Microwave assisted synthesis of phenanthridinones and dihydrophenanthridines by vasicine/KO: T Bu promoted intramolecular C-H arylation

Article abstract of DOI:10.1039/c6ob01362g

A simple, efficient, rapid and transition metal-free methodology has been developed by utilizing vasicine (a natural product), as a catalyst for the synthesis of phenanthridinones and dihydrophenanthridines. The reaction proceeds through intramolecular C-H arylation with aryl halides in the presence of KOtBu as a base under microwave irradiation in sulfolane as a solvent. The reaction proceeds well with various aryl iodides, bromides and more remarkably with less reactive aryl chlorides for 15 minutes, providing the corresponding products in 45-90% yields.

Full text of DOI:10.1039/c6ob01362g

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Kumar, S. Sharma, O. S. Nayal, N. Kumar, B. Singh and U. Sharma, Org. Biomol. Chem., 2016, DOI:
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DOI: 10.1039/C6OB01362G
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ARTICLE
Microwave Assisted Synthesis of Phenanthridinones and
Dihydrophenanthridines by Vasicine/KOtBu Promoted Intramolecular
C-H Arylation
Received 00th January 20xx,
Accepted 00th January 20xx
Sushila Sharma,a,b Manoranjan Kumar,a,b Shruti Sharma,a Onkar S. Nayal,a,b Neeraj Kumar,$ Bikram
DOI: 10.1039/x0xx00000x
Singh*a,b and Upendra Sharma*a,b
www.rsc.org/
A simple, efficient, rapid and transition metal-free methodology has been developed by utilizing vasicine (a natural
product), as catalyst for the synthesis of phenanthridinones and dihydrophenanthridines. The reaction proceeds through
intramolecular C-H arylation with aryl halides in the presence of KOtBu as base under microwave irradiation in sulfolane as
solvent. The reaction proceeds well with various aryl iodides, bromides and more remarkably with less reactive aryl
chlorides within 15 minutes providing corresponding products in 45-90% yields.
iodine promoted oxidative coupling,5 reductive cyclization of
nitro carbonyl biphenyls,6 anionic ring closure,7 annulations of
arynes with o-halobenzmides8 and transition metal catalyzed
Introduction
Phenanthridinone is an important structural unit in various
natural products and pharmaceuticals with a wide range of
biological activities such as antitumour, antifungal,
antileukemic, antiviral, antiprotozoal etc. (Figure 1).1 Similarly
dihydrophenanthridines though less abundant in nature
exhibit biological activities compared to that of
phenanthridines.2
direct C-H arylation (Scheme 1).9 However, only few protocols
are available for dihydrophenanthridine synthesis.9c,10 Though
significantly useful methods are available, the development of
economical and environmentally benign methodologies is
highly stipulated.
Figure 1Phenanthridinone and dihydrophenanthridine based natural products.
Owing to its immense importance various strategies have
been developed for the synthesis of phenanthridinones. These
include, aminocarbonylation,3 deamidation,4 hypervalent
Scheme 1 Synthetic approaches for phenanthridinone synthesis.
In recent years transition metal-free direct C-H arylation
with aryl halides has gained immense attention and used as
powerful method for biaryl synthesis.11 In 2008, Itami and co-
workers first reported KOtBu mediated coupling of electron
deficient heteroarenes with aryl halides.12 Later, in 2010, Shi et
al.,13 Kwong/Lei,14 and Shirakawa/Hayashi15 disclosed DMEDA,
1,10-phenanthroline, and its derivatives promoted transition
metal-free biaryl synthesis through homolytic aromatic
substitution mechanism. After these reports, several
methodologies have emerged that demonstrated different
aDepartment of Natural Product Chemistry and Process Development, CSIR-
Institute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh 176
061, INDIA
bAcademy of Scientific and Innovative Research, CSIR-IHBT, Palampur, Himachal
Pradesh 176 061, INDIA.
Email: upendra@ihbt.res.in; upendraihbt@gmail.com (US);
bikramsingh@ihbt.res.in (BS)
$Dedicated to Dr. Neeraj Kumar (deceased on 28th March 2016) who was a great
mentor and a brilliant scientist
Electronic Supplementary Information (ESI) available: [1H and 13C NMR spectra].
See DOI: 10.1039/x0xx00000x
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N/O- based ligand promoted transition metal free biaryl was proposed that vasicine interacts with KOtBuViwewhAirctihclehOenllipnes
coupling.16
in single electron transfer to aryl halide resulting in generation
DOI: 10.1039/C6OB01362G
However, in context of transition metal free intramolecular of aryl radical after dehalogenation (Scheme 2A). So we
biaryl coupling for the synthesis of phenanthridinone and planned to explore the vasicine-KOtBu catalytic system in
dihydrophenanthridine scaffolds, few reports are available. In intramolecular aromatic substitution reaction for the synthesis
2011, Charette et al. and Shi et al. independently reported of
phenanthridinones
and
dihydrophenanthridines.
KOtBu promoted intramolecular arylation of various aryl Disappointingly, the intermolecular coupling method was
iodides and bromides in the presence of phenanthroline and unsuccessful in case of aryl chlorides as coupling partner which
its derivatives for the synthesis of different fused may be due to less reactivity of aryl chlorides as compared to
heterocycles.17 Kumar et al. reported the synthesis of aryl iodides and bromides (Scheme 2B). To realize the goal of
phenanthridinone
halobenzamides using the combination of 1,10-phenanthroline chlorides, we started investigating the reaction conditions with
or AIBN with KOtBu in benzene.18 Bisai and co-workers 2-chloro-N-methyl-N-phenyl-benzamide
1a as model
and
dibenzoazepinones
from
2- intramolecular coupling with aryl halides particularly aryl
(
)
reported the synthesis of pyrrolophenanthridinone scaffold substrate (Table 1). Under our previously reported
and demonstrated the utility of the method for the synthesis conditions,25a no reaction was observed (Scheme 2C).
of
Amaryllidaceae
alkaloids,
oxoassoanine
and
anhydrolycorinone, with the aid of bidentate organic ligands.19
Recently, Yamashita et al. carried out the synthesis of
pyrrolophenanthridinone derivatives by samarium(II)-iodide
mediated reductive cyclization.20 Even though successful
methodologies are available but the use of aryl chlorides and
aryl bromides as substrate in transition metal-free coupling is
limited and is still in demand. Aryl chlorides are generally less
reactive as compared to aryl bromides and aryl iodides. Also,
aryl chlorides are less expensive and readily available than
iodides, making their use in cross-coupling reactions highly
desirable. So, Kwong and co-workers carried out similar
coupling method using N-(2-chloroaryl)benzoimines and
derivatives as substrates in the presence of ethylene glycol and
KOtBu for the synthesis of phenanthridines.21
Nowadays, methodologies involving the use of non-
traditional methods such as microwave irradiation,
environment friendly solvents, catalysts etc. are highly
sought.22 Particularly, microwave assisted reactions offers
several advantages like short reaction time, enhanced yield,
cleaner
reactions
and
acceleration
of
sluggish
transformations.23 Moreover, plant-derived natural products
are an attractive alternatives to metal-based catalysts in terms
of stability, selectivity, and economy, therefore emerged as
Scheme 2. Vasicine catalyzed C-H arylation with aryl halides.
promising
organocatalysts
for
various
organic
transformations.24
Delightfully, switching to microwave conditions resulted in
formation of product, 5-methyl-5H-phenanthridin-6-one (2a),
albeit in poor yield (9%) (Table 1, entry 1). After extensive
screening of various reaction parameters, i.e., solvent, ligands,
bases and temperature, the best result was observed with 50
mol% of vasicine (L1), KOtBu (4 equiv), sulfolane as solvent at
In the quest of utilizing natural products as
reagent/catalyst in organic transformations,25 we have
previously demonstrated the potential of vasicine as an
efficient organocatalyst for coupling25a and reduction
reaction.25c Vasicine is
a quinazoline alkaloid present
o
abundantly in leaves of Adhatoda vasica. In continuation of
our previous work on vasicine catalyzed C-H arylation of
unactivated arenes, herein, we first time report vasicine and
KOtBu promoted intramolecular C-H arylation with aryl halides
120 C for 15 minutes under microwave irradiation, affording
the desired product 2a in 49% isolated yield (Table 1, entry 2).
Sulfolane is a dipolar aprotic solvent, commonly used as an
industrial solvent, but also used recently in various organic
reactions.26 The poor yield of the desired product was
observed with other solvents such as 1,4-dioxane, DMF and
DMSO, while no reaction was observed in case of acetonitrile
and tBuOH as solvent (Table 1, entries 3-7). Among different
ligands, L2 provided the product 2a in comparable yield (Table
1, entry 8). Ligands with free NH- or OH- group that were
earlier reported to catalyze the coupling reaction efficiently
for
the
synthesis
of
phenanthridinone
and
dihydrophenanthridines under microwave condition.
Results and Discussion
In our previous report on metal free intermolecular direct
arylation of unactivated arenes with aryl halides (Scheme 2), it
2 | J. Name., 2016, 00, 1-3
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were also tested in present reaction (L3
did not afford the desired product (Table 1, entries 9-11). L6 significant change was observed with higher amount of
was able to access the product 2a in 6% yield only (Table 1, catalyst or base (Table 1, entries 19-25). The control
ARTICLE
-
L5), but unfortunately, equivalents, respectively, led to a decrease in theVyieiwelAdrticalenOdnnlinoe
DOI: 10.1039/C6OB01362G
entry 12).
experiments revealed that in the absence of L1, dehalogenated
product (corresponding amide) was observed, while in the
absence of KOtBu, no reaction was observed (Table 1, entries
26 and 27). The lower yield of the desired product was
observed when the reaction was carried out at lower
temperature or for shorter reaction time (Table 1, entries 28-
30). At higher temperature, no effect on the yield was
observed (Table 1, entry 31). Also, reaction carried out under
Table 1. Reaction condition optimizationa
o
conventional heating at 120 C provided comparatively lower
yield of the desired product (Table 1, entry 32).
With the optimized reaction conditions in hand, the scope
and limitations of the present method were investigated
(Table 2). Phenanthridinone (2a) was observed in 90, 70 and
49% yield in case of iodo-, bromo- and chlorobenzamides,
respectively (Table 2, 2a).
entry catalyst
(mol%)
base
(equiv)
solvent
conv
(%)
15
99
28
16
50
-
-
73
-
-
-
yield (%)b
2a
9
2ab
1
2
3
4
5
6
7
8
9
L1 (50)
L1 (50)
L1 (50)
L1 (50)
L1 (50)
L1 (50)
L1 (50)
L2 (50)
L3 (50)
L4 (50)
L5 (50)
L6 (50)
L1 (50)
L1 (50)
L1 (50)
L1 (50)
L1 (50)
L1 (50)
L1 (20)
L1 (40)
L1 (60)
L1 (50)
L1 (50)
L1 (50)
L1 (50)
-
KOtBu (4)
KOtBu (4)
KOtBu (4)
KOtBu (4)
KOtBu (4)
KOtBu (4)
KOtBu (4)
KOtBu (4)
KOtBu (4)
KOtBu (4)
KOtBu (4)
KOtBu (4)
K2CO3 (4)
KOAc (4)
K3PO4 (4)
NaHCO3(4)
Toluene
Sulfolane
1,4-diox
DMF
-
49
9
35
15
13
25
-
-
30
-
-
-
10
-
-
>5
10
nr
nr
38
nr
nr
nr
6
nr
nr
nr
nr
19
15
25
33
45
21
28
47
42
nd
nr
35
38
45
50
26
Table 2. Scope of intramolecular cyclization reaction for the synthesis of 5-alkyl-5H-
phenanthridinonesa,b
DMSO
MeCN
tBuOH
Sulfolane
Sulfolane
Sulfolane
Sulfolane
Sulfolane
Sulfolane
Sulfolane
Sulfolane
Sulfolane
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26c
27
28d
29e
30f
31 g
32h
95
-
-
-
-
-
-
NaOtBu (4) Sulfolane
99
95
58
79
99
75
89
99
99
95
-
90
92
99
99
66
30
20
21
28
40
48
50
43
45
KOH (4)
KOtBu (4)
KOtBu (4)
KOtBu (4)
KOtBu (2)
KOtBu (3)
KOtBu (5)
KOtBu (6)
KOtBu (4)
-
KOtBu (4)
KOtBu (4)
KOtBu (4)
KOtBu (4)
KOtBu (4)
Sulfolane
Sulfolane
Sulfolane
Sulfolane
Sulfolane
Sulfolane
Sulfolane
Sulfolane
Sulfolane
Sulfolane
Sulfolane
Sulfolane
Sulfolane
Sulfolane
Sulfolane
L1 (50)
L1 (50)
L1 (50)
L1 (50)
L1 (50)
L1 (50)
-
49
48
39
40
32
a Reaction was carried out with 0.25 mmol of 1a in the presence of catalyst
b
and base in 0.4 mL of solvent under µW. Isolated yield. In most cases
dechlorination of 1a yielding corresponding amide and cleavage of 1a,
aReaction was carried out with 0.25 mmol of 1 in the presence of 0.12 mmol of
catalyst and 1.0 mmol of KOtBu in 0.4 mL of solvent at 120 oC for 15 minutes
under 120 W, µW. Isolated yields. In all cases, dechlorination of 1 yielding 20-
yielding N-methylaniline was observed. c Mixture of amide+N-methylaniline
f
d Reaction was carried out at 80 oC. e Reaction carried out for 5 minutes.
b
h
Reaction carried out for 10 minutes. g Reaction was carried out at 150 oC.
25% of corresponding amide and cleavage of 1, yielding 15-20% of N-
Reaction carried out under conventional heating at 120 oC for 16 h. 1,4-diox
= 1,4-dioxane.
methylaniline was observed. c Ratio determined by 1H NMR.
The reaction of 2-chloro-N-methyl-N-(4-fluorophenyl)
benzamide afforded the cyclized product 2b in 56% yield
(Table 2, 2b). Electron rich substrates provided the
corresponding phenanthridinones in moderate yield (Table 2,
No reaction occurred in the presence of other bases such as
K2CO3, KOAc, K3PO4 and NaHCO3, while NaOtBu and KOH
afforded the product in poor yield (Table 1, entries 13-18).
Lowering the quantity of ligand and base below 0.5 and 4
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2c-2h) while no product formation was observed with electron Earlier reports have described this metal free aVriyelwaAtiroticnle Ownilitnhe
DOI: 10.1039/C6OB01362G
deficient substrates (Table 2, entry 2i). In case of nitro aryl halides approach to proceed via base promoted radical
substituted substrate, decomposition of starting material was mechanism.27 So, assuming that the same mechanism is valid
observed as no unreacted starting material was left after in present case, the reaction was carried out under standard
completion of the reaction. 2-Chloro-N-methyl-N-pyridin-2-yl- conditions in the presence of radical scavenger (TEMPO). A
benzamide provided the product 2j in 54% yield. The cylization decrease in the yield was observed with 1 equivalent of
reaction of N-ethyl substituted amide gave the corresponding TEMPO while its 3 equivalent provided the product in traces.
phenanthridinone in 45% yield (Table 2, entry 2k). (Scheme 3A). Thus a radical mechanism may be involved in
Furthermore, m-substituted aniline derived amides provided present reaction. When reaction was attempted with m-chloro
mixture of regioisomers in 1: 1 ratio (Table 2, entries 2l/2l’ and substituted amide, product 2a was not observed (Scheme 3B).
2m/2m’). The reaction of p-chloro substituted aniline derived Moreover,
amides provided dechlorinated cyclized products as major phenylbenzamide (1a) in the presence of strong base nBuLi
product (See supporting information, Table S1). showed no product formation (Scheme 3C) which indicated
the
reaction
of
2-chloro-N-methyl-N-
Further the scope of the method was extended for the that the reaction does not proceed through the benzyne
synthesis of dihydrophenanthridines (Table 3). Inspite of the pathway. Further an intermolecular competition experiment
efforts, N-(2-chlorobenzyl)-N-methylaniline did not work well was carried out between equimolar mixtures of iodo-, bromo-
and the desired product 5-methyl-5,6-dihydrophenanthridine and chloro-substituted amides in one pot (Scheme 3D). While
(4a) was detected in trace amount. However, the bromo- full conversion was observed with iodo-substituted amide (I),
analogue afforded the corresponding product 4a in good yield the conversion of chloro- substituted amide (III) was lower
(Table 3, 4a). Electron rich substrates such as N-(2-bromo-4,5- than that of bromo-substituted amide (II). These results clearly
dimethoxybenzyl)-N-methylaniline,
dimethoxybenzyl)-N-methyl-4-fluoroaniline
N-(2-bromo-4,5- indicated the reactivity order which can be inferred as I > Br >
gave the Cl.
corresponding dihydrophenanthridines in good yields (Table 3,
4b and 4c). Similarly, N-(2-bromo-4-methybenzyl)-N-
methyaniline,
N-(2-bromo-4-methylbenzyl)-N-methyl-p-
anisidine and N-(2-bromobenzyl)-N-methyl-2,4-dimethylaniline
underwent the cyclization reaction smoothly and afforded the
corresponding products 4d, 4e and 4f in moderate to good
yield (Table 3, 4d 4e and 4f). N-(2-Bromobenzyl)-N-sec-butyl-
,
p-anisidine provided the cyclization product 4g in 71% yield.
Electron deficient aryl halides were also tested as susbtrate,
however, the desired product was not obtained and the
substrate decomposed under present reaction conditions (see
supporting information).
Table 3. Scope of intramolecular cyclization reaction for the synthesis of 5-alkyl-5,6-
dihydrophenanthridinesa,b
a Reaction was carried out with 0.25 mmol of 3 in the presence of 0.12 mmol of
catalyst and 1.0 mmol of KOtBu in 0.4 mL of solvent at 120 oC for 15 minutes
under 120 W, µW. Isolated yields. b In all cases, cleavage of 1, yielding 15-20% of
N-methylaniline was observed
Scheme 3 Control experiments: Reaction mechanism.
Therefore, on the basis of literature17,18 and control
experiments a possible mechanism is proposed in Scheme 4
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which represents the intramolecular version of the accepted volume was 2 µL in GC grade dichloromethane. Nitrogen was
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-1
DOI: 10.1039/C6OB01362G
mechanism for intermolecular C-H arylation reaction as used as carrier gas at a flow rate of 1.1 mL min on split mode
depicted in scheme 2B
.
(1: 50). Mass spectra were recorded on QTOF-Micro of Waters
Micromass.
Procedure for the isolation of vasicine and vasicinone
Dried leaves of Adhatoda vasica (5 Kg) were powdered and
extracted with MeOH: H2O (80: 20). The extracts were
collected and concentrated using rotary evaporator. The
extract was then treated with 2N HCl and stirred at room
temperature for few hours. It was then filtered and filtrate was
extracted with ethyl acetate. The aqueous acidic layer was
basified with ammonium hydroxide to pH 9 and then extracted
with CHCl3. The chloroform extract was concentrated using
rotary evaporator to give crude alkaloid extract. The crude
alkaloidal extract was then subjected to column
chromatography on basic alumina and eluted with hexane:
ethyl acetate: MeOH in increasing polarity. Fractions eluted
with ethyl acetate afforded vasicinone (1 g). Fractions eluted
with ethyl acetate: MeOH (9: 1) provided vasicine (8.54 g). The
identification and characterization of compound were carried
Scheme 4 Proposed reaction mechanism
out using 1H NMR and 13C NMR.
1
Vasicine
(
L1): H NMR (600 MHz, CDCl3): δ 7.13-6.83 (m,
Conclusions
4H), 4.75-4.73 (m, 1H), 4.55-4.50 (m, 2H), 3.35-3.19 (m, 2H),
2.37-2.36 (m, 1H) 2.12-2.09 (m, 1H); 13C NMR (150 MHz,
CDCl3): δ 163.9, 142.4, 128.4, 125.8, 124.1, 123.7, 119.0, 70.2,
48.1, 47.1, 28.9. MS (ESI-TOF) m/z: [M+H]+ for C11H13N2O
189.26.
In conclusion, vasicine, a natural product in combination with
KOtBu as base has been established as an efficient catalytic
system for transition metal-free intramolecular coupling with
aryl halides for the synthesis of phenanthridinones and
dihydrophenanthridines. The use of MW as energy as well as
avoiding the use of transition metal as catalyst makes the
present method environmentally friendly.
Vasicinone (
L2): 1H NMR (600 MHz, MeOD): δ 8.32-8.29
(m, 1H), 7.75 (m, 1H), 7.53-7.49 (m, 2H) 5.31-5.26 (m, 1H),
4.40-4.35 (m, 1H), 4.12-4.02 (m, 1H), 2.70-2.66 (m, 1H), 2.37-
2.33 (m, 1H); 13C NMR (150 MHz, MeOD): δ 160.6, 160.1,
148.6, 134.4, 126.9, 126.7, 126.6, 121.0, 71.9, 43.4, 29.3. MS
(ESI-TOF) m/z: [M+H]+ for C11H11N2O2 203.09.
Experimental
General methods
General procedure for the preparation of amides (1a-1m)9f
All reagents, high grade solvents and materials were used as
received from commercial sources unless otherwise stated.
Toluene was distilled from sodium and benzophenone. Column
chromatography was carried out with 100-200 mesh silica gel
(Merck India). TLC silica gel 60 F254 plates and 100-200 mesh
silica gel were purchased from Merck India Ltd. 2-Halobenzoic
acid, anilines and NMR solvents were purchased from sigma
Aldrich. 1H NMR and 13C NMR experiments were performed on
Bruker Avance-300 and 600 MHz spectrometer. NMR spectra
were recorded in CDCl3. Chemical shifts are reported in parts
per million (ppm) downfield from an internal standard.
Splitting patterns are given as follows: s, singlet; d, doublet; t,
triplet; q, quartet; m, multiplet; br, broad; brs, broad singlet;
dd, double doublet. All coupling constants are given in Hertz
(Hz). All experiments were performed on CEM Discover
focused microwave (2450 MHz, 300W). The GC-MS analysis
was carried out using DB-5 MS capillary column, (30 m x 0.25
mm i.d., 0.25 µm) on a Shimadzu (QP 2010) series Gas
Chromatogram-Mass Spectrometer (Tokyo, Japan) coupled
with AOC-20i auto-sampler. The initial temperature of column
was 70 °C held for 4 min. and was programmed upto 230 °C at
4°C/min, then held for 15 min at 230 °C; the sample injection
(i) Procedure for the preparation of 2-halobenzoyl chloride:
A round bottomed flask was charged with 2-halobenzoic acid
o
(1.0 equivalent) in toluene (5 mL per mmol) and cooled to 0 C
on ice bath. To this solution was added N,N-DMF (0.1 equiv)
o
followed by SOCl2 (1.5 equiv) dropwise. After stirring at 0 C
for five minutes, the reaction mixture was placed on oil-bath
while maintaining the temperature to 80 ºC and stirred for
another 3 h at same temperature. Upon completion of the
reaction (monitoring by TLC), the reaction mixture was cooled
and used directly for coupling reaction, without further
purification.
(ii) Procedure for the preparation of amide:
A round-
bottomed flask was charged with aniline (1.0 equiv) and
triethylamine (3.0 equiv) in dichloromethane (10 mL per
mmol) and cooled to 0 ºC on an ice-bath. After 5 minutes of
stirring, a toluene solution of acid chloride (1.0 equiv) was
added drop wise to the reaction mixture and allowed to warm
to rt. Upon completion of the reaction (monitoring by TLC), the
reaction mixture was then diluted with dichloromethane. The
solution was washed with 1N HCl. The organic layer was
filtered on a short silica gel column and washed with ethyl
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acetate. The crude product was purified by column (ESI-TOF) m/z: [M+H]+ calcd for C16H16NO3 270V.1ie1w3A0rticlFeoOunlninde
DOI: 10.1039/C6OB01362G
9-Amino-5-methylphenanthridin-6(5H)-one (
2f): 1H NMR
chromatography (4:1 n-hexanes/EtOAc) to afford pure amides. 270.1115.
General procedure for the synthesis of phenanthridinones
(2a-2m): To an oven dried 10 mL glass tube charged with
magnetic bar was added 2-halo-N-methyl-N-phenylbenzamide
(0.25 mmol), vasicine (0.12 mmol), KOtBu (1 mmol) and
sulfolane (0.4 mL). The tube was sealed with a septum stirred
and placed in the microwave and subjected to microwave
irradiation of 120 W. The temperature was ramped from rt to
(600 MHz, CDCl3): δ 8.33 (d, J = 8.5 Hz, 1H), 8.13 (d, J = 7.9 Hz,
1H), 7.51 (t, J = 7.7 Hz, 1H), 7.37 (t, J = 7.8 Hz, 2H), 7.26 (t, J =
7.5 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 4.21 (brs, 2H), 3.76 (s, 3H);
13C NMR (150 MHz, CDCl3): δ 161.5, 150.3, 138.6, 135.4, 130.8,
129.4, 123.1, 121.9, 119.1, 117.2, 116.1, 114.9, 104.6, 29.6.
HRMS (ESI-TOF) m/z: [M+H]+ calcd for C14H13N2O 225.1028
o
o
120 C and held at 120 C for 15 min. Note that under current Found 225.1011.
29c
(2g) :
1H
reaction condition microwave temperature was fixed at 120
8-Methoxy-5-methylphenanthridin-6(5H)-one
oC. The initial power of microwave was 120 W which changed
during the reaction to maintain the temperature. The reaction
mixture was allowed to cool and extracted with ethyl acetate.
The ethyl acetate layer was then washed with water and the
solvent was removed under vacuum. The crude residue was
subjected to column chromatography on silica gel using n-
hexane: EtOAc to afford the cyclized product.
NMR (600 MHz, CDCl3): δ 8.21-8.19 (m, 2H), 7.98 (d, J = 2.8 Hz,
1H), 7.52-7.49 (m, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.35 (dd, J = 3.9
Hz, 1H), 7.33-7.30 (m, 1H), 3.97 (s, 3H), 3.84 (s, 3H); 13C NMR
(150 MHz, CDCl3): δ 161.4, 159.5, 137.0, 128.4, 127.1, 126.9,
123.4, 122.6, 122.5, 122.3, 119.4, 115.0, 109.2, 55.7, 30.1.
HRMS (ESI-TOF) m/z: [M+H]+ calcd for C15H14NO2 240.1025
Found 240.1009.
5-Methylphenanthridin-6(5H)-one (
2a)8a: 1H NMR (600
2-Fluoro-8-methoxy-5-methylphenanthridin-6(5H)-one
2h): H NMR (600 MHz, CDCl3): δ 8.21 (d, J = 8.8 Hz, 1H), 8.10
MHz, CDCl3): δ 8.49 (d, J = 7.9 Hz, 1H), 8.23 (t, J = 7.2 Hz, 2H),
7.70 (t, J = 7.6 Hz, 1H), 7.54-7.48 (m, 2H), 7.37 (d, J = 8.4 Hz,
1H), 7.27 (t, J = 7.5 Hz, 1H), 3.76 (s, 3H); 13C NMR (150 MHz,
CDCl3): δ 161.6, 138.0, 133.5, 132.3, 129.5, 128.8, 127.9, 125.5,
123.2, 122.4, 121.6, 119.2, 115.0, 29.9. HRMS (ESI-TOF) m/z:
[M+H]+ calcd for C14H12NO 210.0919 Found 210.0901.
1
(
(d, J = 2.8 Hz, 1H), 7.98 (dd, J = 4.1 Hz, 1H), 7.51-7.48 (m, 2H),
7.37-7.34 (m, 1H), 4.11 (s, 3H), 3.96 (s, 3H); 13C NMR (150 MHz,
CDCl3): δ 161.0, 160.0, 158.6 (J = 241.7 Hz), 133.4, 127.2, 126.1
(J = 3.0 Hz), 123.6, 122.3, 120.8 (J = 7.6 Hz), 116.3 (J = 8.0 Hz),
115.6 (J = 23.2 Hz), 109.5, 108.6 (J = 24.0 Hz), 55.7, 30.3. HRMS
(ESI-TOF) m/z: [M+H]+ calcd for C15H13FNO2 258.0930 Found
258.0916.
2-Fluoro-5-methylphenanthridin-6(5H)-one (2b)8a: 1H NMR
(600 MHz, CDCl3): δ 8.55 (d, J = 7.9 Hz, 1H), 8.16 (t, J = 8.1 Hz,
1H), 7.93 (dd, J = 4.1 Hz, 1H), 7.77 (t, J = 7.5 Hz, 1H), 7.62 (d, J =
7.5 Hz, 1H), 7.38-7.36 (m, 1H), 7.28-7.25 (m, 1H), 3.81 (s, 3H);
13C NMR (150 MHz, CDCl3): δ 161.2, 158.5 (J = 241.9 Hz), 134.5,
132.6 (J = 2.5 Hz), 132.5, 129.0, 128.6, 125.8, 121.8, 120.7 (J =
7.7 Hz), 116.7 (J = 23.2 Hz), 116.5 (J = 7.9 Hz), 109.2 (J = 24.0
Hz), 30.2. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C14H11FNO
5-Methyl-5H-benzo[c][1,8]naphthyridin-6-one
(
2j): 1H
NMR (600 MHz, CDCl3): δ 8.59 (dd, J = 8.0 Hz, 1H), 8.56 (dd, J =
0.9, 7.0 Hz, 1H), 8.52 (dd, J = 1.6, 6.2 Hz, 1H), 8.22 (d, J = 1.6,
6.2 Hz, 1H), 7.78 (dt, J = 1.3, 6.9 Hz, 1H), 7.62-7.65 (m, J = 0.9,
7.1 Hz, 1H), 7.26 (t, J = 6.2 Hz, 1H), 3.93 (s, 3H); 13C NMR (150
MHz, CDCl3): δ 162.5, 148.7, 148.5, 132.6, 131.8, 131.1, 128.9,
128.7, 125.8, 121.6, 118.1, 114.8, 28.8. HRMS (ESI-TOF) m/z:
228.0825 Found 228.0803.
29a
2-Methoxy-5-methylphenanthridin-6(5H)-one
(2c) :
1H
[M+H]+ calcd for C13H11N2O 211.0871 Found 211.0859
NMR (600 MHz, CDCl3): δ 8.54 (d, J = 7.9 Hz, 1H), 8.19 (d, J =
8.1 Hz, 1H), 7.75-7.72 (m, 2H), 7.58 (t, J = 7.5 Hz, 1H), 7.33 (d, J
= 9.0 Hz, 1H), 7.13 (dd, J = 3.8 Hz, 1H), 3.92 (s, 3H), 3.78 (s,
3H); 13C NMR (150 MHz, CDCl3): δ 161.1, 155.0, 133.1, 132.3,
132.1, 128.9, 127.9, 125.8, 121.5, 120.1, 116.4, 116.0, 107.1,
55.6, 29.9. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C15H14NO2
240.1025 Found 240.1005.
29a
5-Ethylphenanthridin-6(5H)-one
(2k) :
1H NMR (600
MHz, CDCl3): δ 8.56 (d, J = 7.9 Hz, 1H), 8.32-8.28 (m, 2H), 7.76
(t, J = 7.6 Hz, 1H), 7.60-7.54 (m, 2H), 7.45 (d, J = 8.4 Hz, 1H),
7.32 (t, J = 7.5 Hz, 1H), 4.48 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1
Hz, 3H); 13C NMR (150 MHz, CDCl3): δ 161.1, 136.9, 133.5,
132.3, 129.5, 128.8, 127.9, 125.6, 123.5, 122.2, 121.5, 119.5,
114.9, 37.6, 12.7. HRMS (ESI-TOF) m/z: [M+H]+ calcd for
C15H14NO 224.1075 Found 224.1055.
2,5-Dimethylphenanthridin-6(5H)-one (
2d)8a: 1H NMR (600
MHz, CDCl3): δ 8.54 (d, J = 7.9 Hz, 1H), 8.26 (d, J = 8.1 Hz, 1H),
8.06 (s, 1H), 7.74 (t, J = 7.5 Hz, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.35
(d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 3.79 (s, 3H), 2.49 (s,
3H); 13C NMR (150 MHz, CDCl3): δ 161.5, 135.9, 133.5, 132.2,
131.8, 130.5, 128.9, 127.8, 125.7, 123.3, 121.5, 119.1, 114.9,
29.9, 20.9. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C15H14NO
Mixture of 3,5-Dimethylphenanthridin-6(5H)-one + 1,5-
1
Dimethylphenanthridin-6(5H)-one
(
2l and 2l’): H NMR (600
MHz, CDCl3): δ 8.56 (dd, J = 1.1, 6.7 Hz, 1H), 8.45 (d, J = 7.9 Hz
1H), 8.36 (d, J = 8.3 Hz, 1H), 8.14 (d, J = 8.1 Hz, 1H), 8.07 (d, J =
8.1 Hz, 1H), 7.67-7.64 (m, 2H), 7.51 (t, J = 7.5 Hz, 1H), 7.47 (t, J
= 7.5 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.25 (d, J = 8.3 Hz, 1H),
7.13 (s, 1H), 7.09 (d, J = 7.3 Hz, 1H), 7.06 (d, J = 8.1 Hz, 1H),
3.73 (s, 3H), 3.72 (s, 3H), 2.87 (s, 3H), 2.43 (s, 3H); 13C NMR
(150 MHz, CDCl3): δ 161.8, 161.6, 139.9, 139.1, 138.0, 136.3,
134.6, 133.6, 132.3, 131.4, 128.9, 128.8, 128.3, 127.4, 127.2,
127.2, 126.6, 125.1, 123.6, 123.1, 121.3, 119.2, 116.8, 115.4,
113.3, 30.8, 29.9, 26.4, 21.9. HRMS (ESI-TOF) m/z: [M+H]+
calcd for C15H14NO 224.1075 Found 224.1051.
224.1075 Found 224.1058.
29b
2,3-Dimethoxy-5-methylphenanthridin-6(5H)-one
(2e
)
:
1H NMR (600 MHz, CDCl3): δ 8.53 (d, J = 7.8 Hz, 1H), 8.13 (d, J =
8.1 Hz, 1H), 7.74 (t, J = 7.5 Hz, 1H), 7.66 (s, 1H), 7.53 (d, J = 7.5
Hz, 1H), 6.87 (s, 1H), 4.03 (s, 6H), 3.82 (s, 3H); 13C NMR (150
MHz, CDCl3): δ 161.7, 150.6, 145.0, 133.4, 132.9, 132.3, 129.0,
126.9, 124.5, 121.1, 111.8, 104.9, 98.3, 56.3, 56.1, 30.3. HRMS
6 | J. Name., 2016, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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Page 7 of 9
Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
Mixture of 5-methyl-1-phenylphenanthridin-6(5H)-one + 108.8, 106.0, 56.1, 56.0, 54.7, 38.6. HRMS (EVSieI-wTAOrtFic)le Omnl/inze:
1
+
DOI: 10.1039/C6OB01362G
5-Methyl-3-phenylphenanthridin-6(5H)-one
NMR (600 MHz, CDCl3): δ 8.56 (d, J = 7.8 Hz, 1H), 8.51 (d, J =
7.9 Hz 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.28 (d, J = 8.1 Hz, 1H), dihydrophenanthridine
(
2m and 2m’): H [M+H] calcd for C16H18NO2 256.1338 Found 256.1214.
2-Fluoro-8,9-dimethoxy-5-methyl-5,6
1
(
4c): H NMR (600 MHz, CDCl3): δ 7.29
7.78-7.75 (m, 1H), 7.69 (d, J = 7.3 Hz, 2H), 7.59 (t, J = 7.4 Hz, (d, J = 9.7 Hz, 1H), 7.12 (s, 1H), 6.88 (t, J = 8.5 Hz, 1H), 6.65 (s,
2H), 7.56-7.54 (m, 1H), 7.52-7.50 (m, 3H), 7.46-7.39 (m, 6H), 1H), 6.64-6.62 (m, 1H), 4.08 (s, 2H), 3.95 (s, 3H), 3.90 (s, 3H),
7.36-7.34 (m, 2H), 7.26 (d, J = 8.2 Hz, 1H), 7.20-7.18 (m, 1H), 2.87 (s, 3H); 13C NMR (150 MHz, CDCl3): δ 156.8 (J = 236.1 Hz),
7.15 (d, J = 6.7 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H); 13C NMR (150 148.9, 148.8, 142.8, 126.5, 125.0 (J = 9.6 Hz), 124.0, 114.0 (J =
MHz, CDCl3): δ 161.8, 161.7, 143.8, 142.6, 141.2, 140.4, 139.1, 22.3 Hz), 112.9 (J = 7.7 Hz), 109.5 (J = 23.4 Hz), 108.8, 106.0,
138.4, 133.6, 133.3, 132.5, 130.5, 129.1, 129.0, 128.9, 128.8, 56.1, 56.0, 54.8, 38.9. HRMS (ESI-TOF) m/z: [M+H]+ calcd for
128.4, 128.2, 128.0, 127.9, 127.6, 127.5, 127.3, 127.3, 126.7, C16H17FNO2 274.1243 Found 274.1222.
17a
125.5, 123.7, 121.6, 121.5, 118.3, 117.8, 114.3, 113.6, 30.7,
5,9-Dimethyl-5,6-dihydrophenanthridine (4d) :
1H NMR
30.0. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C20H16NO (600 MHz, CDCl3): δ 7.72 (dd, J = 1.5, 6.1 Hz, 1H), 7.54 (s, 1H),
286.1232 Found 286.1212.
7.25-7.22 (m, 1H), 7.19-7.15 (m, 1H), 7.06-7.02 (m, 1H), 6.87
(dt, J = 1.0, 6.4 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 4.15 (s, 2H),
2.92 (s, 3H), 2.39 (s, 3H); 13C NMR (150 MHz, CDCl3): δ 147.3,
137.1, 131.9, 128.9, 127.7, 127.5, 125.5, 123.4, 123.4, 123.0,
118.5, 112.3, 54.8, 38.6, 21.4. HRMS (ESI-TOF) m/z: [M+H]+
calcd for C15H16N 210.1283 Found 210.1266.
General Procedure for the synthesis of N-aryl-N-alkyl-2-
halobenzylamines (3a-3g):28 To
a
stirred solution of
SnCl2•2H2O (0.2 mmol) in MeOH (3 mL) were added 2-
bromobenzaldehyde derivative (1.1 mmol), amine (1.0 mmol)
and PMHS (2.0 H equiv) at room temperature, and the
temperature was raised to 70 °C. After 6 h, the reaction
mixture was allowed to cool, filtered and passed through
anhydrous sodium sulfate. The crude product was purified by
column chromatography over silica gel (60-120 mesh) with an
appropriate mixture of n-hexane and ethyl acetate.
2-Methoxy-5,9-dimethyl-5,6-dihydrophenanthridine (4e):
1H NMR (600 MHz, CDCl3): δ 7.49 (s, 1H), 7.29 (d, J = 2.8 Hz,
1H), 7.05 (s, 2H), 6.82 (dd, J = 2.8, 5.8 Hz, 1H), 6.70 (d, J = 8.7
Hz, 1H), 4.05 (s, 2H), 3.84 (s, 3H), 2.27 (s, 3H), 2.39 (s, 3H); 13C
NMR (150 MHz, CDCl3): δ 152.9, 141.8, 137.1, 131.8, 131.1,
128.0, 125.5, 124.8, 123.2, 114.1, 113.2, 109.7, 55.8, 55.2,
39.0, 21.4. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H18NO
240.1388 Found 210.1365
General
Procedure
for
the
synthesis
of
dihydrophenanthridines (4a-4g): To an oven dried microwave
tube with screw cap charged with magnetic bar was added N-
aryl-N-alkyl-2-halobenzylamines (0.25 mmol), vasicine (0.12
mmol), KOtBu (1 mmol) and sulfolane (0.4 mL). The tube was
sealed with a septum stirred and placed in the microwave and
subjected to microwave irradiation of 100 W. The temperature
was ramped from rt to 120 C and held at 120 C for 15 min.
Note that under current reaction condition microwave
temperature was fixed at 120 oC. The initial power of
microwave was 120 W which changed during the reaction to
maintain the temperature. After the reaction, the reaction
mixture was allowed to cool and was diluted with ethyl
acetate. The organic layer was then washed with water and
the solvent was removed under vacuo. The crude residue was
subjected to column chromatography on silica gel using n-
2,4,5-Trimethyl-5,6-dihydrophenanthridine (
4f): 1H NMR
(600 MHz, CDCl3): δ 7.75 (d, J = 7.6 Hz, 1H), 7.47 (s, 1H), 7.35
(dt, J = 1.0, 6.4 Hz, 1H), 7.29 (dt, J = 1.0, 6.2 Hz, 1H), 7.22 (d, J =
6.9 Hz, 1H), 7.01 (s, 1H), 4.10 (s, 2H), 2.46 (s, 3H), 2.38 (s, 3H),
2.37 (s, 3H); 13C NMR (150 MHz, CDCl3): δ 144.3, 133.5, 133.2,
132.6, 132.3, 131.3, 128.8, 127.4, 127.2, 126.7, 122.9, 122.1,
55.4, 40.5, 21.1, 17.4. HRMS (ESI-TOF) m/z: [M+H]+ calcd for
C16H18NO 224.1439 Found 224.1414.
o
o
2-Methoxy-5-sec-butyl-5,6-dihydrophenanthridine
(4g):
1H NMR (600 MHz, CDCl3): δ 7.66 (d, J = 7.8 Hz, 1H), 7.33-7.30
(m, 2H), 7.23 (t, J = 7.3 Hz, 1H), 7.15 (d, J = 7.3 Hz, 1H), 6.84
(dd, J = 2.7, 6.1 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 4.03 (s, 2H),
3.87 (t, J = 7.5 Hz, 1H), 3.84 (s, 3H), 3.63 (q, J = 6.7 Hz, 1H),
1.79-1.72 (m, 1H), 1.20 (d, J = 6.5 Hz, 3H), 0.94 (t, J = 7.4 Hz,
3H); 13C NMR (150 MHz, CDCl3): δ 152.1, 141.2, 134.2, 132.3,
127.3, 127.0, 125.3, 125.2, 122.5, 114.6, 114.4, 109.7, 55.8,
54.1, 44.3, 26.7, 15.7, 11.5. HRMS (ESI-TOF) m/z: [M+H]+ calcd
for C18H22NO 268.1701 Found 268.1695.
hexane: EtOAc to afford the cyclized product.
1
5-Methyl-5,6-dihydrophenanthridine
(4a
)
17a: H NMR (600
MHz, CDCl3): δ 7.74 (d, J = 7.5 Hz, 2H), 7.34 (t, J = 7.6 Hz, 1H),
7.25 (q, J = 8.2 Hz, 2H), 7.15 (d, J = 7.3 Hz, 1H), 6.90 (t, J = 7.4
Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 4.20 (s, 2H), 2.94 (s, 3H); 13C
NMR (150 MHz, CDCl3): δ 147.2, 133.2, 132.1, 129.1, 127.7,
127.0, 125.6, 123.5, 123.4, 122.5, 118.6, 112.3, 55.1, 38.6.
HRMS (ESI-TOF) m/z: [M+H]+ calcd for C14H14N 196.1126 Found
196.1109.
Acknowledgements
The authors are grateful to the Director of the Institute for
encouragement and support. SS and MK also thank UGC for
granting research fellowship. Financial support from CSIR
8,9-Dimethoxy-5-methyl-5,6-dihydrophenanthridine
1
19a: H NMR (600 MHz, CDCl3): δ 7.60 (d, J = 7.6 Hz, 1H),
(ORIGIN,
CSC-0108)
is
also
acknowledged.
IHBT
(4b
)
communication no. for this publication is 3980.
7.22 (s, 1H), 7.19 (t, J = 7.7 Hz, 1H), 6.86 (t, J = 7.4 Hz, 1H),
6.74 (t, J = 8.1 Hz, 1H), 6.65 (s, 1H), 4.14 (s, 2H), 3.95 (s, 3H),
3.90 (s, 3H), 2.91 (s, 3H); 13C NMR (150 MHz, CDCl3): δ 148.7,
148.5, 146.4, 128.2, 125.8, 124.8, 123.4, 122.7, 118.5, 112.2,
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This journal is © The Royal Society of Chemistry 20xx
J. Name., 2016, 00, 1-3 | 7
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Organic & Biomolecular Chemistry
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C6OB01362G
Microwave
Assisted
Synthesis
of
Phenanthridinones
and
Dihydrophenanthridines by Vasicine/KOtBu Promoted Intramolecular
C-H Arylation
Sushila Sharma, Manoranjan Kumar, Shruti Sharma, Onkar S. Nayal, Neeraj Kumar, Bikram
Singh* and Upendra Sharma*
Natural product as catalyst: Vasicine and KOtBu promoted intramolecular C-H arylation has
been demonstrated for synthesis of phenanthridinones and dihydrophenanthridines with various
aryl iodides, bromides and less reactive aryl chlorides in microwave condition within 15 minutes
providing products in 45-90% yields.