, 1594.7, 1474.4, 1338.3, 1159.1,
1061.8 cm-1; 1H NMR (300 MHz, CDCl3): δ 1.93 (s, 3H), 5.07 (s, 2H), 6.62 (d, J = 7.8 Hz, 2H),
7.01 (d, J = 7.8 Hz, 2H), 7.48-7.60 (m, 4H), 7.77 (s, 1H), 7.84 (d, J = 7.5 Hz, 1H), 8.45 (d, J =
7.2 Hz, 1H) ;13C NMR (75 MHz, CDCl3): δ 20.9, 49.4, 124.8, 126.5, 126.7, 127.3, 127.7, 128.0,
128.5, 128.7, 130.0, 130.1, 131.2, 131.4, 131.5, 134.1, 134.9, 138.5, 142.3, 144.0, 150.2. Anal
Calcd for C23H16Cl2N2O2S: C, 60.67; H, 3.54; N, 6.15. Found: C, 60.41; H, 3.62; N, 6.37.
16
ACS Paragon Plus Environment

Page 17 of 27
The Journal of Organic Chemistry
1
2
3
4
9-Bromo-5-tosyl-5,6-dihydrodibenzo[b,h][1,6]naphthyridine (3i). Colourless solid; mp 167-
5
6
o
168 C; yield: 182 mg, 78%; IR (neat) 3048.5, 2933.2, 1596.7, 1479.5, 1339.0, 1156.0, 1078.1
7
8
9
cm-1; 1H NMR (300 MHz, CDCl3): δ 1.87 (s, 3H), 5.06 (s, 2H), 6.61 (d, J = 8.1 Hz, 2H), 7.02 (d,
J = 8.1 Hz, 2H), 7.49 (t, J = 7.5 Hz, 1H), 7.57 (t, J = 6.9 Hz, 1H), 7.63 (s, 1H), 7.73 (d, J = 9.0
Hz, 1H), 7.83-7.89 (m, 3H), 8.35 (d, J = 6.9 Hz, 1H); 13C NMR (75 MHz, CDCl3)*: δ 20.9, 49.5,
120.4, 125.7, 126.0, 127.2, 127.9, 128.2, 128.7, 129.1, 130.3, 130.8, 130.9, 131.1, 132.8, 134.3,
138.4, 143.8, 146.2, 149.9. Anal Calcd for C23H17BrN2O2S: C, 59.36; H, 3.68; N, 6.02. Found:
C, 58.99; H, 3.64; N, 6.13. *One aromatic carbon is merged with others.
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
5-Tosyl-5,6-dihydrodibenzo[b,h][1,6]naphthyridin-11-ol (3j). Colourless solid; mp 184-185
oC; yield: 151 mg, 75%; IR (neat) 3354.3, 2958.5, 1601.9, 1487.0, 1351.0, 1332.6, 1154.6,
1058.5 cm-1; 1H NMR (300 MHz, CDCl3): δ 1.86 (s, 3H), 5.06 (s, 2H), 6.52 (d, J = 8.1 Hz, 2H),
6.95 (d, 8.1 Hz, 2H), 7.13 (dd, J = 7.8, 1.2 Hz, 1H), 7.24 (dd, J = 7.8, 1.2 Hz, 1H), 7.42 (t, J =
7.8 Hz, 1H), 7.48 (td, J = 7.5, 1.2 Hz, 1H), 7.56 (td, J = 7.8, 1.5 Hz, 1H), 7.73 (s, 1H), 7.83 (dd, J
= 8.1, 1.2 Hz, 1H), 8.03 (brs, 1H), 8.28 (dd, J = 7.5, 1.8 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ
20.9, 49.7, 110.0, 117.4, 125.5, 125.7, 127.2, 127.5, 127.8, 127.9, 128.0, 128.5, 130.2, 130.8,
132.4, 134.0, 137.3, 138.5, 143.9, 147.4, 152.0. Anal Calcd for C23H18N2O3S: C, 68.64; H, 4.51;
N, 6.96. Found: C, 68.50; H, 4.61; N, 7.05.
2-Bromo-5-tosyl-5,6-dihydrodibenzo[b,h][1,6]naphthyridine (3k). Colourless solid; mp 185-
o
1
188 C; yield: 191 mg, 82%; IR (neat) 2938.4, 1592.5, 1434.3, 1354.6, 1161.8, 1051.3 cm-1; H
NMR (300 MHz, CDCl3): δ 1.80 (s, 3H), 5.03 (s, 2H), 6.58 (d, J = 8.1 Hz, 2H), 7.04 (d, J = 8.1
Hz, 2H), 7.52 (td, J = 8.1, 1.2 Hz, 1H), 7.62-7.73 (m, 5H), 7.99 (d, J = 8.4, Hz, 1H), 8.51 (d, J =
2.1 Hz, 1H); 13C NMR (75 MHz, CDCl3)*: δ 20.9, 49.5, 121.7, 124.3, 127.0, 127.1, 127.2, 127.3,
128.8, 129.2, 129.5, 129.6, 132.2, 132.4, 133.4, 134.1, 137.3, 144.0, 147.5, 148.1. Anal Calcd for
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 27
1
2
3
4
5
6
C23H17BrN2O2S: C, 59.36; H, 3.68; N, 6.02. Found: 59.02; H, 3.66; N, 6.19. *One aromatic
carbon is merged with others.
7
8
9
2-Bromo-9,11-dimethyl-5-tosyl-5,6-dihydrodibenzo[b,h][1,6]naphthyridine (3l). Colourless
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
solid; mp 213-218 C; yield: 207 mg, 84%; IR (neat) 2915.9, 1593.1, 1485.9, 1349.2, 1161.2,
1046.0 cm-1; 1H NMR (300 MHz, CDCl3): δ 1.66 (s, 3H), 2.31 (s, 3H), 2.54 (s, 3H), 4.83 (s, 2H),
6.38 (d, J = 8.1 Hz, 2H), 6.82 (d, J = 8.1 Hz, 2H), 7.12 (s, 1H), 7.17 (s, 1H), 7.38 (s, 1H), 7.40
(dd, J = 8.4, 2.1 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 8.30 (d, J = 2.1 Hz, 1H); 13C NMR (75 MHz,
CDCl3): δ 17.7, 20.9, 21.7, 49.5, 121.5, 123.7, 123.8, 127.2, 127.5, 128.5, 128.6, 129.3, 131.7,
131.9, 132.8, 133.0, 134.1, 136.6, 137.0, 137.1, 143.8, 145.1, 145.8. Anal Calcd for
C25H21BrN2O2S: C, 60.86; H, 4.29; N, 5.68. Found: C, 60.57; H, 4.24; N, 5.86.
2-Bromo-9-chloro-5-tosyl-5,6-dihydrodibenzo[b,h][1,6]naphthyridine (3m). Colourless solid;
o
mp 195-197 C; yield: 200 mg, 80%; IR (neat) 3048.6, 2900.0, 1597.1, 1484.0, 1343.3, 1163.8,
1048.3 cm-1; 1H NMR (300 MHz, CDCl3): δ 1.86 (s, 3H), 5.03 (s, 2H), 6.62 (d, J = 8.4 Hz, 2H),
7.03 (d, J = 8.4 Hz, 2H), 7.59-7.68 (m, 3H), 7.69-7.72 (m, 2H), 7.92 (d, J = 9.0 Hz, 1H), 8.48 (d,
13
J = 2.4 Hz, 1H); C NMR (75 MHz, CDCl3): δ 20.9, 49.3, 121.7, 125.4, 125.7, 127.2, 127.9,
128.7, 128.8, 129.5, 130.6, 130.8, 131.4, 131.7, 132.7, 133.7, 134.0, 137.3, 144.0, 145.8, 148.4.
Anal Calcd for C23H16BrClN2O2S: C, 55.27; H, 3.23; N, 5.60. Found: C, 55.04; H, 3.16; N, 5.57.
2-Bromo-9-methoxy-5-tosyl-5,6-dihydrodibenzo[b,h][1,6]naphthyridine (3n). Colourless
o
solid; mp 201-204 C; yield: 211 mg, 85%; IR (neat) 3045.3, 2958.5, 1622.9, 1497.4, 1345.2,
1246.7, 1156.8, 1037.6 cm-1; H NMR (300 MHz, CDCl3): δ 1.88 (s, 3H), 3.97 (s, 3H), 5.03 (s,
1
2H), 6.61 (d, J = 8.1 Hz, 2H), 6.99 (d, J = 2.7 Hz, 1H), 7.04 (d, J = 8.1 Hz, 2H), 7.33 (dd, J =
9.3, 2.7 Hz, 1H), 7.61(dd, J = 8.7, 2.4 Hz, 1H), 7.63 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.88 (d, J
= 8.4 Hz, 1H), 8.45(d, J = 2.4 Hz, 1H); 13C NMR (75 MHz, CDCl3)*: δ 21.0, 49.5, 55.6, 104.6,
18
ACS Paragon Plus Environment

Page 19 of 27
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
121.6, 122.4, 124.6, 127.2, 128.3, 128.5, 128.7, 129.3, 130.7, 131.1, 132.4, 132.8, 134.1, 136.8,
143.7, 143.9, 145.7 . Anal Calcd for C24H19BrN2O3S: C, 58.19; H, 3.87; N, 5.65. Found: C,
57.81; H, 3.84; N, 5.79. *One aromatic carbon is merged with others.
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
9,11-Dimethyl-6-phenyl-5-tosyl-5,6-dihydrodibenzo[b,h][1,6]naphthyridine (3o). Colourless
o
solid; mp 210-212 C; yield: 191 mg, 78%; IR (neat) 3030.6, 2915.9, 1578.7, 1486.1, 1345.2,
1161.9, 1084.5 cm-1; 1H NMR (300 MHz, CDCl3): δ 1.95 (s, 3H), 2.37 (s, 3H), 2.77 (s, 3H), 4.79
(s, 2H), 6.65 (d, J = 8.1 Hz, 2H), 6.97 (d, J = 8.1 Hz, 1H), 7.03 (s, 1H), 7.27 (dd, J = 7.5, 1.8 Hz,
2H), 7.33 (s, 1H), 7.43-7.53 (m, 2H), 7.56-7.64 (m, 3H), 7.77 (dd, J = 7.5, 1.5 Hz, 1H), 8.42 (dd,
J = 7.5, 2.4 Hz, 2H); 13C NMR (75 MHz, CDCl3)*: δ 18.0, 21.0, 21.9, 47.9, 121.1, 122.6, 126.1,
126.5, 127.0, 127.4, 127.5, 128.5, 128.6, 128.9, 129.4, 129.9, 131.5, 131.9, 134.4, 135.4, 136.0,
137.0, 137.9, 143.5, 145.1, 146.7. Anal Calcd for C31H26N2O2S: C, 75.89; H, 5.34; N, 5.71.
Found: C, 75.61; H, 5.40; N, 5.80. *One aromatic carbon is merged with others.
2-Bromo-9,11-dimethyl-6-phenyl-5-tosyl-5,6-dihydrodibenzo[b,h][1,6]naphthyridine (3p).
Colourless solid; mp 221-224 oC; yield: 236 mg, 83%; IR (neat) 2919.0, 1583.1, 1483.1, 1344.5,
1161.9, 1083.6 cm-1; 1H NMR (300 MHz, CDCl3): δ 1.96 (s, 3H), 2.37 (s, 3H), 2.77 (s, 3H), 4.77
(s, 2H), 6.69 (d, J = 8.1 Hz, 2H), 6.99 (d, J = 8.1 Hz, 2H), 7.03 (s, 1H), 7.23-7.26 (m, 2H), 7.35
(s, 1H), 7.57-7.66 (m, 5H), 8.52 (d, J = 2.1 Hz, 1H); 13C NMR (75 MHz, CDCl3)*: δ 18.0, 21.0,
21.9, 47.7, 121.4, 121.9, 122.6, 126.7, 127.0, 128.7, 128.9, 129.0, 129.1, 129.3, 131.7, 132.7,
133.6, 134.1, 135.1, 136.5, 136.8, 137.2, 143.7, 143.8, 145.0, 145.4. Anal Calcd for
C31H25BrN2O2S: C, 65.38; H, 4.42; N, 4.92. Found: C, 65.07; H, 4.41; N, 5.05. *One aromatic
carbon is merged with others.
2-Bromo-11-methoxy-6-phenyl-5-tosyl-5,6-dihydrodibenzo[b,h][1,6]naphthyridine
(3q).
Colourless solid; mp 220-222 oC; yield: 234 mg, 82%; IR (neat) 2932.9, 1593.7, 1485.3, 1344.7,
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 27
1
2
3
4
5
6
7
8
9
1257.8, 1161.1, 1072.6 cm-1; H NMR (300 MHz, CDCl3): δ 1.96 (s, 3H), 4.09 (s, 3H), 4.82 (s,
2H), 6.78 (d, J = 8.1 Hz, 2H), 7.00-7.05 (m, 2H), 7.08 (d, J = 8.1 Hz, 2H), 7.24-7.27 (m, 2H),
7.33 (t, J = 7.8 Hz, 1H), 7.58-7.69 (m, 5H), 8.60 (d, J = 2.1Hz, 1H); 13C NMR (75 MHz,
CDCl3)*: δ 21.0, 47.5, 56.2, 107.7, 117.8, 121.7, 123.1, 126.9, 127.0, 127.8, 129.0, 129.1, 129.3,
132.5, 133.2, 134.6, 134.7, 136.8, 139.5, 143.9, 144.5, 146.8, 155.4. Anal Calcd for
C30H23BrN2O3S: C, 63.05; H, 4.06; N, 4.90. Found: C, 62.90; H, 3.95; N, 4.97. *Three aromatic
carbons are merged with others.
1
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-Bromo-9-fluoro-6-phenyl-5-tosyl-5,6-dihydrodibenzo[b,h][1,6]naphthyridine
(3r).
Colourless solid; mp 228-230 oC; yield: 249 mg, 89%; IR (neat) 3030.8, 1619.2, 1489.0, 1333.3,
1229.7, 1159.7, 1079.9 cm-1; 1H NMR (300 MHz, CDCl3): δ 1.96 (s, 3H), 4.81 (s, 2H), 6.73 (d, J
= 8.4 Hz, 2H), 7.00 (d, J = 8.4 Hz, 2H), 7.10 (dd, J = 9.9, 2.7Hz, 1H), 7.25-7.28 (m, 2H), 7.40-
13
7.46 (m, 1H), 7.57-7.69 (m, 5H), 8.03 (dd, J = 9.0, 5.4 Hz, 1H), 8.51 (d, J = 1.8 Hz, 1H); C
NMR (75 MHz, CDCl3)*: δ 21.1, 47.6, 109.4 (d, J = 23.3 Hz), 119.7 (d, J = 26.3 Hz), 121.7,
123.2, 127.0, 127.5 (d, J = 9.0 Hz), 128.8, 128.9, 129.1, 129.2, 129.3, 131.9 (d, J = 9.0 Hz),
132.5, 133.4, 134.0, 134.1, 137.0, 143.9, 144.1, 144.5, 147.3 (d, J = 2.3 Hz), 160.7 (d, J = 8.4
Hz). Anal Calcd for C29H20BrFN2O2S: C, 62.26; H, 3.60; N, 5.01. Found: C, 61.97; H, 3.56; N,
5.22. *One aromatic carbon is merged with others.
9-Fluoro-2,3-dimethoxy-5-tosyl-5,6-dihydrodibenzo[b,h][1,6]naphthyridine (3s). Colourless
o
solid; mp 206-209 C; yield: 191 mg, 82%; IR (neat) 3002.8, 2934.6, 1602.0, 1507.4, 1357.5,
1
1283.9, 1212.5, 1160.7 cm-1; H NMR (300 MHz, CDCl3): δ 1.85 (s, 3H), 4.05 (s, 3H), 4.06 (s,
3H), 5.00 (s, 2H), 6.60 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 7.31 (dd, J = 8.7, 2.7 Hz,
1H), 7.33 (s,1H), 7.40 (td, J = 9.0, 2.7 Hz, 1H), 7.61 (s, 1H), 7.79 (s, 1H), 7.95 (dd, J = 9.0, 5.1
13
Hz, 1H); C NMR (75 MHz, CDCl3)*: δ 20.9, 49.9, 56.2, 56.4, 107.0, 110.2 (d, J = 21.0 Hz),
20
ACS Paragon Plus Environment

Page 21 of 27
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
110.6, 119.4 (d, J = 18.0 Hz), 123.2, 125.0, 126.9, 127.3, 127.5 (d, J = 9.8 Hz), 128.6, 131.2 (d, J
= 15.8 Hz), 131.3, 132.2, 134.0, 143.7, 144.6, 148.9, 149.0, 150.9, 160.2 (d, J = 246.8 Hz), Anal
Calcd for C25H21FN2O4S: C, 64.64; H, 4.56; N, 6.03. Found: C, 64.32; H, 4.44; N, 6.00.
11-Ethyl-2,3-dimethoxy-5-tosyl-5,6-dihydrodibenzo[b,h][1,6]naphthyridine (3t). Colourless
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
solid; mp 192-196 C; yield: 188 mg, 79%; IR (neat) 3011.5, 2967.4, 2928.1, 1602.7, 1510.6,
1346.4, 1210.2, 1160.6 cm-1; H NMR (300 MHz, CDCl3): δ 1.35 (t, J = 7.5 Hz, 3H), 1.77 (s,
1
3H), 3.23 (q, J = 7.5 Hz, 2H), 4.04 (s, 3H), 4.05 (s, 3H), 5.01 (s, 2H), 6.52 (d, J = 7.8 Hz, 2H),
7.00 (d, J = 7.8 Hz, 2H), 7.31 (s, 1H), 7.37 (t, J = 7.2 Hz, 1H), 7.47 (d, J = 7.2 Hz, 1H), 7.52 (d,
13
J = 8.1 Hz, 1H), 7.61 (s, 1H), 7.87 (s, 1H); C NMR (75 MHz, CDCl3)*: δ 15.2, 20.8, 24.9,
50.0, 56.1, 56.4, 107.3, 110.6, 123.4, 124.3, 125.0, 126.0, 127.0, 127.4, 127.8, 128.4, 132.1,
133.9, 142.8, 143.5, 145.8, 147.8, 148.8, 150.7. Anal Calcd for C27H26N2O4S: C, 68.33; H, 5.52;
N, 5.90. Found: C, 68.01; H, 5.44; N, 5.79. *One aromatic carbon is merged with others.
5-Tosyl-5,6-dihydrobenzo[h]naphtho[1,2-b][1,6]naphthyridine (3u). Pale yellow solid; mp
o
201-203 C; yield: 188 mg, 86%; IR (neat) 3058.7, 2977.3, 1593.7, 1398.2, 1341.8, 1159.6,
1073.9 cm-1; 1H NMR (300 MHz, CDCl3): δ 1.52 (s, 3H), 5.03 (s, 2H), 6.43 (d, J = 8.1 Hz, 2H),
6.93 (d, J = 8.1 Hz, 2H), 7.41-7.50 (m, 2H), 7.53 (d, J = 8.7 Hz, 1H), 7.64-7.68 (m, 3H), 7.71 (d,
J = 8.7 Hz, 1H), 7.77-7.84 (m, 2H), 8.48 (dd, J = 7.5, 2.4 Hz, 1H), 9.22 (dd, J = 7.2, 1.8 Hz, 1H);
13C NMR (75 MHz, CDCl3)*: δ 20.7, 49.6, 124.5, 124.7, 124.8, 125.4, 125.9, 126.9, 127.2,
127.7, 127.8, 127.9, 128.2, 128.5, 130.3, 131.2, 131.4, 132.1, 133.5, 134.3, 138.1, 143.7, 145.6,
147.8. Anal Calcd for C27H20N2O2S: C, 74.29; H, 4.62; N, 6.42. Found: 73.98; H, 4.63; N, 6.64.
*One aromatic carbon is merged with others.
2,3-Dimethoxy-5-tosyl-5,6-dihydrobenzo[h]naphtho[1,2-b][1,6]naphthyridine
(3v).
Colourless solid; mp 203-206oC; yield: 181 mg, 73%; IR (neat) 3004.6, 2931.2, 1598.2, 1514.0,
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 27
1
2
3
4
1
1341.2, 1284.7, 1208.2, 1161.2 cm-1; H NMR (300 MHz, CDCl3): δ 1.60 (s, 3H), 4.06 (s, 3H),
5
6
7
8
4.13 (s, 3H), 5.07 (s, 2H), 6.51 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 8.4 Hz, 2H), 7.36 (s, 1H), 7.58
(d, J = 8.7 Hz, 1H), 7.68-7.77 (m, 4H), 7.90 (dd, J = 6.6, 2.4 Hz, 1H), 8.00 (s, 1H), 9.26 (dd, 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
7.2, 2.1 Hz, 1H); C NMR (75 MHz, CDCl3)*: δ 20.7, 49.8, 56.3, 56.4, 107.2, 110.5, 124.0,
124.3, 124.8, 124.9, 126.8, 127.2, 127.3, 127.8, 128.1, 128.4, 131.3, 131.9, 133.5, 134.0, 143.7,
145.4, 147.8, 148.8, 150.7. Anal Calcd for C29H24N2O4S: C, 70.14; H, 4.87; N, 5.64. Found:
69.88; H, 4.81; N, 5.56. *Two aromatic carbons are merged with others.
o
bis-Dibenzo[b,h][1,6]naphthyridine (4).* Colourless solid; mp 269-271 C; yield: 177 mg,
51%; IR (neat) 3065.9, 2922.5, 1599.8, 1483.2, 1418.1, 1349.3, 1163.5 cm-1; H NMR (300
1
MHz, CDCl3): δ 1.77 (s, 6H), 5.24 (s, 4H), 6.57 (d, J = 8.1 Hz, 4H), 7.04 (d, J = 8.1 Hz, 4H),
7.51 (t, J = 7.8 Hz, 2H), 7.59 (t, J = 7.8 Hz, 2H), 7.77 (d, J = 7.2 Hz, 2H), 8.01 (s, 2H), 8.38 (dd,
J = 7.8, 1.8 Hz, 2H), 8.89 (s, 2H); Anal Calcd for C40H30N4O4S2: C, 69.15; H, 4.35; N, 8.06.
Found: 68.88; H, 4.31; N, 7.97. *This compound is insoluble in common NMR solvents and
sparingly soluble only in CDCl3. The concentration in CDCl3 was not sufficient enough to record
13C NMR.
12-Tosyl-12,13-dihydro-6H-benzo[h]chromeno[3,4-b][1,6]naphthyridin-6-one
(6a).
Colourless solid; mp 254-256 oC; yield: 168 mg, 74%; IR (neat) 3071.0, 2917.5, 1742.5, 1602.7,
1468.8, 1435.3, 1348.2, 1166.6, 1091.5 cm-1; H NMR (300 MHz, CDCl3): δ 1.97 (s, 3H), 5.12
1
(s, 2H), 6.73 (d, J = 8.1 Hz, 2H), 7.07 (d, J = 8.1 Hz, 2H), 7.42-7.50 (m, 3H), 7.54-7.62 (m,
2H), 7.83 (dd, J = 8.1, 0.9 Hz, 1H), 7.99 (d, J = 7.8 Hz, 1H), 8.04 (s, 1H), 8.42 (dd, J = 7.8, 1.5
13
Hz, 1H); C NMR (75 MHz, CDCl3)*: δ 21.1, 49.3, 116.4, 118.0, 122.8, 125.1, 126.6, 126.9,
127.2, 127.4, 128.0, 128.8, 129.0, 130.4, 131.5, 132.2, 134.4, 136.9, 137.7, 144.3, 150.9, 151.1,
22
ACS Paragon Plus Environment

Page 23 of 27
The Journal of Organic Chemistry
1
2
3
4
5
6
158.5. Anal Calcd for C26H18N2O4S: C, 68.71; H, 3.99; N, 6.16. Found: 68.48; H, 3.82; N, 6.11.
*One aromatic carbon is merged with others.
7
8
9
9-Bromo-12-tosyl-12,13-dihydro-6H-benzo[h]chromeno[3,4-b][1,6]naphthyridin-6-one (6b).
Colourless solid; mp 262-264 oC; yield: 211 mg, 79%; IR (neat) 3060.8, 2967.4, 1746.7, 1601.5,
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
1463.5, 1340.3, 1164.1, 1088.0 cm-1; H NMR (300 MHz, CDCl3): δ 1.98 (s, 3H), 5.11 (s, 2H),
6.77 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 8.1 Hz, 2H), 7.41-7.48 (m, 2H), 7.58-7.73 (m, 3H), 7.98
13
(dd, J = 8.1, 1.2 Hz, 1H), 8.06 (s, 1H), 8.51 (d, J = 2.1 Hz, 1H); C NMR (75 MHz, CDCl3): δ
21.1, 49.0, 116.1, 118.0, 121.9, 123.0, 125.2, 127.1, 127.2, 128.9, 129.0, 129.1, 130.2, 130.9,
131.8, 132.2, 134.3, 134.4, 136.6, 136.8, 144.5, 149.8, 150.9, 158.2. Anal Calcd for
C26H17BrN2O4S: C, 58.55; H, 3.21; N, 5.25. Found: 58.24; H, 3.17; N, 5.16.
ASSOCIATED CONTENT
Supporting information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
Copies of 1H and 13C NMR spectra of compounds 3, 4 and 6.
AUTHOR INFORMATION
Corresponding Author
*Email: vsridharan@scbt.sastra.edu; vesridharan@gmail.com
Notes
The authors declare no competing financial interest.
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 27
1
2
3
4
ACKNOWLEDGEMENTS
5
6
7
8
Financial support from the Department of Science and Technology, DST (No. SB/FT/CS-
006/2013 & No. INT/AUA/BMWF/P-26/2015) and the Council of Scientific and
Industrial Research, CSIR (No. 02(0219)/14/EMR-II) is gratefully acknowledged. JCM
acknowledges financial support from MINECO, grant CTQ2012-33272-BQU.
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
REFERENCES
1. Povarov, L. S. Russ. Chem. Rev. 1967, 36, 656.
2. For reviews on Povarov reaction, see: (a) Bello, D.; Ramón, R.; Lavilla, R. Curr. Org.
Chem. 2010, 14, 332. (b) Kouznetsov, V. V. Tetrahedron 2009, 65, 2721. (c) Glushkov,
V. A.; Tolstikov, A. G. Russ. Chem. Rev. 2008, 77, 137.
3. For a summary of catalysts used for Povarov reaction, see section 6 in: Sridharan, V.;
Suryavanshi, P. A.; Menéndez, J. C. Chem. Rev. 2011, 111, 7157.
4. For reviews on asymmetric IEDDAs, see: (a) Fochi, M.; Caruana, L.; Bernardi, L.
Synthesis 2014, 46, 135. (b) Jiang, X.; Wang, R. Chem. Rev. 2013, 113, 5515.
5. For selected examples of intramolecular Povarov reaction, see: (a) Maiti, S.; Panja, S. K.;
Sadhukhan, K.; Ghosh, J.; Bandyopadhyay, C. Tetrahedron Lett. 2012, 53, 694. (b)
Desrat, S.; van de Weghe, P. J. Org. Chem. 2009, 74, 6728. (c) Muhuhi, J.; Spaller, M. R.
J. Org. Chem. 2006, 71, 5515. (d) Manian, R. D. R. S.; Jayashankaran, J.; Ramesh, R.;
Raghunathan, R. Tetrahedron Lett. 2006, 47, 7571. (e) Yadav, J. S.; Reddy, B. V. S.;
Chetia, L.; Srinivasulu, G.; Kunwar, A. C. Tetrahedron Lett. 2005, 46, 1039. (f) Jacob, R.
G.; Perin, G.; Botteselle, G. V.; Lenardão, E. J. Tetrahedron Lett. 2003, 44, 6809. (g)
Sabitha, G.; Reddy, E. V.; Maruthi, C.; Yadav, J. S. Tetrahedron Lett. 2002, 43, 1573. (h)
24
ACS Paragon Plus Environment

Page 25 of 27
The Journal of Organic Chemistry
1
2
3
4
5
6
Kiselyov, A. S.; Smith II, L.; Armstrong, R. W. Tetrahedron 1998, 54, 5089. (i) Laschat,
S.; Lauterwein, J. J. Org. Chem. 1993, 58, 2856.
7
8
9
6. For selected examples of quinoline synthesis via [4+2] cycloaddition of benzylidene
anilines and alkynes, see: (a) Castillo, J.-C.; Quiroga, J.; Abonia, R.; Rodriguez, J.;
Coquerel, Y. Org. Lett. 2015, 17, 3374. (b) Zhang, X.; Xu, X.; Yu, L.; Zhao, Q. Asian J.
Org. Chem. 2014, 3, 281. (c) Meyet, C. E.; Larsen, C. H. J. Org. Chem. 2014, 79, 9835.
(d) Suresh, R.; Muthusubramanian, S.; Senthilkumaran, R.; Manickam, G. J. Org. Chem.
2012, 77, 1468. (e) Zhang, X.; Liu, B.; Shu, X.; Gao, Y.; Lv, H.; Zhu, J. J. Org. Chem.
2012, 77, 501. (f) Kulkarni, A.; Török, B. Green Chem. 2010, 12, 875.
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. For selected examples of intramolecular [4+2] Povarov-type cycloadditions involving
alkyne dienophiles, see: (a) Belala, M.; Dasa, D. K.; Khan, A. T. Synthesis 2015, 47,
1109. (b) Huang, W.; Lin, W.; Guan, X. Tetrahedron Lett. 2014, 55, 116. (c) Kand, D.;
Kalle, A. M.; Varma, S. J.; Talukdar, P. Chem. Commun. 2012, 48, 2722. (d) Kudale, A.
K.; Miller, D. O.; Dawe, L. N.; Bodwell, G. J. Org. Biomol. Chem. 2011, 9, 7196. (e)
Majumdar, K. C.; Ponra, S.; Taher, A. Synthesis 2011, 463. (f) Ramesh, S.; Gaddam, V.;
Nagarajan, R. Synlett 2010, 757. (g) Majumdar, K. C.; Ponra, S.; Ganai, S. Synlett 2010,
2575. (h) Twin, H.; Batey, R. A. Org. Lett. 2004, 6, 4913.
8. (a) Iachettini, S.; Stevens, M. F. G.; Frigerio, M.; Hummersone, M. G.; Hutchinson, I.;
Garner, T. P.; Searle, M. S.; Wilson, D. W.; Munde, M.; Nanjunda, R.; D’Angelo, C.;
Zizza, P.; Rizzo, A.; Cingolani, C.; De Cicco, F.; Porru, M.; D’Incalci, M.; Leonetti, C.;
Biroccio, A.; Salvati, E. J. Exp. Clin. Cancer Res. 2013, 32, 68. (b) Heald, R. A.;
Stevens, M. F. G. Org. Biomol. Chem. 2003, 1, 3377.
9. Kiselev, E.; Dexheimer, T. S.; Pommier, Y.; Cushman, M. J. Med. Chem. 2010, 53, 8716.
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 27
1
2
3
4
5
6
7
8
9
10. Thompson, A. M.; Connolly, C. J. C.; Hamby, J. M.; Boushelle, S.; Hartl, B. G.; Amar,
A. M.; Kraker, A. J.; Driscoll, D. L.; Steinkampf, R. W.; Patmore, S. J.; Vincent, P. W.;
Roberts, B. J.; Elliott, W. L.; Klohs, W.; Leopold, W. R.; Showalter, H. D. H.; Denny, W.
A. J. Med. Chem. 2000, 43, 4200.
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
11. Zeng, L.-F.; Wang, Y.; Kazemi, R.; Xu, S.; Xu, Z.-L.; Sanchez, T. W.; Yang, L.-M.;
Debnath, B.; Odde, S.; Xie, H.; Zheng, Y.-T.; Ding, J.; Neamati, N.; Long, Y.-Q. J. Med.
Chem. 2012, 55, 9492.
12. (a) Okuma, K.; Koga, T.; Ozaki, S.; Suzuki, Y.; Horigami, K.; Nagahora, N.; Shioji, K.;
Fukuda, M.; Deshimaru, M. Chem. Commun. 2014, 50, 15525.
13. Wu, H.; Lin, W.; Wan, Y.; Xin, H.-Q.; Shi, D.-Q.; Shi, Y.-H.; Yuan, R.; R.-C. Bo.; Yin,
W. J. Comb. Chem. 2010, 12, 31.
14. Manoj, M.; Prasad, K. J. R. Synth. Commun. 2012, 42, 434.
15. (a) Prabha, K.; Prasad, K. J. R. Synth. Commun. 2014, 44, 1441. (b) Manoj, M.; Prasad,
K. J. R. J. Heterocyclic Chem. 2013, 50, 1049. (c) Fiala, F.; Stadlbauer, W. J. Prakt.
Chem. 1993, 335, 128.
16. Mao, D.; Tang, J.; Wang, W.; Liu, X.; Wu, S.; Yu, J.; Wang, L. Org. Biomol. Chem.
2015, 13, 2122.
17. Bashiardes, G.; Safir, I.; Barbot, F.; Laduranty, J. Tetrahedron Lett. 2004, 45, 1567.
18. Sze, E. M. L.; Koh, M. J.; Tjia, Y. M.; Rao, W.; Chan, P. W. H. Tetrahedron 2013, 69,
5558.
19. (a) Serrao, E.; Debnath, B.; Otake, H.; Kuang, Y.; Christ, F.; Debyser, Z.; Neamati, N. J.
Med. Chem. 2013, 56, 2311. (b) Tardito, S.; Barilli, A.; Bassanetti, I.; Tegoni, M.;
Bussolati, O.; Franchi-Gazzola, R.; Mucchino, C.; Marchio, L. J. Med. Chem. 2012, 55,
26
ACS Paragon Plus Environment

Page 27 of 27
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10448. (c) Fernández-Bachiller, M. I.; Pérez, C.; González-Munoz, G. C.; Conde, S.;
Lopez, M. G. Villarroya, M.; García, A. G.; Rodríguez-Franco, M. I. J. Med. Chem.
2010, 53, 4927.
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
20. For selected examples, see: (a) Maresca, A.; Temperini, C.; Pochet, L.; Masereel, B.;
Scozzafava, S.; Supuran, C. T. J. Med. Chem. 2010, 53, 335. (b) Robert, S.; Bertolla, C.;
Masereel, B.; Dogné, J.-M.; Pochet, L. J. Med. Chem. 2008, 51, 3077.
21. (a) Semwal, A.; Nayak, S. K. Synth. Commun. 2006, 36, 227. (b) Mo, L.-P.; Ma, Z.-C.;
Zhang, Z.-H. Synth. Commun. 2005, 35, 1997.
******
27
ACS Paragon Plus Environment