Regioselective 6-endo-dig iodocyclization: An accessible approach for iodo-benzo [a] phenazines

Article abstract of DOI:10.1039/c7ob00671c

A facile approach for the synthesis of substituted iodo-benzo[a]phenazines from 2-aryl-3-(aryl/alkylethynyl)quinoxalines via 6-endo-dig ring closure has been described under mild reaction conditions. Iodocyclization proceeds through the iodonium ion intermediate followed by nucleophilic cyclization with the C-H bond of the arene. Furthermore, the resulting 6-iodo-5-aryl/alkyl benzo[a]phenazine derivatives allowed for structural diversification by employing various coupling reactions. The structure of iodo-benzo[a]phenazine was confirmed by X-ray crystallographic studies of the compound.

Full text of DOI:10.1039/c7ob00671c

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Received 00th January 20xx,
Accepted 00th January 20xx
Regioselective 6-endo-dig Iodocyclization: An accessible approach
for Iodo-benzo[a]phenazines
DOI: 10.1039/x0xx00000x
a
b
a
www.rsc.org/
Sonu Kumar, Mohammad Mujahid and Akhilesh K. Verma *
A facile approach for the synthesis of substituted iodo-benzo[a]phenazines from 2-aryl-3-(aryl/alkylethynyl)quinoxalines
via 6-endo-dig ring closure has been described under mild reaction conditions. The iodocyclization proceeds through the
iodonium ion intermediate followed by nucleophilic cyclization with the C-H bond of the arene. Further, the resulting 6-
iodo-5-aryl/alkyl benzo[a]phenazine derivatives were allowed for structural diversification by employing various coupling
reactions. The structure of iodo-benzo[a]phenazine was confirmed by X-ray crystallographic studies of the compound.
Introduction
The iodocyclization of alkynes represents a useful method for
The iodo
1
2a,b
the construction of important heterocycles.
Phenazine derivatives constitute an important class of
compounds which show a wide range of biological activities
functionality introduced via electrophilic iodocyclization,
provide a useful route for structure elaboration to generate
complex molecules. Iodine reagents have attracted much
attention by organic chemists due to their eco-friendly and
cost effective properties. This developed approach employs
molecular iodine which is more economical and convenient to
use then the transition-metal catalyst.
1
,2
and act as the medicinally important scaffold. Significantly,
reduced as well as oxidized forms of natural and synthetic
phenazines inhibit the growth of malaria (Figure 1, i),
3
a
3
b
4
bacteria (Figure 1, ii) and hepatitis C viral replication. In
particular, benzo[a]phenazine derivatives act as potent
anticancer agents, fluorescers, inhibitors of topoisomerase I
5
6
Due to the vast biological significance of phenazines an
and II of DNA in the cell cycles which are affected by key
enzymes, mycobacterium tuberculosis activity, bioreductive alternative and approachable route for their synthesis is still
antitumor agents (Figure 1, iii) and antifungal activity. Their challenging. Till now, various metal-catalyzed strategies are
7
8
9
10a
1
0b
derivatives have acted as anti chagas’ agent (Figure 1, iv) known for the development of phenazine analogs; however,
and dication DNA-binder (Figure 1, v). Apart from the halogen-induced electrophilic cyclizations remain elusive.
significant biological activity benzo[a]phenazine derivatives are
During the past decade, iodocyclization has emerged as an
1
1
useful in photodynamic therapy (PDT).
efficient tool for the synthesis of functionalized cyclic
14
1
2c,d
13
quinolines, quinolinones,
compounds such as indoles,
1
5
16
17
18
furans,
benzo[b]thiophenes,
selenophene,
pyrroles,
1
9
20
21
naphthalenes, isochromenes and other heterocycles. In
003, Barluenga and co-workers reported the synthesis of
4
fused polycyclic aromatic scaffolds by employing IPy BF -
2
2
2
2
mediated electrophilic cyclization. Later Larock et al. have
reported the synthesis of polycyclic carbocycles from arene-
containing acetylenes via intramolecular electrophilic induced
2
3
cyclization of alkyne (Scheme 1i). In 2014, Chen and fellow-
workers demonstrated the synthesis of iodo-substituted
Figure 1. Biologically Active Phenazines Cores.
dibenzocyclohepten-5-ones
via
7-endo-dig
iodine
monochloride mediated electrophilic cyclization of 1-([1,1
2
′
-
4
biphenyl]-2-yl)alkynone (Scheme 1ii). Gulevskaya group
reported the synthesis of iodophenazines under harsh reaction
25
a.
Synthetic Organic Chemistry Research Laboratory, Department of Chemistry,
University of Delhi, Delhi – 110007, India
Wolfson college, University of Oxford, U.K.
E-mail: averma@acbr.du.ac.in.
b.
condition with less substrate scope. Recently, our group
†
accomplished the synthesis of benzo[a]phenazines derivatives
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
via palladium-catalyzed intramolecular hydroarylation(Scheme
2
1iii).
6
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Owing to the great significance of benzophenazines; To identify the optimal reaction conditions, 2-(p-tolyl)-3-(p-
regioselective, inexpensive and environmental benign strategy tolylethynyl)quinoxaline 4a was chosen as representative
for the synthesis of highly functionalized iodo- substrates along with various electrophile and organic solvents
benzo[a]phenazines under mild reaction conditions remains at different reaction temperatures (Table 1). Initially, the
elusive. In continuation of our interest in iodocyclization reaction was performed with 2-(p-tolyl)-3-(p-tolylethynyl)
2
7
chemistry here, we reported a versatile and efficient quinoxaline 4a, iodine and K
protocol for the construction of diversified iodo afford the desired product 6-iodo-3-methyl-5-(p-tolyl)
benzophenazines using iodine-mediated electrophilic benzo[a]phenazine 5a in 45% yield (entry 1). Increasing the
2 3 2 2
CO in CH Cl for 25 h at 25°C to
cyclization at room temperature. This provides a variety of amount of iodine from 1.0 to 1.5 equiv afforded the desired
functional group variations on the halo benzo[a]phenazines phenazine product 5a in 55% yield (entry 2). Further increasing
which were further elaborated using various palladium- the amount of iodine made no significant improvement in the
catalyzed coupling reactions.
yield of the product 5a (entries 3-4). When NaHCO
employed, the corresponding iodocyclized product 5a was
Scheme 1. Iodine-mediated Electrophilic Cyclization from obtained in 78% yield in 25 h (entry 5). On running the reaction
3
was
Arenes
for a longer time made no improvement in the yield of desired
a
Table 1. Optimization of Reaction Conditions
entry reagent (solvent)
equiv)
base
(equiv)
temp time
yield
(%)
b
(
(◦C)
(h)
1
2
3
4
5
6
7
8
9
I
I
I
I
I
I
I
I
I
I
2
2
2
2
2
2
2
2
2
2
(1.0)
(1.5)
(2.0)
(2.5)
(2.0)
(2.0)
(2.0)
(2.0)
(2.0)
(2.0)
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
DCE
DCE
DMF
MeCN
CH
CH Cl
2
2
2
2
2
2
2
2
2
2
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
2
2
2
2
2
K
K
K
K
2
2
2
2
CO
CO
3
25
25
25
25
25
25
25
25
25
25
25
50
50
50
0
25
25
25
25
25
40
40
25
25
25
25
25
25
25
25
25
25
25
25
45
55
60
62
78
75
68
52
65
20
65
68
44
38
57
48
76
20
trace
3
CO
CO
3
3
NaHCO
NaHCO
KHCO
Cs CO
KO Bu
Et
NaHCO
NaHCO
NaHCO
NaHCO
NaHCO
NaHCO3
NaHCO
NaHCO3
NaHCO
3
3
3
2
3
t
1
0
1
2
3
4
5
6
3
N
1
1
1
1
1
1
I
2
(2.0)
(2.0)
(1.0)
(1.0)
3
3
3
3
3
I
I
I
2
2
2
ICl (2.0)
NIS (2.0)
2
Cl
2
25
25
25
25
2
2
Results and discussion
c
1
7
I
2
(2.0)
I2 (2.0)
(2.0)
CH
MeOH
H
2
Cl
2
3
1
1
8
9
Synthesis of 2-aryl/alkyl-3-(aryl/alkylethynyl)quinoxaline.
I
2
2
O
3
a
Starting substrates 2-aryl/alkyl-3-(aryl/alkylethynyl)quinoxaline
All reactions were performed using 0.5 mmol of the 2-(p-olyl)-
4a–w
and 6a-i required for examining the scope and generality 3-(p-tolylethynyl)quinoxaline 4a, 2.0 equiv. of base, and 2.0 mL
of this designed chemistry were readily prepared by the of solvent under inert atmosphere conditions. Isolated yields.
b
c
2
.5 equiv. of the base was used
reported Sonogashira and Suzuki coupling of corresponding o-
dichloroquinoxaline 1a and 1b with commercially available
2
6d
product 5a (entry 6). Other bases like KHCO
3
, Cs
KO Bu afforded the product in 52-68% yield (entries 7-9).
However, an organic base such as Et N was ineffective (entry
0). When the reaction proceeded in DCE at 25 °C and 50 °C,
2 3
CO and
terminal alkynes and boronic acids
3
(Scheme 2)
.
t
Scheme 2. Synthesis of 2-aryl/alkyl-3-(aryl/alkylethynyl)
quinoxaline
3
1
the desired compound was obtained in 71% and 68% yield,
respectively (entries 11-12). When DMF and MeCN were used
as solvents lower yield of the desired product 5a was observed
(entries 13-14). Use of other electrophiles like ICl and NIS
provided the product in lower yields (entries 15-16). Using 2.5
2
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equiv of NaHCO
3
made no appreciable amendment in the yield electron-rich quinoxalines having a para, meta and ortho
substituted methyl arenes attached to carbon-carbon triple
bond (5a−c). Substrates 4d bearing thienyl group afforded the
desired iodophenazine 5d in 75% yield. The reaction of bulky
substrate 4e in the presence of molecular iodine provided the
desired product 5e in 74% yield. The X-ray crystallographic
studies further confirmed the formation of product 5e. The
of desired product 5a (entry 17). Inferior results were obtained
on performing the reaction of 4a with MeOH and H
8-19).
2
O (entries
1
a
Scheme 3. Synthesis of 6-Iodo-5-aryl/alkylbenzo[a]phenazine
3
,5-dimethoxyphenylethynylquinoxaline
successful in providing the desired products 5f–g in 88% and
4% yields respectively. Treatment of cyclopropylethynyl
4f–g were also
8
dimethoxyphenylquinoxaline 4h with I2 provided the iodo
phenazine 5h in 76% yield. The reaction of quinoxaline alkynes
4i having aliphatic substituents provided the desired
iodocyclized product 5i in 71% yields. Substrates 4j–p
containing trimethoxy group underwent cyclization smoothly
to afford the iodo phenazines derivatives 5j–p in 72-88%
yields. Generally, the substrates 4q–r bearing an electron-
neutral phenyl ring neighboring to the carbon-carbon triple
bond furnished the desired iodo cyclized product 5q and 5r in
7
2% and 76% yield respectively (Scheme 3). Substrates 4s
bearing aliphatic n-butyl group to the carbon-carbon triple
bond tolerated the reaction conditions and provided the
desired product 5s in 68% yield. Thienyl substituted substrates
4t-w provided the cyclized products 5t-w in good yields
(Scheme 3).
Scheme 4. Synthesis of 6-Iodo-9-methyl-5-aryl/alkylbenzo[a]
phenazine
a
a b
Using optimized conditions (entry 5, Table 1). Isolated yield.
Synthesis of 6-methyl substituted iodo benzo[a]phenazine.
Encouraged by the above results; we further extended the
scope of iodocyclization chemistry by using substituted
quinoxaline (Scheme 4). The reactions of 6-methyl substituted
quinoxalines 6a–b having thiophene and cyclopropyl ethynyl
moieties provided the corresponding iodo benzo[a]phenazine
a
b
Using optimized conditions (entry 5, Table 1). Isolated yield.
CCDC numbers of 5e is 1518194.
7
a–b in 76% and 72% yields (Scheme 4). We observed that
reaction of p-methoxyphenyl-substituted quinoxalines 6c with
underwent iodocyclization and afforded the iodo
benzo[a]phenazine 7c in 78% yields. Similar electronic effects
of substituents were observed with electron-rich quinoxalines
After optimizing the reaction conditions, scope and
generality of the reaction were explored with substituted
substrates 2-aryl-3 (aryl/alkylethynyl)quinoxaline 4a–w for the
synthesis of diversified iodo-benzo[a]phenazines derivatives
I
2
6d-h and products were obtained in good yield. The presence
5a–w (Scheme 3). The reaction was well tolerated with
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of thiophene ethynyl)quinoxaline 6i afforded the desired off an experiment using 0.5 mmol and 1.0 mmol of the alkyne
iodocyclized product 7i in 84 % yield.
2a, in first case mono-alkynyl-mono-chloro product 1aa was
obtained in 80% yield with 5% of di-alkynyl product 1ab
(
Scheme 7i). In the second experiment when 1.0 mmol of
alkyne was used the di-alkynyl product 1ab was obtained in
7% with 8% of product 1aa (Scheme 7ii).
Scheme 5. Synthetic Elaboration of Iodo-benzophenazine 5q
7
2
1
On the basis of previous literature, a plausible mechanism
was proposed for this iodine-induced intramolecular
cyclization of 2-aryl-3 (aryl/alkylethynyl) quinoxaline in Scheme
8
. The reaction initiates with the coordination of iodine with
carbon-carbon triple bond to form an electrophilic acetylenic
iodonium complex , which then undergoes cyclization
P
triggered through the nucleophilic attack of the neighbouring
aromatic ring of the quinoxaline on the carbon-carbon triple
bond to generate the intermediate Q. After the deprotonation
of species Q, the desired iodo aryl/alkylbenzo[a]phenazine was
obtained.
Scheme 8. Plausible Mechanism
Inspired by these results, we next elaborated the scope of
iodo-substituted benzo[a]phenazine using palladium-catalyzed
Sonogashira and Suzuki cross-coupling reactions (Scheme 5).
The reaction of 6-iodo-5-phenylbenzo[a]phenazine 5q with 1-
ethynyl-4-methoxybenzene (
boronic acid ( ) provide the corresponding coupling product
and 11 in 84% and 89% yields respectively.
8) and (3,4,5-trimethoxyphenyl)
9
10
Scheme 6. Synthesis of 6-Bromo-2,3,4-trimethoxy-5-(o-tolyl)
benzo[a]phenazine
Conclusions
In conclusion, we have developed a versatile protocol for the
synthesis of iodo benzophenazine derivatives with high
functional group tolerance via the molecular iodine induced
electrophilic intramolecular regioselective cyclization of 2-aryl-
Encouraged by the above results, we explored the Bromo
cyclization of 2-(o-tolylethynyl)-3-(3,4,5-trimethoxy phenyl)
quinoxaline 4n with N-bromosuccinimide; desired product 6-
bromo-2,3,4-trimethoxy-5-(o-tolyl)benzo[a] phenazine 5x was
obtained in 76% yield (Scheme 6).
3
-(aryl/alkylethynyl)quinoxaline
conditions. This methodology accommodates a wide range of
-iodo-5-aryl/alkylbenzo[a]phenazine derivatives in good to
under
mild
reaction
6
excellent yields. The regioselectivity of the cyclic products was
confirmed by the X-ray crystallography studies. The cyclized
products 6-iodo-5-phenylbenzo[a]phenazine having iodo
group could be further elaborate for using organopalladium
chemistry. Developed approach is general, operationally
simple, and expands the synthetic utility of o-alkynyl aryl
Scheme 7. Control Experiment
quinoxaline for the synthesis of
a variety of iodo
benzophenazine which are of great importance in medicinal
chemistry as well as in natural products.
Acknowledgements
The work was supported by Department of Science and
Technology. S.K. and M. M are thankful to Council of Scientific
and Industrial Research, University Grants Commission, for
fellowships. We gratefully acknowledge University of Delhi for
providing the instrumentation facilities.
In order to confirm the reactivity and selectivity of the
Sonogashira coupling reaction on 1a, we performed two sets
4
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EXPERIMENTAL SECTION
was washed with aqueous saturated brine solution, dried over
Na SO . Organic layer was concentrated under reduced
General Method. Nuclear Magnetic Resonance spectra were pressure. The crude material so obtained was purified by
2
4
1
13
recorded in CDCl
spectra at ambient temperature. Chemical shifts (
protons are reported in parts per million (ppm) and were of known starting materials were confirmed by comparison of
3
H NMR (400 MHz) and C NMR (100 MHz) column chromatography on silica gel (hexane: ethyl acetate)
δ
) for all and recrystallization in DCM: hexane. The structure and purity
1
13
measured relative to residual CHCl
internal reference in the deuterated solvent. Chemical shifts 2-Chloro-3-(phenylethynyl)quinoxaline
for all spectra were reported in ppm relative to obtained as a yellow solid; (105.9 mg, 80%): mp 102–106 °C;
3
and TMS resonance as an their physical and spectral data ( H NMR, C NMR, and HRMS).
(
1aa). The product was
1
1
deuterochloroform (77.0 ppm) and all were obtained with H
3
H NMR (400 MHz, CDCl ) δ 8.12–8.08 (m, 1H), 8.02–7.99 (m,
decoupling. The following abbreviations were used to describe 1H), 7.81–7.77 (m, 2H), 7.73–7.71 (m, 2H), 7.48–7.40(m, 3H);
1
3
1
the multiplicities: when appropriate s = singlet, d = doublet, t =
3
C{ H} NMR (100 MHz, CDCl ) δ 148.0, 140.7, 140.3, 138.6,
triplet, q = quartet, m = multiplet, dd = doublet of doublet. 132.5, 131.4, 130.7, 130.1, 128.8, 128.6, 128.2, 121.2, 97.1,
+
Reactions were monitored using thin-layer chromatography on 85.4; HRMS (ESI-TOF) Calcd for C16
commercially prepared silica gel plates and visualized by either 265.0533, found 265.0538.
9 2
H ClN requires [M+H]
UV irradiation or by staining with I
referred to the pure isolated substances. Chromatographic obtained as a yellow oil; (127.2 mg, 77%), H NMR (400 MHz,
Purification of the label compounds was accomplished by CDCl ) δ 8.09–8.05 (m, 2H), 7.77–7.69 (m, 4H), 7.44–7.36 (m,
2
. Chemical yields are 2,3-Bis(phenylethynyl)quinoxaline (1ab). The product was
1
3
1
3
1
column chromatography using 100-200 mesh size silica gels.
5H), 7.27 (t, J = 7.6 Hz, 1H), 7.18–7.11(m, 2H); C{ H} NMR
(100 MHz, CDCl ) δ 140.9, 140.3, 132.3, 130.9, 129.8, 128.9,
General Procedure for the Synthesis of Starting Substrate
3
General
Sonogashira/Suzuki coupling reaction and Analytic data of TOF) Calcd for C24
a-w and 6a-i 331.1237.
To a solution of substituted 2,3-dichloroquinoxaline (0.5 2-(p-Tolyl)-3-(m-tolylethynyl)quinoxaline (4b). The product
mmol) in DMF (2 mL), 2 mol% of Pd(PPh Cl was added. The was obtained as a yellow needles (120.3 mg, 75%): mp 80–84
reaction vial was then sealed and flushed with nitrogen. Then, °C; H NMR (400 MHz, CDCl
.5 equiv of Et N and 0.51 mmol of alkyne were added to the (m, 2H), 7.74–7.72 (m, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.31–7.29
reaction mixture. The reaction was then stirred at 70 °C until (m, 2H ), 7.24–7.16 (m, 2H), 2.47 (s, 3H), 2.31 (s, 3H); C{ H}
TLC revealed complete conversion of the starting material. NMR (100 MHz,CDCl 154.8, 140.6, 139.8, 138.0, 137.9,
After the completion of the first coupling reaction (Monitored 134.5, 132.6, 130.5, 130.4, 130.1, 129.8, 129.6, 129.1, 129.0,
by TLC) 3 mol% of Pd(PPh Cl , 0.5 mmol of boronic acid , 1.5 128.8, 128.4, 128.2, 121.4, 115.3, 95.4, 88.0, 21.4, 21.1; HRMS
equiv of Et N was added under nitrogen atmosphere. The (ESI) calcd for [C24
reaction was then stirred at 80 °C until TLC revealed complete 357.1360.
conversion of the starting material. The reaction mixture was 2-(p-Tolyl)-3-(o-tolylethynyl)quinoxaline (4c). The product was
then allowed to cool and diluted with H O and extracted with obtained as a brown needles (125.4 mg, 75%): mp 122–125 °C;
EtOAc (3X10 mL). The combined organic layers were dried over
Na SO , concentrated under vacuum, and purified by column Hz, 2H), 7.69–7.65 (m, 2H), 7.44 (d, J = 7.32 Hz, 1H), 7.25 (d, J =
chromatography using 100−200 mesh size silica gels (hexane: 7.96 Hz, 2H), 7.21–7.16 (m, 1H), 7.12–7.06 (m, 2H), 2.37 (s,
experimental
procedure
for
sequential 128.5, 128.2, 128.1, 127.6, 125.6, 121.6, 95.8, 86.7; HRMS (ESI-
+
14 2
H N requires [M+H] 331.1235, found
4
3
)
2
2
1
3
) δ 8.13–8.10 (m, 2H), 8.05–8.02
1
3
2
1
3
1
3
) δ
3
)
2
2
3
+
3
18 2
H N ] requires [M+Na] 357.1368, found
2
1
3
H NMR (400 MHz, CDCl ) δ 8.07–8.01 (m, 2H), 7.88 (d, J = 8.56
2
4
1
3
1
ethylacetate) to afford the corresponding product. The 3H), 2.24 (s, 3H); C{ H} NMR (100 MHz, CDCl
structure and purity of known starting materials 4a, 4d-j, 4l-r, 141.0, 140.7, 139.7, 138.3, 135.0, 132.8, 130.5, 130.0, 129.54,
t-w, 6b and 6h, were confirmed by comparison of their 129.50, 129.2, 128.9, 128.7, 125.6, 121.6, 94.0, 91.9, 21.4,
3
) δ 155.1, 141.2,
4
1
13
+
18 2
physical and spectral data ( H NMR and C NMR) with those 20.5; HRMS (ESI) calcd for [C24H N ] requires [M+Na]
2
6d
reported in the literature
.
357.1368, found 357.1360.
-((4-Ethylphenyl)ethynyl)-3-(3,4,5-
2
General
experimental
Procedure
for
6-Iodo-5- trimethoxyphenyl)quinoxaline (4k). The product was obtained
1
as a yellow needles (157.0 mg, 74%): mp 94–98 °C; H NMR
aryl/alylbenzo[a] Phenazine 5a-w and 7a-i
(
400 MHz, CDCl
In a oven-dried round bottom flask, a solution of o-alkynylaryl (d, J = 7.6 Hz, 2H), 7.41 (s, 2H), 7.23 (d, J = 7.6 Hz, 2H ), 4.00 (s,
derivatives and (0.5 mmol) in 2.0 mL of DCM as a solvent 3H), 3.96 (s, 6H), 2.70 (q, J = 7.6 Hz, 2H), 1.27 (t, J = 7.6 Hz, 3H);
and 2.0 equiv of NaHCO
3
) δ 8.18–8.15 (m, 2H), 7.82–7.79 (m, 2H), 7.46
4
6
1
3
1
3
then added 2.0 equiv of I
2
. The
3
C{ H} NMR (100 MHz,CDCl ) δ 154.5, 152.8, 146.3, 140.8,
resulting reaction mixture was stirred at 25°C for 4-26 h. 140.3, 139.2, 137.9, 132.8, 132.0, 130.5, 129.0, 128.6, 128.0,
Progression of the reaction was monitored by TLC, while 125.9, 118.5, 106.9, 95.7, 87.9, 60.9, 56.1, 28.8, 15.1; HRMS
+
] requires [M+H] 425.1865, found
noticing complete consumption of o-alkynylaryls the reaction (ESI) calcd for [C26
H
22
N
2
O
3
mixture was quenched with saturated aq sodium thiosulfate 425.1862.
solution. The resulting mixture was extracted with ethyl 2-(Hex-1-yn-1-yl)-3-phenylquinoxaline (4s). The product was
1
acetate (10 mL) and water (15 mL) and then filtered through a obtained as a brown oil (97.3 mg, 68%); H NMR (400 MHz,
plug of Celite. The layers were separated, and the organic layer CDCl
3
)
δ
8.04–7.99 (m, 2H), 7.95–7.93 (m, 1H), 7.67–7.63 (m,
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J. Name., 2013, 00, 1-3 | 5
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Organic & Biomolecular Chemistry
Page 6 of 20
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DOI: 10.1039/C7OB00671C
ARTICLE
Journal Name
2
1
2
1
1
H), 7.44–7.41 (m, 2H), 7.11 (t, J = 7.6 Hz, 1H ), 6.79–6.74 (m, 106.9, 104.5, 90.5, 88.2, 61.0, 56.2, 21.9; HRMS (EI-TOF) calcd
+
H), 2.34 (t, J = 7.6 Hz, 2H), 1.49–1.41 (m, 2H), 1.30–1.22 (m, for [C24
H
20
N
2
O
3
S] requires [M] 416.1195, found 416.1191.
6-Methyl-3-(phenylethynyl)-2-(thiophen-3-yl)quinoxaline (6g).
56.1, 154.9, 140.7, 140.5, 138.4, 137.5, 130.4, 129.5, 129.1, The product was obtained as a yellow needles (124.0 mg,
1
3
1
3
H), 0.79 (t, J = 7.6 Hz, 3H); C{ H} NMR (100 MHz,CDCl ) δ
1
28.4, 128.0, 120.1, 115.4, 98.0, 79.7, 29.7, 21.9, 19.3, 13.5; 76%): mp 102–106 °C; H NMR (400 MHz, CDCl
3
)
δ
8.30–8.26
] requires [M+H] 287.1548, (m, 1H), 7.87–7.84 (m, 1H), 7.81– 7.76 (m, 1H), 7.67–7.65 (m ,
1H), 7.48–7.45 (m, 2H), 7.37–7.34 (m, 1H), 7.30–7.28 (m, 1H),
+
HRMS (ESI) calcd for [C20
found 287.1552.
18 2
H N
1
3
1
6
-Methyl-2-phenyl-3-(thiophen-2-ylethynyl)quinoxaline (6a). 7.24–7.21 (m, 3H), 2.39 (s, 3H); C{ H} NMR (100 MHz, CDCl
The product was obtained as a brown needles (114.2 mg, 148.5, 141.2, 140.4, 138.94, 138.86, 136.7, 132.9, 131.9,
8.00–7.97 129.4, 128.7, 128.4, 127.5, 127.2, 125.0, 121.5, 94.4, 88.6,
3
)
δ
1
7
0%): mp 123–127 °C; H NMR (400 MHz, CDCl
m, 2H), 7.93-7.90 (m,1H), 7.81–7.79 (m, 1H), 7.50–7.41 (m, 21.7; HRMS (ESI) calcd for [C21
H), 7.19–7.17 (m,1H), 7.04(d, J = 4.8 Hz, 1H), 2.50 (s, 3H); 327.0956, found 327.0982.
3
) δ
+
(
14 2
H N S] requires [M+H]
5
1
3
1
C{ H} NMR (100 MHz, CDCl
3
) δ 154.1, 141.4, 140.9, 140.7, 6-Methyl-2-(thiophen-3-yl)-3-(thiophen-3
1
1
39.1, 137.6, 132.9, 132.6, 131.1, 129.6,128.7, 128.0, 127.4, ylethynyl)quinoxaline (6i). The product was obtained as a
1
25.6, 120.9, 90.3, 88.1 ,21.9; HRMS (ESI) calcd for [C21
H
14
N
2
S] yellow needles (121.3 mg, 73%): mp 111–115 °C; H NMR (400
MHz, CDCl 8.39–8.36 (m, 1H), 7.97–7.91 (m, 2H), 7.80 (s,
1H), 7.67–7.66 (m , 1H), 7.54–7.51(m, 1H), 7.43–7.40 (m, 1H),
+
requires [M+Na] 327.0956, found 327.0982.
-(2,5-Dimethoxyphenyl)-3-((4-methoxyphenyl)ethynyl)-6-
methylquinoxaline (6c). The product was obtained as a yellow 7.32–7.30 (m, 1H), 7.25 (d, J = 5.4 Hz, 1H), 2.54 (s, 3H); C{ H}
3
) δ
2
1
3
1
1
needles (160.0 mg, 78%): mp 108–112 °C; H NMR (400 MHz, NMR (100 MHz,CDCl
CDCl 8.01 (d, J = 8.4Hz, 1H), 7.88 (s,1H), 7.60–7.56 (m, 1H), 132.4, 131.2, 131.1, 129.6, 128.8, 128.5, 127.9, 127.6, 127.4,
.25 (d , J = 8.4Hz, 2H), 7.08–7.04 (m, 2H), 7.00–6.98 (m, 1H), 125.8, 125.2, 120.8, 90.1, 88.4, 21.9; HRMS (EI-TOF) calcd for
3
) δ 148.6, 140.6, 139.1, 136.9, 133.0,
3
) δ
7
6
2
1
1
5
+
.81 (d, J= 8.4 Hz, 2H), 3.83 (s, 3H), 3.79 (s, 3H), 3.73 (s, 3H), [C19
H
12
N
2
S
2
] requires [M] 332.0442, found 332.0438.
160.3, 153.8, 6-Iodo-3-methyl-5-(p-tolyl)benzo[a]phenazine (5a).
53.5, 151.9, 141.1, 140.7, 140.2, 138.8, 133.8, 132.3, 128.7, product was obtained as a yellow needles (179.5 mg, 78%): mp
1
3
1
.60 (s, 3H) ; C{ H} NMR (100 MHz, CDCl
3
)
δ
The
1
3
28.1, 127.5, 116.1, 115.7, 114.0, 113.8, 112.0, 94.1, 87.1, 271–274 °C; H NMR (400 MHz, CDCl ) δ 9.26 (d, J = 8.2 Hz,
6.1, 55.8, 55.2, 21.9; HRMS (ESI) calcd for [C26
+
H
22
N
2
O
3
]
1H), 8.34–8.29 (m, 2H), 7.84–7.77 (m, 2H), 7.53 (d, J = 8.2 Hz,
1H), 7.34 (d, J =7.8 Hz, 3H), 7.15 (d, J = 8.6 Hz, 2H), 2.46 (s, 3H),
requires [M+Na] 433.1528, found 433.1523.
-((4-(tert-Butyl)phenyl)ethynyl)-2-(2,5-dimethoxyphenyl)-6-
1
3
1
3
3
2.37 (s, 3H); C{ H} NMR (100 MHz, CDCl ) δ 151.0, 143.2,
methylquinoxaline (6d). The product was obtained as a yellow 142.4, 141.7, 141.6, 140.8, 140.4, 137.9, 134.2, 130.4, 129.9,
1
needles (174.6 mg, 80%): mp 84–88 °C; H NMR (400 MHz, 129.64, 129.55, 129.3, 129.2, 129.0, 128.7, 128.3, 125.5, 108.1,
+
CDCl
3
)
δ
7.99 (d, J= 9.2 Hz, 1H), 7.87 (s, 1H), 7.57–7.53 (m, 1H), 21.9, 21.5; HRMS (ESI) calcd for [C24
.30–7.28 (m , 2H), 7.24–7.21(m, 2H), 7.06–7.01 (m, 2H), 6.98– 461.0515, found 461.0532.
.95 (m, 1H), 3.80 (s, 3H), 3.71 (s, 3H), 2.57 (s, 3H), 1.26 (s, 9H); 6-Iodo-3-methyl-5-(m-tolyl)benzo[a]phenazine (5b). The
2
H17IN ] requires [M+H]
7
6
1
3
1
C{ H} NMR (100 MHz,CDCl
41.1, 140.7, 140.1, 138.9, 132.4, 131.9, 128.6, 128.2, 127.5, 239–242 °C; H NMR (400 MHz, CDCl
25.3, 118.8, 116.1, 115.6, 112.0, 94.0, 87.5, 56.1, 55.8, 34.8, 7.83 (d, J = 7.9 Hz, 2H), 7.75–7.72 (m, 2H), 7.30 (d, J = 7.9 Hz,
3
) δ 153.9, 153.5, 152.7, 151.9, product was obtained as a yellow needles (177.2 mg, 77%): mp
1
1
1
3
4
3
3
) δ 8.14–8.10 (m, 2H),
+
1.0, 21.8; HRMS (ESI) calcd for [C29
37.2229, found 437.2229.
28 2 2
H N O ] requires [M+H] 2H), 7.05 (d, J = 7.9 Hz, 1H), 7.01–6.98 (m, 2H), 2.40 (s, 3H),
1
3
1
2.29 (s, 3H); C{ H} NMR (100 MHz, CDCl
3
) δ 151.1, 143.7,
-((4-(tert-Butyl)phenyl)ethynyl)-6-methyl-2-(3,4,5-
143.2, 142.4, 141.7, 141.6, 140.4, 138.2, 134.2, 130.4, 130.1,
trimethoxyphenyl)quinoxaline (6e). The product was obtained 130.0, 129.7, 129.6, 129.0, 128.9, 128.7, 128.4, 128.3, 126.4,
1
2
as a yellow semi-solid (195.9 mg, 84%): H NMR (400 MHz, 125.5, 107.9, 22.0, 21.7; HRMS (ESI) calcd for [C24H17IN ]
+
CDCl
3
) δ 7.91 (d, J = 9.2 Hz, 1H), 7.79 (s, 1H), 7.49 (d, J = 9.1 Hz, requires [M+H] 461.0515, found 461.0531.
1
H), 7.33–7.31 (m , 1H), 7.28–7.24 (m, 4H), 3.85 (s, 3H), 3.81 6-Iodo-3-methyl-5-(o-tolyl)benzo[a]phenazine
1
(5c).
The
3
1
3
(s, 6H), 2.50 (s, 3H), 1.20 (s, 9H); C{ H} NMR (100 MHz,CDCl )
product was obtained as a yellow needles (163.4 mg, 71%): mp
1
δ
1
6
3
152.9, 141.4, 140.9, 140.5, 139.4, 138.9, 137.9, 133.1, 132.6, 220–224 °C; H NMR (400 MHz, CDCl ) δ 9.27 (d, J = 8.2 Hz,
31.8, 128.6, 128.0, 127.4, 125.5, 118.5, 106.9, 95.5, 88.0, 1H), 8.33–8.28 (m, 2H), 7.82–7.77 (m, 2H), 7.54–7.52 (m, 1H),
0.9, 56.2, 34.9, 31.0, 22.0, 21.9; HRMS (EI-TOF) calcd for 7.41–7.31 (m, 3H), 7.13–7.11 (m, 1H), 7.01 (s, 1H), 2.35 (s, 3H),
+
] requires [M] 466.2256, found 466.2252.
13
1.97 (s, 3H); C{ H} NMR (100 MHz, CDCl
1
[C
30
H
30
N
2
O
3
3
) δ 150.7, 143.2,
6-Methyl-3-(thiophen-3-ylethynyl)-2-(3,4,5-
142.5, 141.7, 141.6, 140.7, 135.8, 133.7, 130.4, 130.3, 130.0,
trimethoxyphenyl)quinoxaline (6f). The product was obtained 129.8, 129.6, 129.2, 129.0, 128.9, 128.5, 127.5, 126.2, 125.6,
1
as a yellow needles (131.4 mg, 82%): mp 89–93 °C; H NMR 108.1, 21.9, 19.6; HRMS (ESI) calcd for [C24H17IN ] requires
2
+
7.95–7.92 (m, 1H), 7.83–7.81 (m, 1H), [M+H] 461.0515, found 461.0531.
(
400 MHz, CDCl
3
)
δ
.55–7.51 (m, 2H), 7.28–7.27 (m , 2H), 7.25–7.23(m, 1H), 7.08 6-Iodo-3-methyl-5-(thiophen-3-yl)benzo[a]phenazine
7
(5d).
1
d, J = 5.3 Hz, 1H), 3.87 (s, 3H), 3.85 (s, 6H), 2.54 (s, 3H); C{ H} The product was obtained as a yellow needles (169.6 mg,
3
1
(
1
152.9, 140.9, 139.2, 139.0, 137.6, 75%): mp 246–250 °C; H NMR (400 MHz, CDCl
NMR (100 MHz,CDCl
3
)
δ
33.1, 132.9, 131.2, 131.1, 129.6, 128.6, 127.4, 125.9, 120.8, 8.2 Hz, 1H), 8.33–8.27 (m, 2H), 7.83–7.77 (m, 2H), 7.54–7.50
3
) δ 9.23 (d, J =
1
(m, 2H), 7.32–7.31 (m, 1H), 7.19–7.18 (m, 1H), 7.11–7.09 (m,
6
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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Journal Name
H), 2.38 (s, 3H); C{ H} NMR (100 MHz, CDCl
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C7OB00671C
ARTICLE
1
3
1
1
) δ 146.6, 143.3, 177–180 °C; H NMR (400 MHz, CDCl
1
3
3
) δ 8.79 (s, 1H), 8.31–8.28
143.1, 142.4, 141.6, 140.5, 134.2, 130.5, 130.0, 129.7, 129.6, (m, 2H), 7.82–7.77 (m, 2H), 7.44 (t, J = 6.8 Hz, 2H), 7.38–7.34
1
29.0, 128.6, 127.8, 125.9, 125.5, 124.8, 114.1, 108.7, 21.9; (m, 1H), 7.23–7.21 (m, 2H), 4.13 (s, 3H), 3.83 (s, 3H), 3.19 (s,
13
+
1
HRMS (ESI) calcd for [C21
found 452.9931.
2 3
H13IN S] requires [M+H] 452.9922, 3H); C{ H} NMR (100 MHz, CDCl ) δ 154.2, 150.4, 148.3,
148.2, 145.0, 143.5, 142.1, 141.6, 140.5, 130.4, 130.1, 129.5,
5
-(4-(tert-Butyl)phenyl)-3-ethyl-6-iodobenzo[a]phenazine
128.9, 128.5, 128.1, 127.6, 126.8, 123.0, 109.0, 102.8, 60.9,
+
2 3
(5e). The product was obtained as a yellow needles (191.0 mg, 60.8, 56.2; HRMS (ESI) calcd for [C25H19IN O ] requires [M+Na]
1
7
8
7
3
4%): mp 210–213 °C; H NMR (400 MHz, CDCl ) δ 9.31 (d, J = 545.0338, found 545.0356.
.4 Hz, 1H), 8.35–8.31 (m, 2H), 7.85–7.79 (m, 2H), 7.59 (d, J = 5-(4-Ethylphenyl)-6-iodo-2,3,4-trimethoxybenzo[a]phenazine
.6 Hz, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.22–7.17 (m, 3H), 2.67 (q, (5k). The product was obtained as a yellow needles (242.1 mg,
1
3
1
1
J = 7.6 Hz, 2H), 1.39 (s, 9H), 1.16 (t, J = 6.8 Hz, 3H); C{ H} NMR 88%): mp 281–284 °C; H NMR (400 MHz, CDCl
3
) δ 8.89 (s, 1H),
) δ 151.3, 151.1, 146.7, 143.2, 142.4, 140.9, 8.40–8.38 (m, 2H), 7.89–7.87 (m, 2H), 7.34 (d, J = 7.6 Hz, 2H),
34.4, 130.4, 130.0, 129.6, 129.02, 128.96, 128.4, 127.3, 125.6, 7.20 (d, J = 7.6 Hz, 2H), 4.21 (s, 3H), 3.91 (s, 3H), 3.27 (s, 3H),
(
100 MHz, CDCl
3
1
1
1
3
1
25.44, 125.37, 108.0, 34.8, 31.5, 29.1, 15.5; HRMS (ESI) calcd 2.82–2.76 (m, 2H), 0.87 (t, J = 5.3 Hz, 3H); C{ H} NMR (100
+
for [C28
-Iodo-2,4-dimethoxy-5-(o-tolyl)benzo[a]phenazine (5f). The 141.7, 140.5, 130.3, 130.1, 129.5, 128.9, 128.5, 128.0, 127.0,
product was obtained as a brown needles (222.7 mg, 88%): mp 124.1, 123.5, 115.8, 102.8, 60.9, 56.2, 22.7, 15.8; HRMS (ESI)
H25IN
2
] requires [M+H] 517.1141, found 517.1140.
3
MHz, CDCl ) δ 154.2, 150.5, 148.5, 145.6, 143.5, 142.8, 142.1,
6
1
+
1
1
6
3
1
1
9
88–192 °C; H NMR (400 MHz, CDCl
H), 8.32–8.29 (m, 2H), 7.80–7.77 (m, 2H), 7.24–7.17 (m, 3H), 551.0823.
.98–6.96 (m, 1H), 6.60 (d, J = 2.2 Hz, 1H), 4.03 (s, 3H), 3.29 (s, 6-Iodo-2,3,4-trimethoxy-5-(4
3 2 3
) δ 8.58 (d, J = 2.7 Hz, calcd for [C27H23IN O ] requires [M+H] 551.0832, found
1
3
1
H), 1.99 (s, 3H); C{ H} NMR (100 MHz, CDCl
48.5, 143.8, 142.3, 142.1, 140.7, 134.8, 134.6, 130.3, 130.2, obtained as a brown semisolid (240.2 mg, 87%); H NMR (400
29.5, 129.1, 128.9, 127.6, 126.9, 125.1, 118.9, 106.5, 102.5, MHz, CDCl ) δ 8.80 (s, 1H), 8.31–8.29 (m, 2H), 7.81–7.78 (m,
9.5, 56.1, 55.8, 19.9; HRMS (ESI) calcd for [C25 2H), 7.14 (d, J = 8.36 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H), 4.13 (s,
3
) δ 160.4, 157.8, methoxyphenyl)benzo[a]phenazine (5l). The product was
1
3
2 2
H19IN O ]
+
13
1
requires [M+H] 507.0569, found 507.0586.
-(4-(tert-Butyl)phenyl)-6-iodo-2,4-
3H), 3.84 (s, 6H), 3.24 (s, 3H); C{ H} NMR (100 MHz, CDCl
3
) δ
5
158.5, 154.1, 150.5, 148.1, 145.1, 143.5, 142.1, 141.7, 140.9,
dimethoxybenzo[a]phenazine (5g). The product was obtained 140.5, 130.3, 130.1, 129.5, 129.2, 128.9, 128.4, 123.3, 112.9,
1
as a yellow needles (230.3 mg, 84%): mp 201–205 °C; H NMR 109.9, 102.8, 61.0, 60.9, 56.2, 55.3; HRMS (ESI) calcd for
+
] requires [M+Na] 575.0444, found 575.0445.
(
400 MHz, CDCl
3
) δ 8.629–8.621 (m, 1H), 8.44–8.39 (m, 2H), [C26
H21IN
2
O
4
7
.92–7.89 (m, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 4-(6-Iodo-2,3,4-trimethoxybenzo[a]phenazin-5-yl)-N,N-
H), 6.67–6.66 (m, 1H), 4.14 (s, 3H), 3.34 (s, 3H), 1.49 (s, 9H); dimethylaniline (5m). The product was obtained as a orange
2
1
3
1
1
C{ H} NMR (100 MHz, CDCl
45.8, 143.7, 142.1, 141.8, 140.6, 134.3, 130.2, 130.0, 129.4, CDCl
29.0, 127.6, 124.0, 119.2, 106.6, 102.6, 99.1, 55.9, 55.7, 34.6, 7.22 (d, J = 9.1 Hz, 2H), 6.94 (d, J = 9.1 Hz, 2H), 4.27 (s, 3H),
3
) δ 160.2, 157.5, 149.4, 148.9, needles (226.1 mg, 80%): mp 229–233 °C; H NMR (400 MHz,
1
1
3
5
5
3
) δ 8.94 (s, 1H), 8.46–8.43 (m, 2H), 7.95–7.90 (m, 2H),
+
13
1
1.5; HRMS (ESI) calcd for [C28
49.1039, found 549.1039.
H25IN
2
O
2
] requires [M+H]
3.99 (s, 3H), 3.40 (s, 3H), 3.12 (s, 6H); C{ H} NMR (100 MHz,
CDCl ) δ 154.0, 150.8, 149.4, 148.9, 145.2, 143.5, 142.0, 139.2,
3
-Cyclopropyl-6-iodo-2,4-dimethoxybenzo[a]phenazine (5h). 137.1, 130.2, 129.5, 128.9, 128.4, 124.0, 123.6, 115.9, 114.0,
The product was obtained as a yellow needles (173.3 mg, 111.4, 110.3, 102.8, 61.2, 60.9, 56.2, 40.7; HRMS (ESI) calcd for
+
1
6%): mp 172–176 °C; H NMR (400 MHz, CDCl
7
3 3 3
) δ 8.37–8.26 [C27H24IN O ] requires [M+H] 566.0941, found 566.0930.
(m, 3H), 7.79 (s, 2H), 6.72 (s, 1H), 4.04 (s, 3H), 3.94 (s, 3H), 6-Iodo-2,3,4-trimethoxy-5-(o-tolyl)benzo[a]phenazine
(5n).
2
.51–2.47 (m, 1H), 0.91–0.84 (m, 2H), 0.61–0.54 (m, 2H); The product was obtained as a yellow needles (217.2 mg,
1
C{ H} NMR (100 MHz, CDCl
1
3
1
) δ 159.7, 157.6, 149.5, 143.3, 81%): mp 191–194 °C; H NMR (400 MHz, CDCl
3
3
) δ 8.82 (s, 1H),
141.7, 140.5, 139.2, 133.9, 130.0, 129.7, 129.3, 120.7, 114.0, 8.33–8.30 (m, 2H), 7.81–7.79 (m, 2H), 7.28–7.21 (m, 3H), 7.05
1
08.5, 101.8, 98.3, 55.7, 55.6, 14.1, 13.5; HRMS (ESI) calcd for (d, J = 7.0 Hz, 1H), 4.13 (s, 3H), 3.83 (s, 3H), 3.18 (s, 3H), 2.03 (s,
1
+
] requires [M+H] 457.0413, found 457.0405.
13
3
3H); C{ H} NMR (100 MHz, CDCl ) δ 154.2, 150.5, 148.0,
[C
21
H17IN
2
O
2
5-Butyl-6-iodo-2,4-dimethoxybenzo[a]phenazine (5i). The 147.8, 144.9, 143.5, 142.2, 140.5, 135.2, 130.3, 130.1, 129.5,
product was obtained as a yellow needles (167.6 mg, 71%): mp 129.3, 128.9, 128.5, 127.8, 127.2, 125.3, 122.8, 114.0, 108.6,
1
1
8
3
3 2 3
94–198 °C; H NMR (400 MHz, CDCl ) δ 8.51–8.50 (m, 1H), 102.9, 60.8, 60.6, 56.2, 20.0; HRMS (ESI) calcd for [C26H21IN O ]
+
.32–8.28 (m, 2H), 7.82–7.75 (m, 2H), 6.67 (s, 1H), 4.04 (s, 3H), requires [M+H] 537.0675, found 537.0672.
.90 (s, 3H), 1.71–1.66 (m, 2H), 1.58–1.53 (m, 2H), 1.26–1.22 5-(2-Fluorophenyl)-6-iodo-2,3,4-
1
3
1
(
m, 2H), 1.02 (t, J = 7.3 Hz, 3H); C{ H} NMR (100 MHz, CDCl
3
)
trimethoxybenzo[a]phenazine (5o). The product was obtained
1
δ 159.5, 157.9, 149.0, 143.4, 142.1, 141.4, 140.3, 134.6, 130.0, as a yellow needles (194.5 mg, 72%): mp 170–174 °C; H NMR
3
129.6, 129.1, 128.9, 118.5, 107.3, 102.1, 99.3, 55.7, 55.6, 43.6, (400 MHz, CDCl ) δ 8.79 (s, 1H), 8.32–8.29 (m, 2H), 7.82–7.77
3
1.8, 23.2, 14.0; HRMS (ESI) calcd for [C22 ] requires (m, 2H), 7.41–7.35 (m, 1H), 7.24–7.14 (m, 3H), 4.13 (s, 3H),
13 1
3.85 (s, 3H), 3.28 (s, 3H); C{ H} NMR (100 MHz, CDCl
H
2 2
21IN O
+
M+H] 473.0726, found 473.0734.
[
3
) δ
6-Iodo-2,3,4-trimethoxy-5-phenylbenzo[a]phenazine (5j). The 160.2, 157.7, 154.3, 150.1, 144.8, 143.4, 142.4, 142.3, 141.5,
product was obtained as a yellow needles (201.0 mg, 77%): mp 140.6, 135.9, 135.8, 130.5, 130.3 (d, J = 3.8 Hz, 1C), 130.2,
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ARTICLE
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1
29.5, 129.0, 128.9, 128.5, 123.5 (d, J = 2.8 Hz, 1C), 122.8, 7.59 (d, J = 5.3 Hz, 1H), 7.54–7.48 (m, 1H), 7.41–7.37 (m, 1H),
1
15.0 (d, J = 22.0 Hz, 1C), 109.5, 102.9, 60.9, 60.8, 56.3; HRMS 7.31 (t, J = 7.6 Hz, 1H), 7.24 (t, J = 9.1 Hz, 1H); C{ H} NMR
3
1
1
+
2 3 3
(ESI) calcd for [C25H18FIN O ] requires [M+H] 541.0424, found (100 MHz, CDCl ) δ 158.8 (d, J = 248.2 Hz, 1C), 143.2, 142.8,
5
41.0413.
-Iodo-2,3,4-trimethoxy-5-(4-
142.6, 141.7, 140.3, 139.1 (d, J = 20.1 Hz, 1C), 136.9, 131.2 (d, J
6
= 8.6 Hz, 1C), 130.94, 130.85, 130.82, 130.2, 129.9, 128.9,
(
trifluoromethyl)phenyl)benzo[a]phenazine (5p). The product 128.2, 124.6, 124.53, 124.4, 116.4, (d, J = 22.0 Hz, 1C), 114.1,
+
2
was obtained as a yellow needles (236.0 mg, 80%): mp 195– 104.6; HRMS (ESI) calcd for [C20H10FIN S] requires [M+H]
1
98 °C; H NMR (400 MHz, CDCl
1
3
) δ 8.77 (s, 1H), 8.30–8.28 (m, 456.9672, found 456.9680.
2
H), 7.82–7.77 (m, 2H), 7.70 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.2 4-Cyclohexyl-5-iodothieno[3,2-a]phenazine (5v). The product
1
Hz, 2H), 4.12 (s, 3H), 3.82 (s, 3H), 3.17 (s, 3H); C{ H} NMR was obtained as a yellow needles (159.9 mg, 72%): mp 211–
3
1
1
(
100 MHz, CDCl
3
) δ 154.4, 151.7, 149.9, 146.6, 144.9, 143.5, 216 °C; H NMR (400 MHz, CDCl
42.3, 141.3, 140.4, 130.6, 130.3, 129.5, 128.9, 128.6, 128.5, 7.89 (m, 1H), 7.72–7.68 (m, 1H), 7.67–7.64 (m, 1H), 7.33–7.31
25.8, 124.6 (q, J = 19.0 Hz, 1C), 122.5, 108.4, 102.9, 60.9, (m, 1H), 2.43–2.36 (m, 1H), 1.79–1.73 (m, 4H), 1.55–1.52 (m,
3
) δ 8.07–8.03 (m, 2H), 7.90–
1
1
6
1
3
1
0.6, 56.3; HRMS (ESI) calcd for [C26
H
18
F
3
IN
2
O
3
] requires 1H), 1.49–1.38 (m, 3H), 1.21–1.18 (m, 2H); C{ H} NMR (100
MHz, CDCl ) δ 156.0, 147.3, 141.4, 140.2, 138.7, 130.6, 129.9,
-Iodo-5-phenylbenzo[a]phenazine (5q). The product was 129.1, 129.04, 129.00, 127.7, 125.2, 118.7, 90.8, 52.6, 32.9,
+
[M+H] 591.0392, found 591.0370.
3
6
+
2
obtained as a yellow needles (155.6 mg, 72%): mp 262–264 31.6, 25.5; HRMS (ESI) calcd for [C20H17IN S] requires [M+H]
1
C; H NMR (400 MHz, CDCl
°
3
) δ 9.42 (d, J = 7.9 Hz, 1H), 8.36– 445.0235, found 445.0249.
8
.33 (m, 2H), 7.85–7.83 (m, 2H), 7.73 (t, J = 7.9 Hz, 1H), 7.55– 4-Cyclopropyl-5-iodothieno[3,2-a]phenazine
(5w).
The
1
.48 (m, 4H), 7.36 (d, J = 7.9 Hz, 1H), 7.31–7.29 (m, 2H); C{ H} product was obtained as a yellow needles (148.8 mg, 74%): mp
3
1
7
1
COOD) δ 165.0, 145.0, 144.3, 142.1, 138.5, 180–184 °C; H NMR (400 MHz, CDCl
NMR (100 MHz, CF
3
3
) δ 8.34–8.29 (m, 2H),
1
1
34.4, 134.3, 133.7, 133.5, 132.6, 131.2, 130.8, 130.6, 130.5, 8.23–8.19 (m, 1H), 7.78–7.75 (m, 2H), 7.57–7.55 (m, 1H), 2.31–
1
3
29.6, 129.3, 128.6, 126.4, 120.6, 90.6; HRMS (ESI) calcd for 2.24 (m, 1H), 1.37–1.32 (m, 2H), 1.08–1.04 (m, 2H); C{ H}
1
+
] requires [M+H] 433.0202, found 433.0210.
[C
22
H13IN
2
3
NMR (100 MHz, CDCl ) δ 143.6, 143.4, 143.0, 142.3, 141.9,
4
-(6-Iodobenzo[a]phenazin-5-yl)-N, N-dimethylaniline (5r). 138.6, 136.7, 130.5, 129.9, 129.8, 128.8, 127.1, 124.2, 106.3,
+
2
The product was obtained as a orange needles (180.6 mg, 22.7, 10.7; HRMS (ESI) calcd for [C17H11IN S] requires [M+H]
1
6%): mp 292–296 °C; H NMR (400 MHz, CDCl
7
3
) δ 9.39 (d, J = 402.9766, found 402.9760.
8.3 Hz, 1H), 8.36–8.31 (m, 2H), 7.84–7.80 (m, 2H), 7.73–7.69 6-Bromo-2,3,4-trimethoxy-5-(o-tolyl)benzo[a]phenazine
(
m, 1H), 7.52 (d, J = 3.8 Hz, 2H), 7.18–7.15 (m, 2H), 6.84 (d, J = (5x). The product was obtained as a yellow needles (185.9 mg,
1
3
1
1
8
1
1
4
4
5
3 3
.4 Hz, 2H), 3.02 (s, 6H); C{ H} NMR (100 MHz, CDCl ) δ 76%): mp 171–174 °C; H NMR (400 MHz, CDCl ) δ 8.89 (s, 1H),
51.6, 150.1, 143.4, 142.2, 141.6, 134.6, 131.6, 131.0, 130.3, 8.42–8.38 (m, 2H), 7.92–7.87 (m, 2H), 7.35–7.31 (m, 3H), 7.18–
30.1, 129.9, 129.6, 129.1, 128.8, 128.0, 125.5, 111.8, 108.7, 7.17 (m, 1H), 4.22 (s, 3H), 3.91 (s, 3H), 3.26 (s, 3H), 2.14 (s, 3H);
+
13
1
C{ H} NMR (100 MHz, CDCl
0.4; HRMS (ESI) calcd for [C24
76.0624, found 476.0645.
H18IN
3
] requires [M+H]
3
) δ 154.1, 150.8, 145.2, 143.6,
143.04, 143.96, 141.9, 141.2, 140.5, 135.3, 130.5, 130.3, 129.7,
-Butyl-6-iodobenzo[a]phenazine (5s). The product was 129.2, 128.0, 127.6, 127.1, 125.2, 123.2, 122.5, 102.9, 60.8,
1
obtained as a brown semisolid (140.1 mg, 68%); H NMR (400 60.7, 56.3, 20.0; HRMS (ESI) calcd for [C26
+
) δ 8.10–8.06 (m, 2H), 7.78–7.76 (m, 1H), 7.73–7.69 [M+H] 489.0814, found 489.0805.
H21BrN
2
O
3
] requires
MHz, CDCl
3
(m, 2H), 7.41–7.37 (m, 3H), 2.90–2.82 (m, 1H), 2.61–2.54 (m, 6-Iodo-9-methyl-5-(thiophen-3-yl)benzo[a]phenazine
(7a).
1
3
1
1
H), 1.45–1.38 (m, 2H), 1.23–1.14 (m, 2H), 0.83 (t, J = 7.3 Hz, The product was obtained as a yellow needles (171.8 mg,
1
3
1
1
H); C{ H} NMR (100 MHz, CDCl
40.4, 137.8, 130.7, 130.2, 129.6, 129.3, 129.2, 129.1, 128.0, 8.3 Hz, 1H), 8.19 (t, J = 9.1 Hz, 1H), 8.09–8.05 (m, 1H), 7.70–
09.4, 48.9, 29.8, 21.4, 14.0; HRMS (ESI) calcd for [C20 7.62 (m, 2H), 7.52–7.47 (m, 2H), 7.44–7.42 (m, 1H), 7.31–7.30
3 3
) δ 156.4, 152.5, 141.5, 76%): mp 209–213 °C; H NMR (400 MHz, CDCl ) δ 9.32 (d, J =
H17IN ]
2
+
13
1
requires [M+H] 413.0515, found 413.0503.
-(4-(tert-Butyl)phenyl)-5-iodothieno[3,2-a]phenazine
The product was obtained as a yellow needles (210.1 mg, 133.1, 131.0, 129.7, 129.0, 128.5, 128.1, 128.0, 127.98, 127.93,
(m, 1H), 7.10–7.09 (m, 1H), 2.59 (s, 3H); C{ H} NMR (100
4
(5t). MHz, CDCl ) δ 146.4, 143.4, 143.3, 141.4, 141.0, 133.9, 133.4,
3
1
85%): mp 248–252 °C; H NMR (400 MHz, CDCl
3
) δ 8.41 (d, J = 127.5, 125.8, 125.3, 124.8, 108.8, 22.1; HRMS (ESI) calcd for
+
5.3 Hz, 1H), 8.36–8.33 (m, 1H), 8.30–8.27 (m, 1H), 7.84–7.79 [C21
2
H13IN S] requires [M+H] 452.9922, found 452.9917.
(
m, 2H), 7.58 (d, J = 5.3 Hz, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.38 (d, 5-Cyclopropyl-6-iodo-9-methylbenzo[a]phenazine (7b). The
1
3
1
3
J = 8.4 Hz, 2H), 1.36 (s, 9H); C{ H} NMR (100 MHz, CDCl ) δ product was obtained as a yellow needles (147.6 mg, 72%): mp
1
52.0, 145.8, 143.21, 143.16, 142.5, 142.1, 140.0, 139.0, 136.6, 189–293 °C; H NMR (400 MHz, CDCl
1
1
3
4
4
3
) δ 8.04–8.00 (m, 1H),
30.7, 130.0, 129.8, 128.9, 128.6, 128.4, 125.5, 124.3, 103.1, 7.92–7.89 (m, 1H), 7.82–7.79 (m, 2H), 7.62–7.59 (m, 1H), 7.46–
+
4.9, 31.4; HRMS (ESI) calcd for [C24
95.0392, found 495.0385.
H19IN
2
S] requires [M+H]
7.44 (m, 2H), 2.58 (s, 3H), 1.78–1.71 (m, 1H), 0.93–0.79 (m,
1
3
1
3
4H); C{ H} NMR (100 MHz, CDCl ) δ 156.5, 151.5, 141.4,
-(2-Fluorophenyl)-5-iodothieno[3,2-a]phenazine (5u). The 140.8, 140.6, 140.1, 138.0, 133.0, 132.5, 129.6, 129.2, 128.7,
product was obtained as a yellow needles (184.7 mg, 81%): mp 128.0, 127.9, 114.2, 21.9, 14.1, 11.3, 10.3; HRMS (ESI) calcd for
+
] requires [M+H] 411.0358, found 411.0362.
1
90–194 °C; H NMR (400 MHz, CDCl
1
3
) δ 8.42 (d, J = 5.3 Hz, [C20
H15IN
2
1H), 8.35–8.33 (m, 1H), 8.29–8.27 (m, 1H), 7.85–7.79 (m, 2H),
8
| J. Name., 2012, 00, 1-3
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DOI: 10.1039/C7OB00671C
ARTICLE
6
-Iodo-1,4-dimethoxy-5-(4-methoxyphenyl)-9-
7.56–7.54 (m, 1H), 7.35–7.30 (m, 4H), 2.59 (s, 3H), 2.43 (s, 3H);
1
3
1
methylbenzo[a]phenazine (7c). The product was obtained as a
C{ H} NMR (100 MHz, CDCl
brown needles (209.1 mg, 78%): mp 194–198 °C; H NMR (400 141.3, 140.7, 140.2, 138.8, 138.4, 136.7, 133.6, 129.4, 128.8,
MHz, CDCl ) δ 8.30–8.23 (m, 1H), 8.17–8.13 (m, 1H), 7.71 (d, J 128.3, 128.1, 124.2, 103.2, 22.1, 21.6; HRMS (ESI) calcd for
8.4 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.17–7.13 (m, 3H), 7.02– [C22
.00 (m, 2H), 4.17 (s, 3H), 3.91 (s, 3H), 3.35 (s, 3H), 2.67 (s, 3H); 5-Iodo-8-methyl-4-(thiophen-3-yl)thieno[3,2-a]phenazine (7i).
3
) δ 145.5, 143.3, 142.6, 141.9,
1
3
+
=
2
H15IN S] requires [M+H] 467.0079, found 467.0095.
7
1
3
1
C{ H} NMR (100 MHz, CDCl
42.1, 141.5, 141.1, 140.5, 132.8, 129.1, 128.9, 127.9, 127.5, 84%): mp 212–216 °C; H NMR (400 MHz, CDCl
25.9, 122.1, 115.4, 114.7, 114.5, 113.5, 112.6, 58.1, 57.1, (m, 1H), 8.30–8.22 (m, 1H), 8.18 (s, 1H), 7.74–7.70 (m, 1H),
3
) δ 158.2, 154.1, 151.0, 148.0, The product was obtained as a yellow needles (186.4 mg,
1
1
1
5
5
5
3
) δ 8.46–8.44
+
5.3, 22.1; HRMS (ESI) calcd for [C26
37.0675, found 537.0679.
H21IN
2
O
3
] requires [M+H]
7.66–7.62 (m, 2H), 7.56–7.54 (m, 1H), 7.37–7.34 (m, 1H), 2.67
1
(s, 3H); C{ H} NMR (100 MHz, CDCl
3
1
3
) δ 143.3, 142.6, 141.7,
-(4-(tert-Butyl)phenyl)-6-iodo-1,4-dimethoxy-9-
140.9, 138.4, 136.8, 133.7, 133.0, 129.3, 128.6, 128.31, 128.26,
methylbenzo[a]phenazine (7d). The product was obtained as a 127.1, 125.9, 125.5, 124.3, 114.1, 103.4, 22.1; HRMS (ESI) calcd
1
+
brown needles (230.6 mg, 82%): mp 199–203 °C; H NMR (400 for [C19
MHz, CDCl ) δ 8.35 (d, J = 9.16 Hz, 1H), 8.19 (s, 1H), 7.78–7.75 General Procedure for the synthesis of Sonogashira and
m, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.22 (d, Suzuki coupled Product 10 and 11. The products 10 and 11
2 2
H11IN S ] requires [M+H] 458.9487, found 458.9482.
3
(
2
8
J = 8.4 Hz, 2H), 7.17 (d, J = 9.16 Hz, 1H), 4.22 (s, 3H), 3.30 (s, were synthesized according to the reported protocols .
1
H), 2.72 (s, 3H), 1.48 (s, 9H); C{ H} NMR (100 MHz, CDCl
1
3
3
1
1
1
3
) δ 6-((4-Methoxyphenyl)ethynyl)-5-phenylbenzo[a]phenazine
54.2, 151.0, 149.3, 148.5, 146.3, 142.1, 141.5, 141.1, 140.5, (10). The product was obtained as a yellow needles (183.3 mg,
1
32.8, 128.9, 127.8, 127.5, 126.0, 124.0, 122.1, 115.4, 114.7, 84%): mp 197–201 °C; H NMR (400 MHz, CDCl
3
) δ 9.51 (d, J =
12.7, 58.1, 57.0, 34.6, 31.5, 22.1; HRMS (ESI) calcd for 8.4 Hz, 1H), 8.47–8.44 (m, 1H), 8.42–8.38 (m, 1H), 7.92–7.90
+
] requires [M+H] 563.1195, found 563.1189.
[C
29
H27IN
2
O
2
(m, 2H), 7.82–7.77 (m, 1H), 7.69–7.64 (m, 2H), 7.62–7.56 (m,
1
3
1
5
-(4-(tert-Butyl)phenyl)-6-iodo-2,3,4-trimethoxy-9-
5H), 7.26 (s, 2H), 6.82 (d, J = 8.4 Hz, 2H), 3.81 (s, 3H); C{ H}
159.6, 147.8, 143.0, 142.5, 142.0,
yellow needles (260.6 mg, 88%): mp 226–230 °C; H NMR (400 141.7, 138.7, 133.3, 130.8, 130.3, 130.2, 130.0, 129.8, 129.5,
MHz, CDCl ) δ 8.85–8.84 (m, 1H), 8.27–8.24 (m, 1H), 8.15–8.13 128.2, 128.1, 127.9, 127.6, 125.5, 120.7, 115.6, 113.8, 99.8,
m, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.22 (d, 85.7, 55.3; HRMS (ESI) calcd for [C31
J = 8.4 Hz, 2H), 4.20 (s, 3H), 3.91 (s, 3H), 3.23 (s, 3H), 2.68–2.65 459.1473, found 459.1467.
3
methylbenzo[a]phenazine (7e). The product was obtained as a NMR (100 MHz, CDCl ) δ
1
3
+
(
2
H20IN O] requires [M+Na]
1
3
1
(
m, 3H), 1.44 (s, 9H); C{ H} NMR (100 MHz, CDCl
3
) δ 154.0, 5-Phenyl-6-(3,4,5-trimethoxyphenyl)benzo[a]phenazine (11).
1
1
6
50.4, 149.6, 148.2, 145.4, 144.8, 143.5, 142.2, 140.7, 133.0, The product was obtained as a yellow needles (210.2 mg,
1
28.9, 128.3, 127.9, 127.7, 127.3, 124.3, 123.0, 109.2, 102.5, 89%): mp 211–214 °C; H NMR (400 MHz, CDCl
3
) δ 9.51 (d, J =
0.8, 60.7, 56.2, 34.6, 31.5, 22.0; HRMS (ESI) calcd for 8.3 Hz, 1H), 8.32 (d, J = 9.1 Hz, 1H), 8.14 (d, J = 8.4Hz, 1H),
+
] requires [M+H] 593.1301, found 593.1301.
[C
30
H29IN
2
O
3
7.82–7.78 (m, 1H), 7.75–7.71 (m, 1H), 7.60–7.59 (m, 2H), 7.46
6
-Iodo-2,3,4-trimethoxy-9-methyl-5-(thiophen-3-
(d, J = 8.4 Hz, 1H), 7.27–7.22 (m, 3H), 7.19–7.17 (m, 2H), 6.44
3
1
1
3
yl)benzo[a]phenazine (7f). The product was obtained as a (s, 2H), 3.80 (s, 3H), 3.59 (s, 6H); C{ H} NMR (100 MHz, CDCl )
1
brown semisolid (233.2 mg, 86%); H NMR (400 MHz, CDCl
3
) δ
δ 159.8, 152.0, 149.1, 147.0, 142.8, 142.1, 141.5, 138.7, 136.9,
.82–8.81 (m, 1H), 8.26–8.22 (m, 1H), 8.13 (d, J = 8.4 Hz, 1H), 133.6, 132.5, 130.9, 130.6, 130.0, 129.6, 129.4, 128.0, 127.6,
8
7
.70–7.66 (m, 1H), 7.46–7.44 (m, 1H), 7.15–7.14 (s, 2H), 4.18 127.2, 125.4, 119.1, 114.1, 110.0, 60.8, 56.0; HRMS (ESI) calcd
1
3
1
+
(
s, 3H), 3.92 (s, 3H), 3.40 (s, 3H), 2.67–2.65 (m, 3H); C{ H} for [C31
NMR (100 MHz, CDCl ) δ 154.1, 150.3, 147.7, 144.8, 143.6,
41.4, 141.2, 140.9, 140.8, 139.9, 133.2, 132.9, 129.0, 128.3,
27.9, 127.3, 124.0, 121.6, 109.9, 102.5, 61.0, 60.9, 56.2, 20.0;
24 2 3
H N O ] requires [M+H] 473.1865, found 473.1862.
3
1
1
Notes and references
+
HRMS (ESI) calcd for [C24
found 543.0247.
H19IN
2
O
3
S] requires [M+H] 543.0239,
(1) W. Zhu, M. Dai, Y. Xu and X. Qian, Bioorg. Med. Chem.,
2008, 16, 3255.
(
2) (a) A. Hazra, S. Mondal, A. Maity, S. Naskar, P. Saha, R.
Paira, K. B. Sahu, P. Paira, S. Ghosh, C. Sinha, A.
Samanta, S. Banerjee and N. B. Mondal, Eur. J. Med.
Chem., 2011, 46, 2132; (b) M. Santarem, C. Vanucci-
Bacque and G. Lhommet, J. Org. Chem., 2008, 73, 6466;
(c) Y. Ooyama, N. Yamaguchi, I. Imae, K. Komaguchi, J.
Ohshita and Y. Harima, Chem. Commun., 2013, 49,
5
-Iodo-8-methyl-4-phenylthieno[3,2-a]phenazine (7g). The
product was obtained as a yellow needles (180.9 mg, 80%): mp
1
2
7
7
3
1
1
3
53–257 °C; H NMR (400 MHz, CDCl ) δ 8.10–8.03 (m, 1H),
.95–7.92 (m, 1H), 7.82–7.81 (m, 1H), 7.65–7.60 (m, 1H), 7.48–
.46 (m, 1H), 7.41–7.32 (m, 4H), 6.78–6.75 (m, 1H), 2.59 (s,
1
3
1
3
H); C{ H} NMR (100 MHz, CDCl ) δ 145.4, 143.3, 143.0,
2
548.
41.8, 141.3, 140.8, 138.4, 136.7, 133.7, 132.9, 132.4, 130.9,
(
3) (a) M. E. Makgatho, R. Anderson, J. F. O’Sullivan, T. J.
Egan, J. A. Freese, N. Cornelius and C. E. J. van
Rensburg, Drug Develop. Res., 2000, 50, 195; (b) Y.
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29.0, 128.7, 128.3, 128.1, 124.2, 103.1, 22.1; HRMS (ESI) calcd
+
S] requires [M+H] 452.9922, found 452.9914.
for [C21
H13IN
2
5-Iodo-8-methyl-4-(p-tolyl)thieno[3,2-a]phenazine (7h). The
product was obtained as a brown needles (200.5 mg, 86%): mp
1
23–227 °C; H NMR (400 MHz, CDCl
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3
) δ 8.37 (d, J = 5.5 Hz,
1H), 8.15 (d, J = 8.6 Hz, 1H), 8.10 (s, 1H), 7.65–7.61 (m, 1H),
1
151.
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Graphical Abstract
A tandem approach for the synthesis of iodo benzo[a]phenazine derivatives using molecular iodine
has been described under the mild reaction conditions.