448

SYNTHESIS OF AZACHRYSENES AND MULTI-NITROGENATED

DERIVATIVES
DOI: http://dx.medra.org/10.17374/targets.2017.20.448
Elina Marinho and Fernanda Proença
Chemistry Department, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal
(e-mail: fproenca@quimica.uminho.pt)

Abstract. Azachrysenes are aromatic tetracyclic structures where one carbon atom is replaced by nitrogen
in any symmetrically distinct position of the fused aromatic ring. They can be considered analogs of
azasteroids, with recognized potential as drug candidates. The present review surveys the work carried out
over the last three decades on the synthesis of mono-, di-, tri- and penta-azachryzene derivatives. Although a
diversity of synthetic approaches were described in the literature, there are no recent review articles on this
subject.

Contents
1. Introduction
2. Synthesis of monoazachrysene derivatives
2.1. 2-Azachrysene
2.2. 5-Azachrysene
2.3. 6-Azachrysene
3. Synthesis of diazachrysene derivatives
3.1. 1,7-Diazachrysene
3.2. 5,6-Diazachrysene
3.3. 5,7-Diazachrysene
3.4. 5,8-Diazachrysene
3.5. 5,10b-Diazachrysene
3.6. 5,11-Diazachrysene
3.7. 5,12-Diazachrysene
3.8. 6,12-Diazachrysene
3.9. 7,11- and 8,11-Diazachrysene
4. Synthesis of triazachrysene derivatives
4.1. 1,5,10-, 2,5,9- and 3,5,8-Triazachrysene
4.2. 4b,6,11-Triazachrysene
4.3. 5,6,11-Triazachrysene
4.4. 7,10a,11-Triazachrysene
4.5. 7,13,13d-Triazachrysene
5. Synthesis of pentaazachrysene derivatives
5.1. 1,3,5,8,10-Pentaazachrysene
6. Conclusions
Acknowledgments
 449

References

1. Introduction
Azachrysenes (aza-analogs of chrysene, Figure 1), are tetracyclic aromatic compounds where one of
carbon atoms in the structure is replaced by nitrogen. The substitution pattern in rings A to D has been used
to shape the properties of these N-heterocycles, namely as drug candidates, where these compounds can be
considered as privileged structures.1,2 Their unique structure also makes them valuable intermediates in the
synthesis of azasteroids.3

7 6
6a
8
N5
D C 4b 4
9 4a
10a 3
10 10b B A
11 2
12a 1
12
chrysene azachrysene
R3
fagaronine (R1, R2, R4=OMe, R3=H, R5=OH)
R2
N X fagaridine (R1=H, R2=OCH3, R3=OH, R4 + R5=OCH2O)
R4 isofagaridine (R1=H, R2=OH, R3=OMe, R4 + R5=OCH2O)
R1 nitidine (R1, R2=OMe, R3=H, R4 + R5=OCH2O)
chelerythrine (R1=H, R2, R3,=OMe, R4 + R5=OCH2O)
R5 sanguinarine (R1=H, R2 + R3=OCH2O, R4 + R5=OCH2O)
R3
R2
N nornitidine (R1, R2=OMe, R3=H, R4 + R5=OCH2O)
R4 norchelerythrine ( R1=H, R2, R3,=OMe, R4 + R5=OCH2O)
R1 norsanguinarine (R1=H, R2 + R3=OCH2O, R4 + R5=OCH2O)
decarine (R1=H, R2=OH, R3=OCH3, R4 + R5=OCH2O)
R5
isodecarine (R1=H, R2=OCH3, R3=OH, R4 + R5=OCH2O)

O
MeO N
N

MeO O

N O

ARC-111 (topovale)
Figure 1

The azachrysene scaffold, also referred as benzophenanthridine, was extensively studied in the last
decades2,4 and received significant attention due to the widespread occurrence in nature and broad range of
biological properties. Compounds with this core-structure are known to inhibit leukaemia5 and to act as
antimicrobial6, anticancer7, muscle relaxant 8, anti-inflammatory9 and cardiotonic agents.10 Some analogues
behaved as potent inducers of apoptosis in HCT116 and SW620 cell lines, highlighting their potential
relevance in colon cancer.11 Among the compounds referred in Figure 1, Isofagaridine displayed in vitro
cytotoxicity when tested against different cancer cell lines and behaved as a Topoisomerase I inhibitor.12 Pre-
clinical in vitro and in vivo studies on Sanguinarine showed that this compound causes apoptosis in human
cancer cells and is also an important drug candidate for cancer treatment. 13 Chelerythrine, is a potent protein
kinase C inhibitor14 and Nitidine inhibits topoisomerases I/II.15
 450

Substituted diaza- and triazachrysenes are less known and their synthesis and biological properties are
mainly reported in patented work. Compounds with this core structure (e.g., ARC-111, Figure 1) proved to
be potent topoisomerase-targeting agents with exceptional cytotoxic activity and have been studied as
anticancer agents.16
The preparation of multi-nitrogenated azachrysene derivatives is a significant challenge and only a few
synthetic methodologies were designed to generate the tetracyclic core. The synthetic approaches are usually
based on cyclization reactions to generate rings B- or C- either through free radical-mediated, aryne-
mediated, Bischler-Napieralski, or transition metal-catalysed reactions. The synthesis usually requires
several steps to generate the product but in a few examples the reagents evolve to the product in a single step
or by a cascade reaction.

2. Synthesis of monoazachrysene derivatives

In the past, various synthetic methods were described in the literature for the preparation of
azachrysene derivatives. Former work was reported in a previous review 2 and this section will focus on the
synthetic approaches leading to 2-, 5- and 6-azachrysenes.

2.1. 2-Azachrysene
Estévez et al17 described an efficient synthesis of 2-azachryses 5, from o-styrylbenzoic esters 4
(Scheme 1).

R I Pd(OAc)2, PPh3 UV light

+ CO2Me CO2Me
NEt3 I2 CO2Me
R CO2Me +
R R
R R R
1 2
3 4 R
R=H, 5%:84% 2 steps
R=OMe, 13%:68%
CH2(COH)2,
2 steps piperidine, pyr.
CON3 COOH CHO

R R R
R R R

reflux Bu3N,
Ph2O

POCl3 D C

(85-95%) B A
N=C=O NH N
R R R
R R O R Cl
5 R=H, OMe
Scheme 1
 451

These compounds were prepared by Heck coupling of methyl o-iodobenzoates 2 to styrenes 1. In this
reaction, the 9-coupling product 3 was also formed but in a minor extent. Esters 4 were transformed into the
phenanthrenylbenzoic acids and then into the target compounds 5 by a six-steps sequence including a
Bischler-Napieralski cyclization. The halogen in position 1 of the tetracyclic skeleton is a versatile feature
and allowed the formation of a diversity of derivatives.
The same research group reported another procedure18 involving the Heck coupling reaction between
2-(2-ethoxycarbonylaminoethyl)phenyl esters and styrenes to give [2-(2-styrylphenyl)ethyl]carbamic acid
ethyl esters 8 (Scheme 2). These compounds were cyclized to (2-phenanthren-1-yl-ethyl)carbamic acid ethyl
esters 9, from which 2-azachrysenes 10 were obtained in a five-steps sequence.

3 steps UV light, I2
+
O O HN HN (80%)
CO2Et CO2Et
6 7 8 9 HN
CO2Et
POCl3

Tf2O,
DMPA

NH N X N

O X OEt
OEt
LiAlH4 (85%) X=OP(O)Cl2, OTf

I2, AcONa

(10%)
NH N

10
Scheme 2

2-Azachrysene 13 was obtained by a Wittig condensation of benzyltriphenylphosphonium chloride 11

with isoquinoline-5-carbaldehyde, followed by a photochemical cyclization of the mixture of
diastereoisomeric alkenes 12.19 Methylation of 13 with MeI in THF led to the salt 14 (Scheme 3).

2.2. 5-Azachrysene
Elvidge et al20 generated two dimeric cyclisation products when o-cyanobenzyl cyanide 15 was treated
with sodamine in formamide solution. The use of a strong base was important in the synthesis of the major
product, the 3-benzylisoquinoline 16, formed by nucleophilic attack of the methylene carbanion to the cyano
group of another cyanomethylene substituent. The azachrysene 17 was isolated in only 3% yield when the
 452

carbanion attack occurred to the aromatic cyano group, followed by two intramolecular cyclization reactions
(Scheme 4).

R R R
PPh3 Cl
R N hv MeI
(52%) N (80%) N N

11 12 13 R=H, NBu2 14 R=NBu2 I

Scheme 3

NaNH2, CN CN
NC NC NH NH2
HCO.NH2
NC NC
CN CN
15
CN CN
2 steps

NH2 NH2 NH2

N N N

(3%)
R CN CN
H2N
16 R=CN, CONH2 CN CN
17
Scheme 4

Roussi et al21 reported the formation of dihydrobenzo[c]phenanthridines 20 when substituted

iodobenzylamines 18 were reacted with different tetralones 19 (Scheme 5).

O R2 NH2 R2
N
R2 R4 O
NH2 1 R4 1 R4
+ R R
R1 I R3
R3 R3
18 19
(35-79%) [O], air
2 2
R R
N N
4
R Pd/C R4
R1 R1
(63-98%)
R3 R3
21 20
R1=R2=H, OMe, i-OC3H7, OCH2O
R3,R4=H, OMe, i-OC3H7, OCH2O
Scheme 5
 453

The reaction proceeded by nucleophilic attack of the enolate of 19 to the iodobenzene, followed by
intramolecular cyclization between the amino and carbonyl groups with elimination of water, to yield the 2-
aryltetralones. Dehydrogenation of the tetracyclic ring 20 in the presence of Pd/C, gave the
benzo[c]phenanthridines (or 5-azachrysene) 21.
Kessar et al22 synthesized several benzo[c]phenanthridine alkaloids (Scheme 6). The reaction was
initiated by the synthesis of the Schiff base when the haloaldehyde 22 and naphtylamines were refluxed in
ethanol followed by reduction with sodium borohydride leading to 23. Reaction of this compound with
KNH2/NH3 and manganese dioxide in chloroform led to the 5-azachrysene 24. Compound 24 was also
isolated in 63% yield from direct cyclization of the Schiff base induced by KNH 2/NH3 followed by MnO2.
An analogue of compound 24, with a non-aromatic A ring, was prepared and isolated in good yield from the
corresponding analogue of 23, by an oxidative coupling process promoted by phenyliodine(III)-
bis(trifluoroacetate) (PIFA).23
The imine was also reduced to amine by dimethylamineborane to give the key intermediate 23 in good
yield (Scheme 6).24 The subsequent step also involved a benzyne intermediate generated by treatment of the
substituted benzylamine with LDA. Oxidation with manganese dioxide afforded 5-azachrysene 24 that was
methylated with methyl 2-nitrobenzenesulfonate (ONBSM) to give 25.

NH2
R R6 R R
OHC R 1 R1 R1
R5 N NaBH4 NH
(72-98%) R4 R6
R4 R2 R2 R4 R5 (39-85%) R2
3 3 6 3
R R R R
R5
4 3 23a,b
22a R =Cl, Br, R =H
b R4=H R3=Cl, Br KNH2/NH3
KNH2/NH3
MnO2
R3=H
R R R
R1 R1 R1
N MnO2 NH NH
R6 (10-91%) 2 R6 R6
R2 R R2

R5 R5 R5
24a,b
1. ONBSM
2. deprotection
R
R1 Cl
N
R6
R2

R5
25a,b
R,R1,R2,R5,R6= H, OMe, OH, PhCH2O, OCH2O
Scheme 6

Benzo[c]phenanthridine alkaloids were prepared, from bromonaphthylamine 27.26 The first approach
involved the 2-formylphenylboronic acid 26 that was synthesized from bromobenzaldehyde 22 after
 454

protection and deprotection of the benzaldehyde group (Scheme 7). Reaction of 26 with 2-
bromonaphthylamine 27 gave azachrysenes 28 in 35-58% yield in the presence of palladium acetate and
triphenylphosphate. This reaction was accompanied by extensive deboronation with significant formation of
piperonal as a side product.

R R O R
1. n-BuLi NH2
R1 CHO R1 R1 CHO
OHCH2CH2OH O 2. B(OiPr)3 Br R4
+
(89-98%) R2 (60-61%)
R2 Br Br R2 B(OH)2
R3
22 26 27
(35-58%) Pd(OAc) 2, PPh3
or Pd(PPh3)4
R
R1
N
2 R4
R

R3
1 2 3 4
28 R,R ,R ,R ,R = H, OCH2O, OMe
Scheme 7

Protection of the 1-amino group in 27 by formylation (29) prior to the Suzuki coupling led to much
better yields of the coupled products 31 (Scheme 8).26 These compounds were then methylated using
iodomethane and sodium hydride leading to formamides 32. Naphthalenes 31 and 32 were used as
precursors of azachrysenes 28 and 33 respectively, using the Bischler-Napieraski reaction.

R1
NH2 NHCHO NHCHO
Br R4 Br R4 R1 2 R4
HCO2H Pd(OAc)2, PPh3 R
+
R3 (88-91%) R3 R2 B(OH)2 (74-100%) R3
27 29 30 31
MeI, NaH
(93-99%) POCl3
(100%)
R1 Me R1 R1
N NMeCHO N
POCl3 4
R4 R R4
R R R2
(91-100%)
R3 R3 R3
33 32 28
Scheme 8

Kundu et al27 also developed an efficient and versatile method for the synthesis of
benzophenanthridines upon reaction of phenylboronic acid 35 and bromonaphthylamines 34 (Scheme 9).
The synthesis of compound 36 occurs in a single step, via Suzuki coupling. Combining amine 36 with
aldehydes led to the formation of azachrysene 37 via -cyclization of the intermediate imine, followed by
spontaneous air oxidation.
 455

NH2 R2 R2
Br R1
Pd(PPh3)4 R1
NH2
+
R B(OH)2 (65-80%) R
R3
34 35 36 R3

(57-75%) R4CHO

R2 R4 R2 R4
R1 R1
N [O] NH

R R

R3 R3
37
R, R1, R2=H, CH3, OCH3, R3=H, 3,4-(OCH3)2C6H3, 3,4,5-(CH3)3C6H2
R4=H, 4-OEtC6H4, 4-OHC6H4, 4-BrC6H4, 4-FC6H4, 4-ClC6H4, 4-NO2C6H4,
4-(CH3)2NC6H4, 3,4-(OCH3)2C6H3
Scheme 9

The synthesis of N-nornitidine 42 was reported by Rigby et al28 and is based on the [4+2]
cycloaddition of a substituted benzyne with an appropriate vinyl isocyanate (Scheme 10). N-
Aminobenzotriazole 38, used as the benzyne precursor, was obtained in two steps from nitroaniline, in 45%
overall yield. On the other hand, vinyl isocyanate 39, obtained via modified Curtius rearrangement, was
neither isolated nor characterized and was immediately reacted with the benzyne leading to the cycloaddition
product 40 after slow addition of a slight excess of Pb(OAc) 4. Subsequent exposure of 40 to refluxing POCl3
generated the aromatic chlorobenzophenanthridine 41 in 45% yield. Finally, hydrogenolysis of 41 under
standard conditions gave N-nornitidine 42.

1. HNO2
2. CH2(CO2Et)2 1. HNO2 MeO
MeO NH2 MeO NH2 MeO N
3. H2, PtO2 2. HCl Pb(AcO)4
N
(75%) N (60%)
MeO NO2 MeO N MeO N MeO
H C(CO2Et)2
38 NH2
O
O CO2H N C
1. DPPA OMe
O 3 steps O 2. PhMe, reflux O
+
(48%) OMe
O O O
39
Pd(OAc)4
Cl O
MeO Pd/C-H2 MeO POCl3 MeO
N N NH

O (72%) O MeO O
MeO MeO

O O O
42 41 40
Scheme 10
 456

Ishii et al29 also used the 2-aryl-1-tetralone intermediate as a strategy to produce a number of
benzophenanthridines (Scheme 11). 2-Aryl-1-tetralone derivatives 43 were obtained from chalcones via 2,4-
bisaryl-4-oxobutyronitriles, followed by hydrolysis, hydrogenation using Pd/C and cyclization with
phosphorus pentachloride. Compounds 43 were used as precursors of 44, that were cyclized to the
tetrahydrobenzophenanthridines 45 by the Bischler-Napieralski reaction using phosphorus oxychloride.
Aromatization and quaternization afforded benzophenanthridine alkaloids 46.

R4 O R4 R4
R3 CHO OR NaOH R3 X R3 X
H3 C EtOH KCN
+
OR (77-100%) 2 CN OR
R2 X OR R2 R
1 1 1
R R R
OR OR
X=H, Br O O
(76-100%) H2SO4/AcOH
4 4
R R R4
R3 X R3 X 1. H2, Pd/C R3 X
NHCHO O 2. PCl5
OR OR COR5 OR
R2 R2 R2
1 1 1
R R R
OR OR OR
44 43
O
POCl3
R5=NH2, OH
R4 R4
R3 1. Pd/C R3 CH3SO4
N N CH3
2. Me2SO4
OR OR
R2 R2
1
R R1
OR OR
45 46
Scheme 11

Clement et al30 reported a simple one-step synthesis of 6-aminobenzo[c]phenanthridines 50 that

involved condensation of aromatic aldehydes 47 with 2-methylbenzonitrile 48 (2 equiv.) to give the fused
ring system 49 (Scheme 12).

NH2 NH2

O CN N N
KOtBu, DMPU DDQ
+ 2
R H R1 Me (11-89%) R1 (4-58%) R 1

R R
47 48 50
49
R=H, C6H5, 2-MeOC6H4, 3-MeOC6H4, 4-MeOC6H4, 4-MeC6H4, 3-BrC6H4, 4-ClC6H4, 4-FC6H4, 2-OEtC6H4,
4-OEtC6H4, 2,3-(MeO)2C6H3, 2,4-(MeO)2C6H3, 2,5-(MeO)2C6H3, 3,4-(MeO)2C6H3, 3,5-(MeO)2C6H3, 2,3,4-
(MeO)3C6H2, 2,4,5-(MeO)3C6H2, 2,4,6-(MeO)3C6H2, 3,4,5-(MeO)3C6H2, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-
furyl, 2-thienyl, 4-(2-propyl)phenyl, 1-naphthyl, 3-OH-4-OMeC6H3, 4-OH-3-OMeC6H3, 3-OH-2,4-OMeC6H2,
4-OH-3,5-OMeC6H2, 3,4-methylenedioxyphenyl, 4-Me2NC6H4, R1=H, OMe

DMPU=1,3-dimethyl-3,4,5,6-tetrahydropyrimidine-2-(1H)-one
Scheme 12
 457

The fully aromatized structure was accessible through subsequent oxidation with 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone (DDQ). Benzophenanthridine 50 (R=R1=H, 41%), was also prepared from
naphthylamine and 2-chlorobenzonitrile, in a single step, in the presence of a mixture of sodium and lithium
amide in liquid ammonia.31
Bisagni et al32 synthesized benzophenanthridin-6(5H)-ones 53 where the key step was the preparation
of tetrahydrobenzo[c]phenanthridin-6(5H)-ones 52 from 1-naphthylisocyanates 51 and a morpholino
enamine (Scheme 13). Dehydrogenation of ring D with Pd/C yielded the final product 53. Subsequent
chlorination followed by reaction with alkylamines led to 6-amino-substituted benzo[c]phenanthridine
derivatives 54 bearing a (dimethylamino)alkylamino side chain at the 6-position.

R2

NH2 NCO N N O O
R1 1. HCl R1 R2
2. (Cl3CO)2CO O NH NH
R1 R1
R R (31-73%)
R2
51 R 52 R
(44-89%) 10% Pd/C

NH(CH2)nN(CH3)2 Cl O
R2 R2 R2
N Me2N(CH2)nNH2 N POCl3 NH
R1 R1 R1
(n=2, 30-90%) (63-91%)
(n=3, 58-89%)
R R R
54 R, R1, R2= H, OMe, OH, OiPr 53
Scheme 13

The benzo[c]phenanthridone skeleton 59 was synthesized by Cho et al33 from o-methylbenzonitrile 48

and N-methyl-o-toluamide 55 in seven steps (Scheme 14). Amide 55 was basified with n-butyl lithium to
give the dianion which was reacted with o-methylbenzonitrile 48 to afford the 3-(2-
methyl)phenylisoquinolin-1(2H)-one 56. The reaction proceeded in four steps involving methylation of the
amide nitrogen, bromination followed by aldehyde formation and Wittig reaction, ultimately leading to
styrene 57. Oxyfunctionalization of 57 with thallium trinitrate in methanol gave the acetal 58, which was
then hydrolyzed with 10% HCl to provide the desired 5-methylbenzo[c]phenanthridin-6-one 59, in 34%
yield. Radical cyclization of styrene 57 with tributyl tin hydride in the presence of
azobiscyclohexanecarbonitrile (ACCN) led to the selective formation of 6,11-di-methyl-6,11-dihydro-5H-
indeno[1,2-c]isoquinolin-5-one 60, and not to the benzophenanthridone 59. The authors also realized that the
indeno[1,2-c]isoquinolin-5-one 60 showed excellent in vitro antitumor activity when compared to
benzophenanthridone 59.
Estévez et al34 described the transformation of 1-benzylisoquinolines into benzo[c]phenanthridones
through the C-N cleavage by LDA, in 1-benzylidine derivatives 61 (Scheme 15). Compounds 62 were
 458

transformed into naphtalenes 63 by a Bichler-Napieralski reaction followed by cyclization to the

corresponding tetrasubstituted benzo[c]phenanthridones 64.

O O O O
CN Me
N n-BuLi NH NaI, MeI NMe Br2 NMe
+ H
Me Me (55%) (90%) (64%)
Br
48 55 56 Me Me
Br
Br
CaCO3, H2O (87%)
DMF
O O O O
Me
N NMe NMe NMe
MeOH Ph3PCH3Br
HCl Tl(NO3)3.3H2O n-BuLi
Br Br Br Br
H (34%) MeO (60%) (90%)
O
O MeO H
58 57
(88%) ACCN, n-Bu3SnH
O O

NMe NMe

Me
59 60
Scheme 14

OMe
OMe EtO2C
R H CO2Et R R1
N N
R 1. 10% Pd/C
LDA OMe 2. NaH, MeI OMe
R R
N (100%) (74-75%)
R EtO2C OMe OMe
61 62 63
(58-66%) P2O5, POCl3
O
R Me
N
OMe
R

OMe
64 R=H, OMe, R1=H, Me
Scheme 15

Two years later these authors described a modification of this approach that provides access to
vinylphenylisoquinolinones 65, and a new method for the total synthesis of benzophenanthridones 67
(Scheme 16).35 Compound 62 was reacted with triflic anhydride (Tf2O) and N,N-dimethylaminopyridine
(DMAP) and the Bischler-Napieralski cyclization afforded vinylphenylisoquinolinones 65. Treatment with
 459

thallium (III) trinitrate in methanol afforded the acetal 66, which undergoes hydrolysis, cyclization, and
dehydration on addition of 10% hydrochloric acid, leading to 67. Successive reduction with LiAlH4 and
oxidation with DDQ produced nitidine, fagaronine or chelerythrine, depending on the substitution pattern.

OMe
O
R1 1. LDA
MeO R2 CO2Et Tf2O, DMAP MeO Me
2. NaH,MeI N N
MeO
OMe (40-50%) OMe
(74-100%) MeO MeO
N
MeO
EtO2C R1 R1
61 62 65
MeOH
Tl(NO3)3.3H2O
R3 O O
Cl 1. LiAlH4
R4 Me 2. DDQ MeO Me MeO Me
N 3. H2SO4 N N
2
10% aq HCl
R OMe OMe
R5 (23-30%) MeO (80-95%) MeO
MeO
R1 R1 MeO R1
nitidine (R1+R2=OCH2O, R3=H, R4=R5=OMe) 67 R=OMe, OiPr 66
fagaronine (R1=OH, R2=R4=R5=OMe, R3=H)
chelerythrine (R1+R2=OCH2O, R3=R4=OMe, R5=H)
(R1=OiPr, R2=R4=R5=OMe, R3=H)
Scheme 16

Eight years later, a novel synthesis of benzo[c]phenanthridin-6-one 73 was published by Cho (Scheme
36
17). The initial step was the coupling between o-toluamide 69 and benzonitrile 70 to produce 3-
arylisoquinoline 71. o-Toluamides 69 were synthesized in good yield from the corresponding substituted
benzoic acids 68 by treatment with oxalyl chloride followed by diethylamine. Compound 72 was formed
after N-methylation and hydrolysis of the MOM protecting group with HCl. The alcohol functional group in
72 was oxidized with PCC ultimately leading to the aromatized benzo[c]phenanthridine 73. The catalytic
hydrogenation reaction of 73 (R1=OBn) with 5% Pd/C removed the benzyl group to give the oxyterihanine
(R1=OH) in 53% yield.36b

R O R O R O
1. (COCl)2 1
R1 R CN O n-BuLi R1
OH 2. NHEt2 NEt2 NH
+
R2
Me
(92-85%)
R2
Me MOMO O (27-50%) R2 O

68 69 70 MOMO O
71
(72-90%) K2CO3, MeI

R O R O R O
R1 Me R1 Me R1 Me
N N N
PCC, NaOAc 10% HCl
R2 O R2 O O
(61-76%) (70-80%) R2
O HO O MOMO O
73 R, R1, R2=H, OCH3, OBn, OH, OCH2O 72
Scheme 17
 460

A convenient and versatile synthesis of benzophenanthridones 77, was reported by the internal biaryl
coupling reaction of haloamides 76 using a palladium reagent (Scheme 18).37 Compound 76 resulted from
treatment of 75 with oxalyl chloride followed by addition of amine 74 and trimethylamine. Methylation with
methyl iodide in the presence of sodium hydride in DMF gave the iodoamide or bromoamide 76. The
coupling reaction of haloamides 76 was performed using Pd(OAc)2, PPh3 or P(o-Tol)3 and Ag2CO3 affording
chelerythrines 77. Reduction of 77 with LiAlH4 followed by treatment with HCl gave benzophenanthridine
78, which was reduced with NaBH4 to afford 12-methoxydihydrochelerythrine 79, isolated in 77% yield.

OMe O
NH2 OMe MeO Me
HO2C OMe 1. (COCl)2 N
O 2. MeI, NaH
+ O
X
O X (56-96%)
R O
74 R=H, OMe 75 X= I, Br 76 R

Pd(OAc)2, PPh3 (79-96%)

or P(o-Tol)3, Ag2CO3

OMe OMe OMe O

MeO Me MeO Me 1. LiAlH4 MeO Me
N N N
NaBH4 2. HCl
O O O
(77%) (82%)
O O O
79 OMe 78 OMe 77 R
Scheme 18

Roussi et al21 also reported the formation of benzo[c]phenanthridones 81 starting with an SRN1
reaction between 2-iodobenzoic acids 80 and the enolate of tetralones 19 (Scheme 19). This procedure is
similar to that used for the synthesis of dihydrobenzo[c]phenanthridines 20 described in Scheme 5 and
involved irradiation of the reagents followed by reflux in benzene containing p-toluenesulfonic acid. The
ester evolved to the amide upon heating with methylamine, in a sealed container.

O
O R CO2H R
O O
R CO2H R4 H+
+ R4 R4
R1 R 1
1 3 (60-75%) (65-72%)
R I R R2 R2
R3 R3
R2
80 19 (60-95%) CH3NH2

O O
R CH3 R CH3
N Pd/C N
4
R (83-96%) R4
R1 R1
R2 R2
R3 R3
1 2 3 4 i
81 R=R =R =H, OMe, R , R =H, OMe, O C3H7
Scheme 19
 461

The fully aromatic system was obtained after treatment with Pd/charcoal.
Castedo et al38 developed a highly convergent strategy to benzo[c]phenanthridones based on the ability
of dihydronaphthalenopyrrolinediones to undergo [4+2] cycloadditions with the highly electrophilic benzyne
system (intramolecular benzyne cycloaddition) (Scheme 20). The tetralone 19 was converted into the N-
methylimine and then treated with oxalyl chloride under carefully controlled conditions to provide the
dihydronaphthalenopyrrolinedione 82. Reaction with benzyne 83, was performed in 1,2-dimethoxyethane
(DME) under reflux conditions, and was initiated by nucleophilic attack of the enamine to the electrophilic
benzyne, followed by elimination of carbon monoxide, producing the dihydrobenzo[c]phenanthridin-6(5H)-
one 84.

O CH3
CH3
O N N
R 4 CH3NH2 R4 (COCl) O R4
TiCl4 2

R3 (82-100%) R3
(57-81%) R3 R2 O
1
19 82 R CH3
DME N
(16-49%) R3
R2 R2 R
R1 CO2H Me2CH(CH2)2ONO R1
CCl3COOH R4
84 R, R1, R2= H, OCH2O, OMe
R NH2 R
R3, R4=H, OMe, OCH2O, OiPr
83
Scheme 20

Chiba et al39 prepared benzo[c]phenanthridines 86 by an oxidative radical perfluoroalkylation of

biarylvinyl azides 85 (Scheme 21). Readily available and easily handled Me3SiCF3 was used as the
perfluoroalkyl radical source under oxidative conditions in the presence of PhI(OAc)2 and KF with a
catalytic amount of benzoquinone.

CF3
R R
1 Me3SiCF3, PhI(OAc)2, 1
R R
N N2 KF, Benzoquinone (cat) N
2 2
R (61-76%) R
R3 R3

85 86 R+R1=(CH)4, R2=R3=H
R=R1=H, R2+R3=(CH)4
Scheme 21

2.3. 6-Azachrysene
The reaction between 2-(1-pyrrolidino)-3,4-dihydronaphtalene 87 and N-methylformanilide 88 in the
presence of phosphorus oxychloride afforded the 11,12-dihydro-6-methylbenzo[i]phenanthridinium
hexafluorophosphate 89, isolated after addition of ammonium hexafluorophosphate (Scheme 22).40
Oxidation to the aromatic quaternary benzo[i]phenanthridine 90 occurred in excellent yield in the presence
of iodine.
 462

Me Me Me
POCl3,
N N H N N
NH4PF6 I2
+
O (51%) (96%)

87 88 89 90
Scheme 22

Rigby et al41 reported the synthesis of 7,8,9,10,11,12-hexahydrobenzo[i]phenanthridin-5(6H)-one 92,

in a single step, from the reaction of vinyl isocyanate 91 with enamine 87 (Scheme 23).

H
NCO N N O
+
(61%)
91 87
92
Scheme 23

The synthesis of substituted benzo[i]phenanthridines 97 was also performed from the substituted -
tetralone 93 under bromo-Vilsmeier conditions leading to aldehyde derivatives 94 (Scheme 24).42 Treatment
of this compound with DDQ in toluene provided the bromo-naphthaldehydes 95. Stille coupling of 95 with
various trimethyl(ortho-nitrophenyl)stannanes gave 96, and reduction of the nitro group with zinc dust in
acetic acid followed by intramolecular cyclization with the carbonyl group, provided the
benzo[i]phenanthridines 97 in yields ranging from 40-90%. The synthesized compounds were evaluated as
topoisomerase I-targeting agents and the substituent in the 8-position was important for the pharmacological
activities that were evaluated.

O H O H
1
O R
DMF, PBr3 Br R1 Br R1
DDQ
(80%) (80-96%)
R R R
93 94 95
R3 Sn(CH3)3

(20-95%)
R2 NO2
(CH3)3SnSn(CH3)3
or CuBr, Pd(PPh3)4
R2 N H NO2 H
Zn dust, AcOH R2
O
R1
R3 (40-90%) R1
R3
R
R
97 R,R1=H, OCH3, OCH2O, OBn 96
R2,R3=H, OCH3, OCH2O, NO2, CN, CHO, OBn
Scheme 24
 463

Yanada et al43 reported the synthesis of compounds 100 via a domino intramolecular nucleophilic
attack/intermolecular cycloaddition/dehydration process from the indium(III)-catalyzed tandem reaction of
ortho-alkynylbenzaldehydes 98 and ortho-alkynylanilines 99 (Scheme 25).

R N R
NH2 ln(OTf)3
(10 mol%)
R2 +
R2
COR1 DMF, 120 ºC, 24 h
3
R (30-93%) R3
R1
98 99 100 R=Ph, Bu, R1=H, Me
R2=H, 4-Me, 5-F, 6-F, R3=Bu, SiMe3
Scheme 25

3. Synthesis of diazachrysene derivatives

Diazachrysene derivatives are also known compounds, but only three examples (1,10-, 2,4-, and 4,10-
diazachrysenes) were previously reported in the literature.4a-b This section highlights the advancements in the
synthesis of other diazachrysene derivatives.

3.1. 1,7-Diazachrysene
The only representative example of this heterocyclic system reported in the literature was prepared
from 1,5-diaminonaphthalene 101 (Scheme 26)44 used as a precursor of intermediate 102, generated via a
Conrad-Limpah reaction. Compound 102 was reacted with POCl3 to give the dichloride 103. Nucleophilic
substitution with a variety of diamines, followed by HCl salt formation, led to 1,7-
bis(aminoalkyl)diazachrysene tetrahydrochloride 104.

EtO2C

NH2 O O NH
H
EtO CH3 N
MeSO3H/P2O5 O
(94%) (94%)
NH2 HN O
N
101 102 H
CO2Et
(93%) POCl3
1. RNH2
N N
NHR 2. HCl/EtOH Cl
(55-88%)
NHR Cl
4 HCl N N
104 103
R=CH2CH2CH2CH2NH2, CH2CH2CH2NH2, CH2CH2NH2, CH2CH2CH2N(CH3)2,
CH2CH2N(CH3)2, CH2CH2CH2NEt2, CH2CH2NEt2, CH2CH2CH2N(CH2)4, CH2CH2N(CH2)4,
CH2CH2CH2N(CH2)5, CH2CH2N(CH2)5, CH2CH2CH2N(CH2CH2)2O, CH2CH2N(CH2CH2)2O
Scheme 26
 464

3.2. 5,6-Diazachrysene
LaVoie et al45 reported the synthesis of substituted dibenzo[c,h]cinnolines 112 (Scheme 27) and
evaluated these compounds as topoisomerase I-targeting anticancer agents. The reaction sequence started
with the coupling of 105 with o-iodonitrobenzene 106, under conditions analogous to those used in the Heck
reaction, leading to 107. Oxidation of 107 with DDQ provided the naphthyl derivatives 108. These
compounds were also obtained by a different synthetic approach (Scheme 27) involving substituted ortho-
nitroarylstannanes 109. Stille coupling with naphthalene derivatives 110 led to 108. Reduction of the nitro
group followed by diazotization of the aniline 111 led to the benzo[c,h]cinnolines 112.

R NO2

OH R1 Br
OCH3 (21-66%) (CH3)3SnSn(CH3)3
Pd(PPh3)4

OCH3 R NO2 TfO R3

+
H3PO4 (100%)
R1 Sn(CH3)3 R2
OCH3 109 110
Pd(PPh3)4, CuBr
OCH3
R NO2 R NO2
105
Pd(PPh3)Cl2 DDQ
+ OCH3 R3
R1 R1
R NO2 (29%) (34-91%)
107 OCH3 108 R2
1
R I
(16-100%) H2, Pd/C
106
R N R NH2
N HBr, NaNO2, Cu powder or
3 NaNO2, AcOH, concd HCl R3
R
R1 R1
(11-83%)
R2 R2
112 R, R1, R2, R3= H, OCH3, OCH2O, OBn 111
Scheme 27

3.3. 5,7-Diazachrysene
Takeuchi et al46 combined 5-aminotetralin 113 with sodium nitromalonaldehyde monohydrate to give
compound 114. Cyclization using polyphosphoric acid (PPA) (Scheme 28) led to 115. The nitro group in
115 was reduced to the amine 116 with Raney nickel, followed by the Skraup reaction to give compound
117. Naphto[2,1-f][1,7]naphthyridine 118 was obtained by dehydrogenation of 117 using DDQ.

3.4. 5,8-Diazachrysene
Acid catalyzed condensation of 1-aminoanthracene 119 and 5-bromonicotinaldehyde 120 followed by
reduction with sodium borohydride in methanol afforded compound 121 (Scheme 29). Cyclization with
excess LDA and manganese dioxide dehydrogenation led to diazachrysene 122.47
 465

OHC
NO2 Na. H2O O2N O2N
NH2 N N
OHC PPA
O
(72%) (79%)

113 114 115

(65%) 1. NH2NH2.H2O
2. Ra-Ni
N N H2N
N N Glycerol N
DDQ
(27%) (29%)

118 117 116

Scheme 28

NH2
1. PTSA 1. LDA
Br 2. NaBH4 Br 2. MnO2
+ N NH N N
(52%) (48%)
N
CHO
119 120 121 122
Scheme 29

3.5. 5,10b-Diazachrysene
An efficient iodine-mediated electrophilic tandem cyclization between substituted 2-
alkynylbenzaldehydes 123 and 2-aminobenzamides 124 led to isoquinoline-fused quinazolinones 125
(Scheme 30).48 The presence of the iodo group confers an advantage for further derivatization via robust
cross coupling reactions, that were exemplified by Sonogashira and Suzuki cross-coupling reactions.

O O
CHO I2, K2CO3, Na2SO4
R NH2 R2 N
+ R2
(85-92%)
NH2 N R
R1
123 124 R1
I
125 R= H, 4,5-(OMe)2, 5-F, 5-OMe
R1=Ph, 4-tBuC6H4, 4-MeC6H4, R2=H, 5-NO2
Scheme 30

The reaction of 2-aminobenzonitrile 126 with 3-methylisocoumarin 127 in the presence of potassium
tert-butoxide gave the isocarbostyril 128 (Scheme 31).49 Attempts to induce ring closure of 128 to 131 by
treatment with methanolic hydrogen chloride resulted in compound 129. The novel ring system 12-methyl-
6H-isoquino[2,1-a]quinazolin-6-one 131 was generated by treatment of 128 with alkaline hydrogen
peroxide, leading to 130, followed by cyclization of this compound with boron trifluoride etherate.
 466

CN CO2CH3
CN CH3 O O
t-BuOK HCl -CH3OH
+
O (33%) N N
NH2
O H3C H3C
126 127 128 129
(81%) H2O2
O
CONH2 BF3.Et2O
O N
(42%)
N N

H3C H3C
130 131
Scheme 31

Fu et al50 report a novel and efficient copper-catalyzed one-pot synthesis of

tetrahydroisoquinolino[2,1-a]quinazolinone derivatives 136 (Scheme 32). In this case copper-catalysed N-
arylation of substituted 1,2,3,4-tetrahydroisoquinoline 133 with amide 132 provided 134. Intramolecular
aerobic oxidation of 134 in the presence of base (two or four equivalents of K3PO4) led to 135.
Intramolecular nucleophilic attack of the amide nitrogen to the imine carbon in 135 led to the N-fused
heterocycles 136.
The enantioselective C-N bond-forming reaction to produce 136 was described in the literature and
was also catalyzed by chiral phosphate anions,51 palladium(II)-porphyrin complex,52 tris(4-
bromophenyl)aminium hexachloroantimonate (TBPA+SbCl6ˉ)53 or iodine(III).54

O O
R1 1. CuI, K3PO4, DMSO, 80 ºC, R1
N HN 12-24 h, N2 N
R H + R 2
R
Y X 2. 120-125 ºC, 48-72 h, O2 Y N
R2
132 133 (41-89%)
136
CuI, K3PO4, DMSO, N2
N-arylation
O O
R1 R1
N N
R H K3PO4, O2 R
Y N Y N
R2 R2
H2O
134 135
Scheme 32

3.6. 5,11-Diazachrysene
The synthesis of dibenzo[c,h]-1,5-naphthyridine derivatives was reported to occur from substituted
benzaldehydes 137 and arylacetic acid 138 (Scheme 33).55 The 4-amino-3-aryl-isoquinolin-1-(2H)-ones 139
were prepared in five steps and then combined with ethyl chloroformate or acetic anhydride leading to the
acylated derivatives 140. Thermal cyclisation of compounds 140 (R2=OEt) provided dibenzo[c,h]-1,5-
 467

naphthyridinediones 141. Compounds 140 (R2=CH3) were used as precursors of dibenzo[c,h]-1,5-

naphthyridine derivatives 144 in another five steps. The different amino substituted derivatives 144 were
obtained from the chloro-substituted analogues 143 by reaction with 2-dimethylaminoethylamine or 3-
dimethylaminopropylamine under reflux conditions.

O O
R R1 R1 R1
NH2 ClCOOEt HN R2 (C6H5)2O NH
R1 5 steps or (CH3CO)2O NBu3
+ R2=OEt, 83-93%
(53-95%) R2=OEt
HN 2 HN HN
R R =CH3, 56-91% R R
CHO CO2K
O O O
137 138 139 140 141
POCl3 C6H5P(O)Cl2
R2=CH3 160 ºC

NH(CH2)nN(CH3)2 Cl Cl
R1 R1 R1
N N N
NH2(CH2)nN(CH3)2

n=2, 50-94%
N n=3, 70-85% N N
R R R
R2 CH3 Cl
144 R, R1=H, OCH3, R2=H, CH3 143 142
Scheme 33

Cushman et al56 recently reported another alternative for the synthesis of dibenzo[c,h]-1,5-
naphthyridinediones 153, analogous to 141, where one of the isoquinolinone nitrogens was replaced by an
aminopropyl side chain (Scheme 34). The synthetic approach involved the reaction of 145 with 3-
chloropropylamine, followed by reaction of the resulting Schiff base 146 with 4,5-dimethoxyhomophthalic
anhydride to produce the cis-isoquinolonic acid 147. Thermal decarboxylation of 147 led to
dihydroisoquinolone 148, that was treated with DDQ to provide the dehydrogenated isoquinolone 149. The
nitration of compound 149 occurred in the 3-position yielding 150. The Finkelstein reaction of 150 with
sodium iodide led to 151, which was further reacted with imidazole or morpholine to give amines 152.
Reduction of the nitro group with sodium bisulfite resulted in the formation of the dibenzo[c,h]-1,5-
naphthyridinediones 153. The compounds prepared were evaluated for their Topoisomerase I inhibitory and
antiproliferative activities.

3.7. 5,12-Diazachrysene
Papageorgiou et al57 described the synthesis of cis-4b,5,6,10b,11,12-hexahydro-5,12-diazachrysene
156. The reaction proceeded by intramolecular cyclization of 2,3-diphenylsuccinic acid 154 in the presence
of methanesulfonic acid (Scheme 35). The reductive Beckmann rearrangement of the oxime converted
indeno[2,1-a]indene-5,10-dione 155 to the 5,12-diazachrysene 156.
Another procedure for the synthesis of 5,12-diazachrysene was described from a readily available
indole 157 (Scheme 36).58 Reaction with aromatic aldehydes led to 10-benzylidene-5-methyl-5,10-
dihydroindeno[1,2-b]indole 158 that was oxidized with hydrogen peroxide to give the
dioxodibenzo[b,f]azocine 159. Refluxing 159 with ethylamine generated the new diazachrysene 160,
isolated in 50% yield. This compound exhibited strong yellow fluorescence under ultraviolet light.
 468

MeO O Cl

O O O O
Cl(CH2)3NH2.HCl MeO MeO
OMe MgSO4 OMe O N CO2Me
H (99%) N Cl
(82%) MeO
O CO2H
145 146 cis-147

(54%) heat
Cl Cl Cl
O O O
HNO3
MeO MeO MeO
N CO2Me CH3CO2H N CO2Me DDQ N CO2Me
(72%) (70%)
MeO MeO MeO
NO2
150 149 148

(98%) NaI
I R R

O imidazole or O O
MeO morpholine, MeO NaHSO3 MeO
N CO2Me K2CO3 N CO2Me N
(97-100%) (51-64%)
MeO MeO MeO
NO2 NO2 HN

151 152 O
153 R= N N N O

Scheme 34

O N OH
CO2H MeSO3H, HONH2.HCl DIBAH, NH
P2O5 Na2CO3 HCl
(50%) (26-90%) (23%)
CO2H
O N N
154 155 OH 156 H
Scheme 35

Mackay et al40 reported the synthesis of 6-methyl-12-oxodibenzo[c,h][1,6]naphthyridine 163 in three

steps from the benzopyrano[4,3-c]quinolinium phosphodichloridate 161 (Scheme 37). Cleavage of the
lactone moiety by ammonia solution yielded the amide 162. The aromatic dibenzo[c,h][1,6]naphthryridine
163 was obtain in high yield by intramolecular cyclisation in the presence of caesium carbonate, with
subsequent dehydration.
LaVoie et al16a,59 described the synthesis of analogues of ARC-111 (170) with NH2, N-alkyl, N,N-
dialkyl, pyrrolidinyl, piperidinyl and piperazinyl substituents at the 2-position of a 5-ethyl group (Scheme
38). Compound 165, prepared by reaction of o-aminoacetophenone 164 with ethyl formate in sodium
hydride, was used as the starting material. Chlorination of 165 with phosphoryl chloride provided 4-chloro-
6,7-methylenedioxyquinoline 166, used as the precursor of 4-aminoquinolines 167 after heating with
primary amines.
 469

Me Me O Me
N N
N
ArCHO H2O2
(60%)

157 O

158 Me 159
Me
(50%) NH2Et

O O O
Et
Et Et N
N N
OH H

N HN NH
O
Me Me Me Me
Me Me
160
Scheme 36

O O O
NH2
O O N
NH3 (aq) Cs2CO3
(87%) (92%)
N N N
Me Me Me
161 162 163
Scheme 37

H
O NH2 O N O N O N
NaH, HCO2Et POCl3 RNH2
O CH3 (89%) O (91%) O (8-87%) O
O O Cl HN R
164 165 166 167
R3 CO2H
(36-90%)
R2 X
R1
O O Pd(OAc)2 R3 O
R3 R RaNi R3 R P(o-tolyl)3
N NH2NH2.H2O N R
Ag2CO3 R2 N
1 (22-63%)
R2 O R =NO2 R2 O O
R1 X
R1 O R1 O
N N N O
170 169 168

R= CH2CH2N(CH3)2, CH2CH2CH2N(CH3)2, CHCH3CH2N(CH3)2, CH2CH2CH2CH3, CH2CH2N(Bn)CH3,

CH2CH2N(Bn)CH2CH3, CH2CH2N(Bn)i-Pr, CH2CH2N(Bn)t-Bu, CH2CH2N(Bn)2, CH2CH2N(Et)2, CH2CH2N(i-Pr)2

H2CH2C N , H2CH2C N , H2CH2C N CH3 , H2CH2C N N Br, H2CH2C N N CH3 , H2C

O
R1, R2, R3=H, NO2, OCH3, NH2, X=I, Br
Scheme 38
 470

The conversion of benzoic acid to the acid chloride using oxalyl chloride, followed by immediate
reaction with 167 provided variable yields of the amides 168. The Heck reaction was used for the cyclization
of these benzamides to generate 5,12-diazachrysene-6-ones 169, that were reduced with Ra-Ni in the
presence of hydrazine to give the corresponding amino analogues 170.
Kappe et al60 reported the synthesis of a 5,12-diazachrysene 173, initially as a by-product in the
reaction between 4-hydroxy-3-phenyl-2-quinolone 171 with benzylamine (Scheme 39). They realized that
the dibenzo[c,h][1,6]naphthyridine 173 could also be synthesized by thermolysis of 174. The primary amine
in the 4-position of 2-quinolone 172 allowed the preparation of different imines by condensation with
aldehydes and compounds 175 were cyclized to 173 upon heating.

heat
(15-24%)
R R R Ph
N O N O N O
PhCH2NH2 PhCH2NH2.HCl N
+
(52-91%) Ph (3-72%) Ph
Ph
HN OH NH2
CH2Ph O N
174 171 R= H, Me, Ph 172 R
(22-95%) PhCHO 173
heat
R (39-47%)
N O

Ph
N
175 Ph
Scheme 39

Dibenzo[c,h][1,6]naphthyridinediones 182 with various side chains attached to the isoquinoline lactam
were synthesized from the N-protected o-aminobenzaldehyde 176 (Scheme 40).61 Imine 177, isolated from
the reaction of aldehyde 176 with different primary amines followed by reaction with 4,5-
dimethoxyhomophthalic anhydride led to a mixture of cis- and trans-178 (isolated by filtration or by
evaporation of the filtrate and recrystallization of the crude product, respectively). The reaction proceeded to
naphthyridinediones 182 and this compound was reacted with POCl3 to yield chloronaphthyridinones 183 or
the dichloride 184, as shown in Scheme 40. The reaction of dichloride 184 with sodium methoxide gave the
tetramethoxydibenzonaphthyridine 185.

3.8. 6,12-Diazachrysene
LaVoie et al62 performed the synthesis of several 6-substituted dibenzo[c,h][2,6]naphthyridin-5-ones
193 that can be considered reversed lactam analogues of ARC-111 and these compounds were evaluated for
their topoisomerase I-targeting activity and citotoxicity (Scheme 41). 6,7-Methylenedioxy-4-
quinolinecarboxylic acid 188 was prepared from 186 after two sequential oxidation steps. Compound 190
was prepared by hydrolysis of o-iodoacetamide 189 using aqueous NaOH. The amide 191 was obtained by
 471

coupling 188 and 190 using thionyl chloride. Treatment with sodium hydride led to the amide anion, which
was reacted with substituted alkyl halides to form tertiary amide intermediates 192. Photocyclization of 192
in the presence of HCl provided the desired products 193.

O OMe

NH

O
176
RNH2
(95-99%) MgSO
4
MeO O
O OMe
O O O
NH MeO MeO R MeO R
O N NHCO2Me N NHCO2Me
H +
MeO MeO
N HO O
R HO O
177 cis-178 trans-178
SOCl2, MeOH
O O
MeO R MeO R
N NHCO2Me KOH N NHCO2Me

MeO water-ethylene glycol MeO

(1:1)
H3CO O H3CO O
180 179

O O O
MeO R MeO R MeO R
N NH2 N POCl3 N
+
MeO MeO (61-66%) MeO
HO O O N Cl N
H
181 182 183
R=Me, 96% POCl3

OMe Cl
MeO MeO
N NaOMe, MeOH N

MeO (71%) MeO

MeO N Cl N
185 184
Scheme 40

Papageorgiou et al63 report a new class of diazachrysenes starting from oxindole 194 and isatine 195 to
generate isoindigo 196 (Scheme 42). The double bond in 196 was reduced with Zn in AcOH affording 197
 472

as a 1:1 mixture of the meso and racemic form. Refluxing in HCl gave a diastereoisomerically pure δ-lactam
198 that was treated with LiAlH4 to yield the corresponding hexahydro-diazachrysene 199.

O N H3CO I
O
O H3CO N CH3
H
186 CH3 189
(65%) SeO2 (93%) NaOH
H3CO
N H
O O N H3CO I N O
KMnO4 SOCl2
+ H3CO
O (90%) O (56%) O
H3CO NH2 I
CO2H
187 O H 188 190 191 N O
RCl.HCl
(75-92%) NaH, DMF or
NaNH2, PhCH3
R H3CO R
H3CO N O N
HCl, hv O
H3CO
H3CO O (5-88%) I O

N O
N O
193 192
R=CH2CH2N(CH3)2, CHCH3CH2N(CH3)2, CH2CH2N(Et)2, CH2CH2CH2N(CH3)2, CH2CH2N(Bn)2, H3C
N
CH2CH2N(Bn)CH3 , H2CH2C N , H2CH2C N , H2CH2C N CH3, H2CH2C N O, H2CH2C

Scheme 41

H H
N N
O O O
H
N AcOH, HCl Zn/AcOH
O + O
N (100%) O O
H N N
194 195 H H
196 197
(85%) HCl

H H
N N O
LiAlH4
(78%)
N O N
H H
199 198
Scheme 42

3.9. 7,11- and 8,11-Diazachrysene

Tillequin et al64 recently published the synthesis and biological activities of a new series of
benzo[c][1,7] and [1,8]phenanthrolines substituted at C1 and C2 by dialkylaminoalkyl side chains (Scheme
 473

43). Condensation of the 2-bromoaldehyde 200 with the 5-amino-quinoline or isoquinoline gave access to
the corresponding Schiff bases. After reduction of the imine function with NaBH 4, treatment with an excess
of LDA allowed the intramolecular cyclization to compound 201 or 204. A spontaneous air oxidation step,
followed by oxidation with m-CPBA, and reaction with POCl3 originated the chloro derivatives 202 or 205.
Finally, heating these compounds with primary alkylamines generated the corresponding substituted
benzo[c]phenanthrolines 203 or 206 in low to moderate yields (6-52%).

NH2 NH2

N
N 1. 1.
Br N
1 1 N Br
R
2. NaBH4
R Br R1
2. NaBH4
HN O HN
R2 R2 R2
1. LDA 200 1. LDA
2. air oxidation 2. air oxidation
N
N
R1 R1

N N
R2 R2
204 201
1. m-CPBA
(68-82%) 1. m-CPBA (56-80%) 2. POCl
2. POCl3 3
Cl
Cl N
N
R1
R1
N
N R2
R2
205 202

(6-52%) NH2(CH2)nN(R3)2 (8-41%) NH2(CH2)nN(R3)2

3 H
HN R N N
R3
N R1
R1 R1,R2=OCH3, OCH2O N
R3=CH2CH2N(CH3)2, CH2CH2CH2N(CH3)2, R2
N 2
R CH2CH2N(CH2CH3)2, CH2CH2CH2N(CH2CH3)2 203
206
Scheme 43

4. Synthesis of triazachrysene derivatives

4.1. 1,5,10-, 2,5,9- and 3,5,8-Triazachrysene
Based on the synthesis of benzo[c]phenanthridines 49 (Scheme 12), Clement et al65 recently reported a
novel class of triazachrysenes (Scheme 44) with high cytotoxic potential as was demonstrated by
preliminary in vitro studies. The process involved a base-catalyzed condensation of various aldehydes 47
with two equivalents of methyl-cyanopyridine 207, 210 or 213 in 1,3-dimethyltetrahydropyrimidin-2-one
(DMPU), used as solvent. The 11-substituted 6-amino-11,12-dihydropyridophenanthrolines 208, 211 or 214
were oxidized with Pd/C in DMPU to provide the fully aromatic triazachrysenes 209, 212 or 215.
 474

N Me
2 NH2 NH2
Method 1:
CN Pd/C DMPU N
N
207 N
N
N Method 2: N
KOtBu, DMPU NaH, DMF
(37-66%) R R
208 209
Me
N NH2
2 NH2
O CN Method 1:
N Pd/C DMPU N
210
R H N N
KOtBu, DMPU Method 2:
(18-33%) N NaH, DMF N
47 R R
211 212
Me
2 NH2 NH2
N
CN Pd/C
N N DMPU N N
213
KOtBu, DMPU N (54-89%) N

(19-69%) R R
214 215
R=H, C6H5, 3-MeOC6H4, 4-MeOC6H4, 2,3-(MeO)2C6H3, 2,5-(MeO)2C6H3, 2,4,6-(MeO)3C6H2,
3,4,5-(MeO)3C6H2, furyl, thienyl, biphenyl, propyl, 3-BrC6H4, 4-BrC6H4, 3-ClC6H4, 4-FC6H4
Scheme 44

4.2. 4b,6,11-Triazachrysene
Refluxing substituted 2-aminobenzonitriles 126 with 4H-3,1-benzoxazin-4-one 216 in benzene gave
the 13H-quinazolino[3,4-a]quinazolin-13-ones 217 (Scheme 45) in a one-pot reaction.49

R NH2 N R2 R N R2
Benzene
+
O (55-80%) N
CN R1
O N
R1
126 216
O
217 R,R1=H, CH3, Cl, R2=CH3, Isopr, Pro
Scheme 45

The 13H-quinazolino[3,4-a]quinazolin-13-one 217 was alternatively synthesized from 218, prepared

by reaction of 2-aminobenzonitrile 126 with 2-cyanophenyl isothiocyanate and a catalytic amount of p-
toluenesulphonic acid (PTSA) (Scheme 46).66 Reaction of 218 with manganese(III)acetate in acetic acid led
to a poor yield of the tetracyclic product 217. The reaction of compound 218 with manganese(III)acetate and
diethyl malonate in acetic acid also generated the triazachrysene 219, used as a precursor of 217 by
desulphuration. In both cases, compounds 217 and 219 were isolated after column chromatography.
Venkateswarlu et al67 described the synthesis of quinazolino[3,4-a]quinazolin-13-ones 217, by
reaction of 2-(2-aminophenyl)quinazolin-4(3H)-one 220 with acetic anhydride followed by cyclization onto
 475

N1 (Scheme 47). The substituted derivatives 220 were obtained from 2-aminobenzamides 124 and 2-
nitrobenzoic acids in three consecutive steps.

NCS
H
NH2 N S N
CN , PTSA (cat.) CN Mn(OAc)3/AcOH
N N
CN (80%) (5%)
NH N
126 218 217
O
Mn(OAc)3 (30%)
diethyl malonate, AcOH

N By desulphuration
S
N

N
219 O
Scheme 46

R2 NO2 R2 NO2 R2 NO2

H
H2N R N R 10% aq KOH N R
R3 COOH R3 R3
(77-85%) O (79-92%) HN
H2NOC R1 H2NOC R1 R1
O
124
(83-90%) Fe/AcOH

R2 N CH3 R2 NH2
Ac2O
N R N R
R3 (20-32%) R3
N HN
R1 R1
O O
217 R=H, OCH3, Br, R1= H, OCH3, Cl, 220
R2=R3=H, OCH3
Scheme 47

The same authors described the synthesis of quinazolino[3,4-a]quinazolin-13-ones 217 from the
dihydro- precursors 223.68,69 These compounds were obtained by reaction of 2-(2-aminophenyl)-2,3-
dihydroquinazolin-4(1H)-one 222 with dimethylformamide-dimethylacetal (DMF-DMA) followed by
intramolecular cyclization (Scheme 48). The aniline moiety in 222 arised from reduction of the nitro
functional group in 221, using iron powder. Compounds 221 were obtained by refluxing 2-aminobenzamides
124 and 2-nitrobenzaldehyde. This reaction sequence provided the selective formation of quinazolino[3,4-
a]quinazolin-13-ones 217, isolated in very good yield.
Proença et al70 described the formation of triazachrysenes 224 via dimerization of anthranilonitrile
through a tandem process (Scheme 49). The sequence involved reaction of 2-aminobenzonitrile 124 with
triethyl orthoformate (TEOF), using a protic acid as catalyst. The dimeric structures 224 were formed
through a cascade reaction, initiated by the acid catalysed nucleophilic attack of a second molecule of
 476

anthranilonitrile 124 to the imidate. Two consecutive intramolecular cyclization processes led to the final
structure 224, always isolated as a salt. Combining compound 224 with acetic anhydride or phenylisocyanate
gave the acylated product 225 isolated in good yield.

R3 NO2 R3 NO2 R3 NH2

H H
H2N R N R Fe/HCl N R
R2 CHO R2 NH4Cl R2
HN HN
H2NOC R1 (71-88%) R1 (70-92%) R1
O O
124 221 222
(82-88%) DMF-DEA
AcOH
R3 N R3 N

N DDQ
R N R
R2 R2
(83-88%)
N HN
R1 R1
O O
217 R=H, OCH3, Cl, Br, R1= H, OCH3, 223
R2=R3=H, OCH3
Scheme 48

R NH2 TEOF, H+ R N H Ac2O or PhNCO R N H

N R N R
CN (41-83%) (73-88%)
124 N N

NH.HX N R1
H R 224 R=H, Cl, R1= CH3, NHPH 225
X H O
R N X= SO4Et, NO3
OEt
CN H2N
CN

H R X H
X H R N
R N
HN N R

N NC NH
N
Scheme 49

More recently, this group also synthesized a novel and highly stable tetracyclic structure 227 (Scheme
50), from the reaction of the hydrochloride salt of quinazoline 226 with aromatic aldehydes, under reflux or
microwave irradiation.71
Bergman et al72 reported the synthesis of the hydroximino triazachysene 230 from isamic acid 228
(Scheme 51). This compound could easily be converted to N-nitrosoisamic acid 229, which when heated in
ethanol underwent a ring expansion to a 13-hydroximino compound 230. The structure of this compound
was confirmed by X-ray spectroscopic analysis.
 477

X
R CHO H H
NH2 N
X R
N N

N (74-97%) N

NH2. HCl NH. HCl

226 227 R=H, 2-Cl, 3-Cl, 4-Cl, 4-CN, 4-NO2, 2-OMe,
3-OMe, 4-OMe, 4-OH, 2-Me, 3,4-OH, X=CH, N
Scheme 50

H H H H
N N N N
O O O H2O O
HNO2 H+
NH NNO NH NH
N N ON N ON N
(54%) (94%) -H2O
H
HOOC HOOC OOC OOC OH
228 229

H H
N O N O

N N
(83%) H
N N
N
N OH OH
230 OH

Scheme 51

4.3. 5,6,11-Triazachrysene
A series of triazachrysenes 23316a was synthesized by conversion of 4-chloro-6,7-
methylenedioxycinnoline 231 into the substituted 4-aminoquinolines 232, in the presence of a primary
amines, under reflux (Scheme 52).

O
H3CO O N
OH N
O N O N I
N RNH2 N H3CO I O

O N OCH3
O R
Cl HN O
R OCH3
231 232
Pd(OAc)2, P(o-tolyl)3
Ag2CO3
O N
N
O OCH3

N
R OCH3
O
233 R=CH2CH2N(CH3)2, CHCH3CH2N(CH3)2,
CH2(C4H7O), CH2CH2CH2CH3
Scheme 52
 478

Condensation with a substituted benzoic acid followed by the Heck reaction led to 5,6,11-
triazachrysen-12-ones 233.

4.4. 7,10a,11-Triazachrysene
Pierini et al73 presented the synthesis of novel triazachrysenes 237 by an intramolecular radical
nucleophilic substitution reaction. The photostimulated reaction of diamine 235 was carried out in NH3(l)
(used as solvent), and the double cyclization products 236 (C-C coupling) and 237 (C-N coupling) were both
formed in 13% yield, together with the monocyclization-reduction product 238 (22%) (Scheme 53). These
authors also reported that the use of DMF as solvent did not improve the yield of cyclic products 237 and
238. The substrate 235 was prepared through a three-step synthetic strategy from 2,6-diaminopyridine 234
with an excess of acetic anhydride. The dianion, generated by addition of NaH, was reacted with o-
iodobenzyl chloride followed by acetal cleavage with HCl, leading the final product 235.

1. NaH
Cl
2.
(CH3CO)2O I I
I
Ac Ac
H2N N NH2 N N N N N N
H H Ac Ac
234
(65%) 1. HCl
2. HO
N
1. t-BuOK, hv, N2
N 2. MnO2 I I
+
N
N N N N N N
H H
237, 13% 236, 13% 235
+

N N N
H
238, 22%
Scheme 53

4.5. 7,13,13d-Triazachrysene
The isocoumarin derivative 239 was reacted with 1,8-naphthalenediamine 240 under basic conditions
to give 12-acetylisoquino[2,1-a]perimidin-13-amine 241 (Scheme 54). When 241 was heated with
polyphosphoric acid, a new hexacyclic system, 7,13,13d-triazachrysene 242 was isolated in good yield.74

5. Synthesis of pentaazachrysene derivatives

5.1. 1,3,5,8,10-Pentaazachrysene
Clement et al65b reported the synthesis of pentaazachrysenes 245 (Scheme 55) by a base-catalyzed
condensation of aldehydes 47 with two equivalents of 4-methyl-5-cyanopyrimidine 243 followed by
dehydrogenation. The fully aromatic ring system 245 was isolated in 77% yield.
 479

O
CN NH2 NH2
CH3 dioxan, NEt3 NH2 polyphosphoric acid N CH3
+
O (68%) N (96%) N

N N N

239 O 240 241 242

Scheme 54

NH2 NH2
O N Me N N N N
2 KOtBu, DMPU NaH, DMF
R H + N N N
CN (77%) N N
(14-39%)
47 243 R N R N
244 245
Scheme 55

6. Conclusions
In the present review, we presented the synthesis of a selection of mono-, di-, tri- and penta-
azachrysene derivatives reported during the last three decades. Different synthetic approaches to the
nitrogenated tetracyclic skeleton have been reported but the most common route involves the construction of
either ring B or C in the final cyclization step.
Several strategies including metal-catalyzed reactions, MCR, microwave-irradiation or conventional
heating methods have been successfully employed to prepare these diversely decorated skeletons, which are
of significant importance for pharmaceutical as well as agrochemical industries.

Acknowledgments
The authors gratefully acknowledge the financial support by the University of Minho and FCT through
the Portuguese NMR network (RNRMN), the Project F-COMP-01-00124-FEDER-022716 (ref. FCT PEst-
C/QUI/UI0686/2011) FEDER-COMPETE, and a PhD grant awarded to Elina Marinho
(SFRH/BD/73659/2010). We are especially grateful to Prof. Pedro Merino and Prof. Orazio A. Attanasi for
the opportunity to contribute with the writing of this chapter.

References
1. Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893.
2. Hearn, M. J.; Swanson, S. L. J. Heterocycl. Chem. 1981, 18, 207.
3. Logothetis, A. L. J. Org. Chem. 1964, 29, 1834.
4. (a) Crawford, J. V., In The Chemistry of Heterocyclic Compounds: Six Membered Heterocyclic Nitrogen
Compounds with Four Condensed Rings, Allen, C. F.H., Ed.; Interscience, New York, N.Y. 1951, pp.
151. (b) Phillips, S. D.; Castle, R. N. J. Heterocycl. Chem. 1981, 18, 223. (c) Simanek, V. “The
Alkaloids, Chemistry and Pharmacology”, Vol. 26, Chapter 4, ed. By Brossi A., Academic Press,
Orlando, 1985, pp. 185 and references therein.
5. Stermitz, F. R.; Gillespie, J. P.; Amoros, L. G.; Romero, R.; Stermitz, T. A.; Larson, K. A.; Earl, S.;
Ogg, J. E. J. Med. Chem. 1975, 18, 708.
 480

6. (a) Varricchio, F.; Doorenbos, N. I.; Stevens, A. J. Bacteriol. 1967, 93, 627. (b) Hubschwerlen, C.;
Panchaud, P.; Specklin, J.-L. 5-Hydroxymethyl-oxazolidin-2-one Antibacterials. U.S. Patent
2010/0,069,376 A1, March 18, 2010 and WO/2008/062379, May 29, 2008.
7. Yapi, A.-D.; Desbois, N.; Chezal, J.-M.; Chavignon, O.; Teulade, J.-C.; Valetin, A.; Blache, Y. Eur. J.
Med. Chem. 2010, 47, 2854.
8. Singh, H.; Paul, D. J. Chem. Soc. Perkin Trans. 1 1974, 1475.
9. Hadida-Ruah, S. S.; He, X.; Nagasawa, J. Y. Modulators of the Glucocorticoid Receptor and Method.
WO/2004/110385 A2, December 23, 2004.
10. Hayazu, R. Japanese Patent 873, 874, 21 February 1959; Chem. Abstr., 54, 89068 and 89070 (1960).
11. Mansor, T. A.; Borralho, P. M.; Luo, X.; Mulhovo, S.; Rodrigues, C. M. P.; Ferreira, M.-J. U. J. Nat.
Prod. 2014, 77, 1825.
12. Cho, W.-J.; Hanaoka, M. Arch. Pharm. Res. 1996, 19, 240.
13. Pica, F.; Balestrieri, E.; Serafino, A.; Sorrentino, R.; Gaziano, R.; Moroni, G.; Moroni, N.; Palmieri, G.;
Mattei, M.; Garaci, E.; Sinibaldi-Vallebona, P. Anticancer Drugs, 2012, 23, 32 and references therein.
14. Chmura, S. J.; Dolan, M. E.; Cha, A.; Mauceri, H. J.; Kufe, D. W.; Weichselbaum, R. R. Clin. Cancer
Res. 2000, 6, 737.
15. Wang, L. K.; Johnson, R. K.; Hecht, S. M. Chem. Res. Toxicol. 1993, 6, 813.
16. (a) Ruchelman, A. L.; Singh, S. K.; Wu, X.; Ray, A.; Yang, J.-M.; Li, T.-K.; Liu, A.; Liu, L. F.; LaVoie,
E. J. Bioorg. Med. Chem. Lett. 2002, 12, 3333. (b) Li, T.-K.; Houghton, P. J.; Desai, S. D.; Daroui, P.;
Liu, A. A.; Hars, E. S.; Ruchelman, A. L.; LaVoie, E. J.; Liu, L. F. Cancer Research 2003, 63, 8400. (c)
Pommier, Y. Nat. Rev. Cancer, 2006, 6, 789.
17. Pampin, C.; Estévez, J. C.; Castedo, L.; Estévez, R. J. Tetrahedron Lett. 2002, 43, 4551.
18. Pampin, M. C.; Estévez, J. C.; Estévez, R. J.; Maestro, M.; Castedo, L.; Tetrahedron 2003, 59, 7231.
19. Sissa, C.; Calabrese, V.; Cavazzini, M.; Grisanti, L.; Terenziani, F.; Quici, S.; Painelli, A. Chem. Eur. J.
2013, 19, 924 and references there in.
20. Barnard, I. F.; Elvidge, J. A. J. Chem. Soc. Perkin Trans. 1 1983, 1137.
21. Beugelmans, R.; Chastanet, J.; Ginsburg, H.; Quintero-Cortes, L.; Roussi, G. J. Org. Chem. 1985, 50,
4933.
22. Kessar, S. V.; Gupta, Y. P.; Balakrishnan, P.; Sawal, K. K.; Mohammad, T.; Dutt, M. J. Org. Chem.
1988, 53, 1708.
23. Moreno, I.; Tellitu, I.; Etayo, J.; SanMartín, R.; Domíngues, E. Tetrahedron 2001, 57, 5403.
24. Nakanishi, T.; Suzuki, M. Org. Lett. 1999, 1, 985.
25. Stýskala, J.; Hlaváč, J.; Cankař, P. Tetrahedron 2013, 69, 4670.
26. Green, G. R.; Mann, I. S.; Mullane, M. V. Tetrahedron 1998, 54, 9875.
27. Mandadapu, A. K.; Saifuddin, M.; Agarwal, P. K.; Kundu, B. Org. Biomol. Chem. 2009, 7, 2796.
28. Rigby, J. H.; Holsworth, D. D. Tetrahedron Lett. 1991, 32, 5757.
29. (a) Ishii, H.; Ishikawa, T.; Deushi, T.; Harada, K.-I.; Watanabe, T.; Ueda, E.; Ishida, T.; Sakamoto, M.;
Kawanabe, E.; Takahashi, T.; Ichikawa, Y.-I.; Takizawa, K.; Masuda, T.; Chen, I.-S. Chem. Pharm.
Bull. 1983, 31, 3024. (b) Ishii, H.; Ichikawa, Y.-I.; Kawanabe, E.; Ishikawa, M.; Ishikawa, T.; Kuretani,
K.; Inomata, M.; Hoshi, A. Chem. Pharm. Bull. 1985, 33, 4139.
30. (a) Clement, B.; Weide, M.; Wolschendorf, U.; Kock, I. Angew. Chem. Int. Ed. 2005, 44, 635. (b) Kock,
I.; Heber, D.; Weide, M.; Wolschendorf, U.; Clement, B. J. Med. Chem. 2005, 48, 2772.
31. Gug, F.; Bach, S.; Blondel, M.; Vierfond, J.-M.; Martin, A.-S.; Galons, H. Tetrahedron 2004, 60, 4705.
32. Janin, Y. L.; Croisy, A.; Riou, J.-F.; Bisagni, E. J. Med. Chem. 1993, 36, 3686.
33. Cho, W.-J.; Park, M.-J.; Imanishi, T.; Chung, B. Chem. Pharm. Bull. 1999, 47, 900.
 481

34. Treus, M.; Estévez; J. C.; Castedo, L.; Estévez, R. J. Tetrahedron Lett. 2000, 41, 6353.
35. Treus, M.; Estévez; J. C.; Castedo, L.; Estévez, R. J. Tetrahedron Lett. 2002, 43, 5323.
36. (a) Le, T. N.; Gang, S. G.; Cho, W.-J. J. Org. Chem. 2004, 69, 2768. (b) Le, T. N.; Van, H. T. M.; Lee,
S.-H.; Choi, H. J.; Lee, K. Y.; Kang, B. Y.; Cho, W.-J. Arch. Pharm. Res. 2008, 31, 6.
37. (a) Harayama, T.; Akiyama, T.; Kawano, K. Chem. Pharm. Bull. 1996, 44, 1634. (b) Harayama, T.;
Akiyama, T.; Akamatsu, H.; Kawano, K.; Abe, H.; Takeuchi, Y. Synthesis 2001, 3, 444.
38. Martin, G.; Guitián, E., Castedo, L.; Saã, J. M. J. Org. Chem. 1992, 57, 5907.
39. Wang, Y.-F.; Lonca, G. H.; Runigo, M. L.; Chiba, S. Org. Lett. 2014, 16, 4272.
40. Hutton, S. M.; Mackay, S. P.; Meth-Cohn, O. Synthesis 2000, 8, 1121.
41. Rigby, J. H.; Balasubramanian, N. J. Org. Chem. 1989, 54, 224.
42. (a) Li, D.; Zhao, B.; LaVoie, E. J. J. Org. Chem. 2000, 65, 2802. (b) Li, D.; Zhao, B.; Sim, S.-P.; Li, T.-
K.; Liu, A.; Liu, L. F.; LaVoie, E. J. Bioorg. Med. Chem. 2003, 11, 521. (c) Makhey, D.; Li, D.; Zhao,
B.; Sim, S.-P.; Li, T.-K.; Liu, A.; Liu, L. F.; LaVoie, E. J. Bioorg. Med. Chem. 2003, 11, 1809. (d) Li,
D.; Zhao, B.; Sim, S.-P.; Li, T.-K.; Liu, A.; Liu, L. F.; LaVoie, E. J. Bioorg. Med. Chem. 2003, 11,
3795.
43. Yanada, R.; Hashimoto, K.; Tokizane, R.; Miwa, Y.; Minadi, H.; Yanada, K.; Ishikura, M.; Takemoto,
Y. J. Org. Chem. 2008, 73, 5135.
44. (a) Hermone, A. R.; Burnett, J. C.; Nuss, J. E.; Tressler, L. E.; Nguyen, T. L.; Šolaja, B. A.;
Vennerstrom, J. V.; Schmidt, J. J.; Wipf, P.; Bavari, S.; Gussio, R. Chem. Med. Chem. 2008, 3, 1905.
(b) Opsenica, I.; Burnett, J. C.; Gussio, R.; Opsenica, D.; Todorović, N.; Lanteri, C. A.; Sciotti, R. J.;
Gettayacamin, M.; Basilico, N.; Taramelli, D.; Nuss, J. E.; Wanner, L.; Panchal, R. G.; Šolaja, B. A.;
Bavari, S. J. Med. Chem. 2011, 54, 1157. (c) Šegan, S.; Trifković, J.; Verbić, T.; Opsenica, D.; Zlatović,
M.; Burnett, J.; Šolaja, B. A.; Milojković-Opsenica, D. J. Pharm. Biomed. Anal. 2013, 72, 231.
45. Yu, Y.; Singh, S. K.; Liu, A.; Li, T.-K.; Liu, L. F.; LaVoie, E. J. Bioorg. Med. Chem. 2003, 11, 1475.
46. Takeuchi, I.; Hamada, Y.; Hirota, M. Chem. Pharm. Bull. 1993, 41, 747.
47. Nutaitis, C. F.; Crawley, M. L.; Obaza-Nutaitis, Org. Prep. Proc. Int. 1998, 30, 481.
48. Dighe, S. U.; Batra, S. Tetrahedron 2013, 69, 9875.
49. Ozaki, K.-I.; Yamada, Y.; Oine, T. Chem. Pharm. Bull. 1984, 32, 2160.
50. Tian, H.; Qiao, H.; Zhu, C.; Fu, H. RSC Adv. 2014, 4, 2694.
51. Neel, A. J.; Hehn, J. P.; Tripet, P. F.; Toste, F. D. J. Am. Chem. Soc. 2013, 135, 14044.
52. To, W.-P.; Liu, Y.; Lau, T.-C.; Che, C.-M. Chem. Eur. J. 2013, 19, 5664.
53. Huo, C.; Wu, M.; Jia, X.; Xie, H.; Yuan, Y.; Tang, J. J. Org.Chem. 2014, 79, 9860.
54. Yang, L.; Zhang-Negrerie, D.; Zhao, K.; Du, Y. J. Org.Chem. 2016, 81, 3372.
55. Bisagni, E.; Landras, C.; Thirot, S.; Huel, C. Tetrahedron 1996, 52, 10427.
56. Kiselev, E.; Empey, N.; Agama, K.; Pommier, Y.; Cushman, M. J. Org. Chem. 2012, 77, 5167.
57. Papageorgiou, C.; Borer, X. J. Org. Chem. 1987, 52, 4403.
58. (a) Letcher, R. M.; Ng, K.-W.; Cheung, K.-K. J. Chem. Soc., Chem. Commun. 1987, 1602. (b) Letcher,
R. M.; Kwok, N.-C.; Lo, W.-H.; Ng, K.-W. J. Chem. Soc., Perkin Trans. 1 1998, 1715.
59. (a) Ruchelman, A. L.; Singh, S. K.; Ray, A.; Wu, X. H.; Yang, J.-M.; Li, T.-K.; Liu, A.; Liu, L. F.;
LaVoie, E. J. Bioorg. Med. Chem. Lett. 2003, 11, 2061. (b) Singh, S. K.; Ruchelman, A. L.; Li, T.-K.;
Liu, A.; Liu, L. F.; LaVoie, E. J. J. Med. Chem. 2003, 46, 2254. (c) Ruchelman, A. L.; Kerrigan, J. E.;
Li, T.-K.; Zhou, N.; Liu, A.; Liu, L. F.; LaVoie, E. J. Bioorg. Med. Chem. 2004, 12, 3731. (d)
Ruchelman, A. L.; Houghton, P. J.; Zhou, N.; Liu, A.; Liu, L. F.; LaVoie, E. J. J. Med. Chem. 2005, 48,
792.
 482

60. (a) Stadlbauer, W.; Kappe, T. Monatsh. Chem. 1982, 113, 751. (b) Stadlbauer, W.; Kappe, T. Monatsh.
Chem. 1984, 115, 467. (c) Stadlbauer, W.; Karem, A.-S.; Kappe, T. Monatsh. Chem. 1987, 118, 81.
61. Kiselev, E.; Dexheimer, T. S.; Pommier, Y.; Cushman, M. J. Med. Chem. 2010, 53, 8716.
62. Zhu, S.; Ruchelman, A. L.; Zhou, N.; Liu, A.; Liu, L. F.; LaVoie, E. J. Bioorg. Med. Chem. 2006, 14,
3131.
63. Papageorgiou, C.; Borer, X. Helv. Chim. Acta 1988, 71, 1079.
64. Serbetçi, T.; Genès, C.; Depauw, S.; Prado, S.; Porée, F.-H.; Hildebrand, M.-P.; David-Cordonnier, M.-
H.; Michel, S.; Tillequin, F. Eur. J. Med. Chem. 2010, 45, 2547.
65. (a) Meier, C.; Kotthaus, J.; Stenzel, L.; Girreser, U.; Heber, D.; Clement, B. Tetrahedron 2012, 68,
9105. (b) Steinhauer, T. N.; Girreser, U.; Meier, C.; Cushman, M.; Clement, B. Chem. Eur. J. 2016, 22,
8301.
66. Calestani, G.; Capella, L.; Leardini, R.; Minozzi, M.; Nanni, D.; Papa, R.; Zanardi, G. Tetrahedron
2001, 57, 7221.
67. Venkateswarlu, S.; Satyanarayana, M.; Murthy, G. N.; Siddaiah, V. Tetrahedron Lett. 2012, 53, 2643.
68. (a) Venkateswarlu, S.; Satyanarayana, M.; Srinivas, K.; Aadisudhakar, K. N. V. V. Tetrahedron Lett.
2013, 54, 128. (b) Venkateswarlu, S.; Satyanarayana, M; Lakshmikanthan, V.; Siddaiah, V. J.
Heterocyclic Chem. 2015, 52, 1631.
69. Venkateswarlu, S.; Satyanarayana, M.; Ravikiran, P.; Vijayakumar, A. Tetrahedron Lett. 2013, 54,
4512.
70. Marinho, E.; Araújo, R.; Proença, F. Tetrahedron 2010, 66, 8681.
71. Marinho, E.; Proença, F. RSC Adv. 2016, 6, 6138.
72. Bergman, J.; Arewang, C.-J.; Svensson, P. H. J. Org. Chem. 2014, 79, 9065.
73. Peisino, L. E.; Solorzano, G. P. C.; Budén, M. E.; Pierini, A. B. RSC Adv. 2015, 5, 36374.
74. Deady, L. W.; Rodemann, T. J. Heterocyclic Chem. 1998, 35, 1417.