Efficient synthesis of phenanthridines using Hendrickson reagent initiated cascade reaction under mild conditions

Article abstract of DOI:10.1055/s-0030-1258081

A number of variously substituted phenanthridines have been synthesized using the newly developed methodology under mild conditions. The Hendrickson reagent initiated cascade annulation, which is composed of a mild conversion of stable amide precursor to highly reactive imido-carbonium intermediate and a subsequent intramolecular Friedel-Crafts reaction, successfully served as the key method. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258081

LETTER
1674
Efficient Synthesis of Phenanthridines Using Hendrickson Reagent Initiated
Cascade Reaction under Mild Conditions
Synthesis
i
of Phen
e
anthridines Xi,a,b Qing-Li Dong,a Guan-Sai Liu,a Shaozhong Wang,a Lin Chen,*b Zhu-Jun Yao*a
a
Nanjing National Laboratory of Microstructures and State Key Laboratory of Coordination Chemistry,
School of Chemistry and Chemical Engineering, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, P. R. of China
Fax +86(25)83593732; E-mail: yaoz@nju.edu.cn
b
School of Chemistry and Biotechnology, Yunnan Nationalities University, Kunming, Yunnan 650031, P. R. of China
Received 16 April 2010
R2
Abstract: A number of variously substituted phenanthridines have
been synthesized using the newly developed methodology under
mild conditions. The Hendrickson reagent initiated cascade annula-
tion, which is composed of a mild conversion of stable amide pre-
cursor to highly reactive imido-carbonium intermediate and a
subsequent intramolecular Friedel–Crafts reaction, successfully
served as the key method.
B
Ph
Ph
O
Ph
Ph
R2
P
P
(OTf)2
A
R1
Ph
Ph
R1
R3
0 °C to r.t.
N
H
R3
O
N
2
1
Key words: phenanthridine, cascade reaction, Hendrickson re-
agent, carbocation, Friedel–Crafts reaction
H
Ph3PO
R2
R2
R2
F–C rxn
R1
R1
H
R3
N
R3
R1
OPPh3
Phenanthridine is a representative core structure of many
alkaloids with interesting biological and pharmaceutical
activities1 and of some materials with optical properties.2
Considerable attentions have been paid in organic synthe-
sis to construction of variously substituted phenan-
thridines. In the past several decades, quite a number of
methods have been developed, including Bischler–
Napieralski cyclizations with P4O10, POCl3, or PCl5 under
high-temperature conditions3 and some recent achieve-
ments using multistep syntheses with metal catalysts un-
der heating, microwave irradiation, or higher temperature
conditions.4 A three-component reaction has also been de-
veloped for the synthesis of phenanthridines by heating
the mixture of aromatic aldehyde, aniline, and benzenedi-
azonium-2-carboxylate in dichloroethane at 80 °C.5 Be-
cause of broad applications of phenanthridine derivatives,
further development of mild, efficient, and flexible syn-
theses of phenanthridines is of great significance.
N
N
R3
intermediate
Scheme 1 Design of the cascade synthesis of phenanthridines in
this work
(Scheme 1). Herein, we wish to report our results in the
synthesis of phenanthridines using the above-mentioned
cascade reaction.
Following the above tentative idea (Scheme 1), a number
of biphenyl-2-amine amides 1 were synthesized for the
examination. At first, starting from commercially avail-
able 2-iodoaniline (3), substrates 1a–j (Scheme 1, R1 = H,
R3 = Me) bearing a variable substituent R2 on ring B were
prepared by corresponding Suzuki couplings and N-
acetylation. Then, they were examined under the standard
conditions of our previous work (Table 1).6–8 Reactions of
1a–i with Hendrickson reagent were all smoothly carried
out at 0 °C to room temperature in short times, affording
phenanthridines 2a–i in satisfactory yields (Table 1, en-
tries 1–9). Obviously, the initial design of cascade synthe-
sis of phenanthridines works. As the exception (entry 10),
the amide 1j bearing a NO2 group on phenyl ring B failed
to undergo the cascade reaction. Such a result could be ex-
plained by the strong electron-withdrawing effects of ni-
tro group, which makes the final intramolecular Friedel–
Crafts reaction unfavorable (Scheme 1). However, amide
1i bearing a bromine atom could work well under the
same conditions, affording the corresponding product 2i
in 78% yield (entry 9). Introduction of a halogen in the
product will help many further modifications to improve
the chemical and physical properties of phenanthridines in
various applications. Poor regioselectivity was observed
when the substrate bearing a methoxyl group at the C-3
position of phenyl ring B (1c, entry 3), and two separable
isomers 2ca and 2cb (ratio = 1:2.5) were given.
In our recent total syntheses of camptothecin-family alka-
loids,6 Hendrickson reagent7 was successfully employed
as a powerful reagent to convert stable aniline amides to
corresponding imidates at ambient temperature. Such re-
active intermediates were further found to undergo a vari-
ety of subsequent reactions, such as intramolecular Diels–
Alder reactions with the dienophiles6 and intermolecular
electrophilic reactions with acetylenes.8 Following the
mechanisms, it was speculated that the in situ generated
imido carboniums might react with the electron-rich are-
nes via Friedel–Crafts reaction. If this cascade works in an
intramolecular way, it will provide a new protocol for the
synthesis of various phenanthridine derivatives
SYNLETT 2010, No. 11, pp 1674–1678
x
x
.x
x
.2
0
1
0
Advanced online publication: 10.06.2010
DOI: 10.1055/s-0030-1258081; Art ID: W04310ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Phenanthridines
1675
Table 1 Synthesis of Phenanthridines 2a–j with a Variable Substituent (R2)a
R2
(HO)2B
Tf2O (1.5 equiv)
Ph3PO (3 equiv)
CH2Cl2
R2
R2
Suzuki
coupling
I
0 °C to r.t.
(see Table 1)
N
NH2
NHR
3
4a–j R = H
2a–i
AcCl
1a–j R = Ac
Entry
1
Yield of 2 (%)b
1
2
1a R2 = H
N
2a 95
O
1b R2 = 4-MeO
N
2b 95
O
N
2ca 26
3
1c R2 = 3-MeO
O
N
2cb 65
4
1d R2 = 4-Me
N
2d 90
O
O
5
1e R2 = 3,4-di-MeO
N
2e 87
O
6
1f R2 = 2-MeO
1g R2 = 4-t-Bu
N
2f 91
t-Bu
7
N
2g 89
Synlett 2010, No. 11, 1674–1678 © Thieme Stuttgart · New York

1676
J. Xi et al.
LETTER
Table 1 Synthesis of Phenanthridines 2a–j with a Variable Substituent (R2)a (continued)
R2
(HO)2B
Tf2O (1.5 equiv)
Ph3PO (3 equiv)
CH2Cl2
R2
R2
Suzuki
coupling
I
0 °C to r.t.
(see Table 1)
N
NH2
NHR
3
4a–j R = H
2a–i
AcCl
1a–j R = Ac
Entry
1
Yield of 2 (%)b
8
1h R2 = 4-Ph
N
2h 98
Br
9
1i R2 = 4-Br
N
2i 78
n.r.
10
1j R2 = 3-O2N
a All reactions were completed in 5–30 min.
b Isolated yields.
To further examine the substrate scope and study the sole 7. Reduction of nitration product 8 with iron power in
effects of substituent R3 (Scheme 1, 1, R1 = H, R2 = 4-MeO), aqueous NH4Cl afforded o-iodoaniline (9). Suzuki cou-
several additional amides 1k–p were prepared by acyla- pling of 9 with 4-methoxyphenyl boric acid followed by
tion of a previously prepared amine 4b with correspond- N-acetylation provided the required amide substrate 1r.
ing acid chlorides (Table 2). Again, smooth reactions
were observed in all examined cases under the standard
(HO)2B
OMe
conditions, affording the corresponding phenanthridines
2k–p in reasonable to satisfactory yields (Table 2). Com-
pared to other substrates, reaction of formamide 1k (entry
2) provided only 30% yield of product 2k. It is believed
that stability of the carbocationic intermediates involved
in this type of reactions (Scheme 1) is crucial to achieve a
better yield, and reaction of 1k (entry 2, R3 = H) proceed-
ed via the relatively unstable carbocationic intermediates
during its cascade process. In another experiment of
amide 1l having a bulky group (entry 3, R3 = t-Bu), a rel-
atively long reaction time (3 h) was observed. For those
benzamides 1n–p whose phenyl either with or without an
electron-donating or an electron-withdrawing group, their
reactions were carried out in short times, affording the
corresponding products in satisfactory yields (entries 5–
7).
I
O2N
I
Ph3P, Br2, AgNO3
MeCN
Suzuki
72%
NH2
55%
NH2
3
5
OMe
OMe
O
O2N
O2N
Cl
91%
NH2
N
H
O
6
1q
OMe
NO2
MeO
I
HNO3
Fe, NH4Cl
H2SO4
67%
MeOH–H2O
71%
I
7
8
OMe
OMe
In order to investigate electronic effects of phenyl ring A,
two representative amides 1q–r having a substituent R1
(Scheme 1, 1, R2 = MeO and R3 = Me) were prepared
(Scheme 2). Amide 1q with a nitro group was prepared by
a three-step procedure, including aromatic nitration of 2-
iodoaniline (3), Suzuki coupling with 4-methoxyphenyl
boric acid, and N-acetylation. Similarly, the other amide
1r having a methoxyl group was prepared from 3-iodoani-
OMe
O
Suzuki
78%
Cl
90%
H
NH2
N
I
NH2
O
MeO
MeO
9
10
1r
Scheme 2 Synthesis of amide substrates 1q–r
Synlett 2010, No. 11, 1674–1678 © Thieme Stuttgart · New York

LETTER
Synthesis of Phenanthridines
1677
Table 2 Synthesis of Phenanthridines 2k–p with a Variable Substituent (R3)a
O
O
O
O
Tf2O (1.5 equiv)
Ph3PO (3 equiv)
CH2Cl2
R3
X = Cl, OEt
X
H
N
R3
0 °C to r.t.
R3
NH2
N
O
4b
2b,k–p
1b,k–p
Entry
1
Yield of 2 (%)
1
2b
3
4
5
6
7
1b R3 = Me
2b 95
2k 30
2l 93
1k R3 = H
1l R3 = t-Bu
1m R3 = CH=CHOEt
1n R3 = Ph
2m 74
2n 94
2o 97
2p 75
1o R3 = 4-MeOC6H4
1p R3 = 4-O2NC6H4
a All reaction were completed in 5–30 min except entry 3 (3 h).
b Et3N (3 equiv) was added.
Under the above mentioned conditions, two phenan-
thridines 2q and 2r were provided in excellent yields, re-
spectively (Scheme 3). Results of these two examples and
the previous reaction of 1b (R1 = H) indicate that electron-
ic property of R1 of amides 1 affects little in this type of
cascade reactions.
References and Notes
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O
O
Tf2O (1.5 equiv)
Ph3PO (3 equiv)
CH2Cl2
R1
R1
0 °C to r.t.
N
N
H
O
1b R1 = H
2b R1 = H 95%
1q R1 = NO2
1r R1 = OMe
2q R1 = NO2 98%
2r
R
1 = OMe 99%
Scheme 3 Synthesis of phenanthridines with a variable substituent R1
In summary, a new efficient approach has been developed
for the synthesis of various phenanthridines utilizing
Hendrickson reagent initiated cascade reactions under
mild metal-free conditions.9 This newly developed meth-
odology can tolerate a wide range of functional groups,
and thus will facilitate future development of the sub-
strates for material and medicinal applications.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
Financial supports from MOST (2010CB833200), MOH
(2009ZX09501) and NSFC (20621062) are greatly appreciated.
Synlett 2010, No. 11, 1674–1678 © Thieme Stuttgart · New York

1678
J. Xi et al.
LETTER
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(9) Representative Procedure for the Synthesis of 6-Methyl-
phenanthridine (2a)
To a solution of Ph3PO (260 mg, 0.9 mmol, 3 equiv) in
anhyd CH2Cl2 (5 mL) was added Tf2O (0.078 mL, 0.45
mmol, 1.5 equiv) dropwise under nitrogen atmosphere at
0 °C. After 15 min, amide 1a (64 mg, 0.3 mmol, 1 equiv) in
anhyd CH2Cl2 (2 mL) was added. The reaction was then
warmed to r.t. and stirred until completion. The reaction was
quenched by addition of sat. aq NaHCO3. The mixture was
extracted with CH2Cl2 (3 × 10 mL). The combined extracts
were washed with brine, dried over anhyd Na2SO4, and
concentrated. The crude product was purified by column
chromatography on silica gel using a mixture of PE and
EtOAc (5:1 to 2:1, v/v) as the eluent to afford a light-yellow
solid 2a (51 mg, 95%).4n 1H NMR (300 MHz, CDCl3): d =
8.64 (1 H, d, J = 8.4 Hz), 8.55 (1 H, d, J = 7.8 Hz), 8.24 (1
H, d, J = 7.8 Hz), 8.11 (1 H, d, J = 7.8 Hz), 7.88–7.61 (4 H,
m), 2.98 (3 H, s). MS (EI): m/z = 193 [M+].
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Synlett 2010, No. 11, 1674–1678 © Thieme Stuttgart · New York