A new synthetic approach to 6-unsubstituted phenanthridine and phenanthridine-like compounds under mild and metal-free conditions

Article abstract of DOI:10.1039/c4ob00797b

A new and mild synthetic approach for the synthesis of 6-unsubstituted phenanthridine and phenanthridine-like compounds under metal-free conditions at room temperature has been developed. The strategy involved a tandem azide rearrangement/intramolecular annulation and oxidation reactions of biarylmethyl azide precursors to obtain the desired products in up to 99% yields with high regioselectivity.

Full text of DOI:10.1039/c4ob00797b

Organic &
Biomolecular Chemistry
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A new synthetic approach to 6-unsubstituted
phenanthridine and phenanthridine-like
compounds under mild and metal-free
conditions†
Cite this: Org. Biomol. Chem., 2014,
12, 5077
Received 17th April 2014,
Accepted 23rd May 2014
Jumreang Tummatorn,*a Suppachai Krajangsri,a Krissada Norseeda,a
DOI: 10.1039/c4ob00797b
www.rsc.org/obc
Charnsak Thongsornkleeba,b and Somsak Ruchirawata,b
A new and mild synthetic approach for the synthesis of 6-unsubsti-
tuted phenanthridine and phenanthridine-like compounds under
metal-free conditions at room temperature has been developed.
The strategy involved a tandem azide rearrangement/intramole-
cular annulation and oxidation reactions of biarylmethyl azide
precursors to obtain the desired products in up to 99% yields with
high regioselectivity.
Fig. 1 Some phenanthridine natural products and a staining agent.
Phenanthridines and related heterocyclic systems are impor-
tant frameworks of natural products, pharmacologically active
compounds and fluorescence staining agents.1 Several syn-
thetic strategies have been reported including C–C bond and
C–N bond formation of the o-functionalized biaryl com-
pounds. Numerous approaches have been described utilizing
metal-catalyzed processes which always proceeded at high reac-
tion temperatures,2 except for a recently published procedure
using an iridium complex.3 Nevertheless, transition metal-free
reaction is one of the most important processes, especially in
the pharmaceutical industry where the requirement for final
products to be completely free of trace metals is crucial. Such
metal-free phenanthridine syntheses involving radical pro-
cesses have been disseminated employing photochemical reac-
tions,4 microwave irradiation5 and the combination of the
Togni reagent and Bu4NI.6 Other metal-free conditions include
KOt-Bu-mediated C–H bond arylation7 and hydrothermal reac-
tion of o-phenylaniline derivatives8 (Fig. 1 and Scheme 1).
Although an array of synthetic methods for phenanthridine
has been described, the approaches for the preparation of
6-unsubstituted phenanthridines are relatively rare, especially
under the metal-free conditions. The construction of such
Scheme 1 Literature methods for phenanthridine synthesis.
systems can be accomplished via two known methods, which
include the photo-irradiation of the iminylbiaryl compounds
and the modified Pictet–Spengler reaction involving the
methyleneiminium ion formation from biarylaniline and
formaldehyde and cyclization under refluxing toluene.9 In this
regard, the formation of such iminium ions can be difficult
and provided the desired product in moderate yields, possibly
aChulabhorn Research Institute, 54 Kamphaeng Phet 6, Laksi, Bangkok 10210,
Thailand. E-mail: jumreang@cri.or.th; Fax: +662 574 0622;
Tel: +662 574 0622 exp 1513
bProgram on Chemical Biology, Chulabhorn Graduate Institute, Center of Excellence
on Environmental Health and Toxicology, CHE, Ministry of Education,
54 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4ob00797b
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Table 1 Screening for the optimal conditions
Yielda
(%)
Scheme 2 Strategy of our proposed methodology.
Entry
R
TfOHe
Oxidante
b
1
H
H
H
H
H
1.5 eq., o/n Air, DCM–MeCN, o/n
1.5 eq., o/n 1.1 eq. NaBO3 MeCN–H2O, 1 h
—
—
due to the use of formaldehyde. We envision that the gene-
ration of the methyleneiminium ion could be more efficient
starting from arylmethyl azide.10 In this work, we reported for
the first time the utilization of o-biarylmethyl azide rearrange-
ment and intramolecular annulation as two key sequential
steps, followed by oxidative aromatization for preparing
phenanthridine and phenanthridine-like derivatives under
mild and metal-free conditions at ambient temperature as
shown in Scheme 2.
To examine our proposed strategy, non-substituted biphenyl-
methyl azide was employed as the model substrate in search of
the optimal conditions. Our previous work has demonstrated
that the ability of TfOH to initiate the azide rearrangement
was crucial for generating the iminium ion intermediate in
situ.10 Therefore in this work, 1.5 equivalents of TfOH were
used in the first step to promote the rearrangement for gener-
2
3c
4
1.5 eq., o/n 1.0 eq. oxone, MeCN–H2O, 0.5 h 16
1.5 eq., o/n 1.0 eq. oxone, MeCN–H2O, 1 h
1.5 eq., o/n 1.0 eq. DDQ, DCM, 0.5 h
33
56
5
6
7
8
9
10
11
12
13
14
15
OMe 1.5 eq., o/n 1.0 eq. DDQ, DCM, 0.5 h
OMe 1.5 eq., o/n O2, CH3CN–DCM (1 : 1), o/n
OMe 1.5 eq., o/n DAIB, DCM
OMe 1.2 eq., 3 h 3.0 eq. I2, THF, o/n
OMe 1.2 eq., 3 h 3.0 eq. I2, DCM, o/n
OMe 1.2 eq., 3 h 2.0 eq. I2, THF, 3 h
OMe 1.2 eq., 3 h 1.2 eq. I2, THF, 3 h
OMe 1.2 eq., 3 h 1.2 eq. I2 in one pot, 3 h
OMe 1.2 eq., 3 h 1.0 eq. PCC, 1 h
Trace
82
—
85
81
99
93
25d
—
H
1.2 eq., 3 h 1.2 eq. I2, THF, 3 h
60
a Isolated yield. b Incomplete conversion was observed and the yield
was not determined. c The reaction was carried out at 0 °C. d NMR
yield. e o/n = overnight.
ating the iminium ion intermediate followed by an intramole- Diacetoxyiodobenzene was also examined and provided a
cular annulation furnishing the crude dihydrophenanthridine complex mixture (entry 8). We found that dihydrophenanthri-
product. In the crude product, we could observe slight autoxi- dine could be effectively oxidized using I2 in THF for overnight
dation of dihydrophenanthridine to phenanthridine after providing the phenanthridine product in 85% yield (entry 9).
work-up. In order to fully oxidize the crude product, it was dis- In fact, I2 has been reported previously to affect oxidation in a
solved in CH3CN and stirred open to air at room temperature. similar system, namely N-alkyldihydrophenanthridine to phen-
However, only a marginal increase in conversion was observed anthridinium salt.18 However to the best of our knowledge,
(entry 1) after stirring overnight. When searching the literature only one example has been reported to oxidize N-unprotected-
for methods for the conversion of dihydrophenanthridine to a dihydrophenanthridine (3) using I2 in the presence of NaOAc
fully aromatic system, several oxidizing agents were reported, under refluxing conditions.19 Using I2 oxidation could provide
including Cu(OAc)2,2i Pd/C,11 Ru(TPP)CO,12 CrO3,13 MnO2,14 the advantage in avoiding the decomposition of multiply-oxy-
and PCC,15 but only a few examples of metal-free conditions genated compounds. After switching the solvent to DCM, the
were presented, such as those employing air/irridation,4c desired product was obtained in slightly lower yield (81%)
DDQ,16 and O2.17 However, the decomposition of the desired (entry 10). To improve the yield, we tried to reduce the equi-
product was observed under some of these conditions17 valent of I2 (2.0 equiv., entry 11) and time (3 h) which could
(Table 1).
provide the product in excellent yield (99%). The yield became
In view of our interest, the metal-free conditions are very slightly lower when the equivalent of I2 was decreased
important; we then tried several oxidizing agents such as (1.2 equivalents, entry 12). We also tried to perform reaction in
NaBO3, oxone and DDQ (entries 2–5), and the results showed one pot by adding I2 to the reaction mixture after the first step
that DDQ oxidation could provide the desired phenanthridine (entry 13). However, the dihydroquinoline could not be oxi-
product in the highest yield (56%). However, we also have a dized to a fully aromatic system under acidic conditions. We
difficulty in purifying the product from colored impurities of also compared our method with the reported oxidation con-
DDQ as reported in the earlier work.17 To confirm the capa- ditions using PCC as the oxidant which gave only a complex
bility of DDQ in the oxidation process, 2,3-dimethoxybiphenyl mixture (entry 14). To further confirm our method, we
methyl azide was investigated under these conditions (entry 6). repeated the oxidation of the unsubstituted dihydrophen-
Unfortunately, we observed only decomposition in the reaction anthridine using I2 in THF as the oxidizing agent instead of
mixture and only a trace amount of the desired product was DDQ and we could obtain the corresponding phenanthridine
obtained after purification. Oxidation using oxygen gas was product in 60% yield. Therefore, the optimal conditions of our
also employed to afford the phenanthridine product in 82% method was concluded using 1.2 equivalents of TfOH in DCM
yield (entry 7). Unfortunately, we were unable to reproduce this in the first step and 2.0 equivalents of I2 in THF in the second
outcome, observing incomplete oxidation in several attempts. step.
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Table 2 Substrate scope for the synthesis of phenanthridinesa
Scheme 3 Proposed reaction mechanism.
The proposed mechanism is illustrated in Scheme 3. The
biarylmethyl azide under the TfOH-promoted aryl migration
generated iminium ions in situ followed by intramolecular
nucleophilic addition to form the carbocation intermediate
which could be stabilized by the adjacent aromatic system.
After rearomatization, dihydrophenanthridine was obtained
and was further oxidized using I2. Under these conditions, the
nitrogen nucleophile attacked I2 to furnish the ammonium ion
intermediate, followed by the elimination of HI to give the pro-
tonated phenanthridine salt, which upon workup afforded
phenanthridine as the final product.
With the optimal reaction conditions in hand, the general-
ity of this synthetic methodology was studied as shown in
Table 2. The unactivated aromatic nucleophile could success-
fully provide the phenanthridine products in moderate yields
(2a, 2b) which is in contrast to our previous report where
toluene could not react intermolecularly with the iminium ion
generated from the rearrangement of arylmethyl azide.10a This
is an indication that the intramolecular nucleophile could
facilitate the cyclization better whereby the carbocation inter-
mediate generated in the reaction could be well-stabilized by
the adjacent aromatic system as shown in Scheme 3. The
1- and 2-naphthyl aromatic nucleophiles furnished the desired
products in good yields (2c, 2d). The results revealed that the
steric hindrance at the ortho-position of the arylmethyl azide
was not a problem in the aryl migration step. It was important
to note that a single regioisomeric product was obtained in
both cases. The electron-donating substituents on the aro-
matic nucleophiles were also investigated. 3-Methoxy biphenyl-
methyl azide provided a mixture of isolable regioisomeric
products in good combined yields (2e–A, 2e–B). The majority
of the phenanthridine product was obtained from the cycliza-
tion by the less sterically hindered carbon nucleophile at the
para-position of the methoxy group. In the case of the 2,3-
dimethoxyphenyl aromatic nucleophile, we fruitfully obtained
the phenanthridine (2f) in excellent yield. Interestingly, a
single regioisomeric product (2g) was obtained in good yield
when 3,4-dimethoxybiphenylmethyl azide (1g) was used as a
precursor. This result indicated that the most reactive nucleo-
philic center was the carbon atom at the para-position to the
3-methoxy group of the diarylmethyl azide. When we
attempted the aromatic nucleophile which bears the
a Isolated yield. b Overnight reaction in the first step.
3,4-methylenedioxy substituent on the phenyl ring, a single
regioisomeric product was obtained in lower yield (2h) due to
the decomposition of the methylenedioxy moiety. The reaction
of 3,5-dimethoxybiarylmethyl azide (1i) effortlessly provided
the phenanthridine product in excellent yield. Remarkably, the
azide precursor 1j provided the electrophilic aromatic substi-
tution product 2j–A as the minor product (36%) whereas the
dechlorinative cyclization product 2j–B was obtained as the
major product (58%). We found that compound 2j–B was
formed directly in the cyclization step without the need for I2
oxidation while compound 2j–A was formed after the addition
of I2. Therefore the reaction mechanism of these transform-
ations was proposed as shown in Scheme 4.
We next explored the variation of both electron-donating
and -withdrawing substituents on the aryl ring of arylmethyl
azide (ring A) which were found to afford products in good to
excellent yields (2k–2n). We would like to point out that the
multimethoxy-substituted system was also tolerated under
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Acknowledgements
This research work was supported in part by grants from the
Center of Excellence on Environmental Health and Toxicology,
Science & Technology Postgraduate Education and Research
Development Office (PERDO), the Ministry of Education,
Chulabhorn Research Institute and Thailand Toray Science
Foundation.
11 T.
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