Synthesis of indolo[1,2-f]phenanthridines from palladium-catalyzed reactions of arynes

Article abstract of DOI:10.1021/jo070625g

(Chemical Equation Presented) A novel convenient approach for the construction of indolo[1,2-f]phenanthridine was developed from the reaction of arynes with 1-(2-bromophenyl)-1H-indole in the presence of palladium catalyst.

Full text of DOI:10.1021/jo070625g

SCHEME 1
Synthesis of Indolo[1,2-f]phenanthridines from
Palladium-Catalyzed Reactions of Arynes
Chunsong Xie, Yuhong Zhang,* Zedu Huang, and Peixin Xu
Department of Chemistry, Zhejiang UniVersity,
Hangzhou 310027, People’s Republic of China
yhzhang@zjuem.zju.edu.cn
TABLE 1. The Optimization Studiesa
ReceiVed April 4, 2007
entry
catalyst and ligand
solvent
T (°C) yieldb %
1
2
3
4
5
6
7
8
9
5% Pd(PPh3)4
2.5% Pd2(dba)3
2.5% Pd2(dba)3 + 10% PPh3 CH3CN and toluene (1:1) 110
2.5% Pd2(dba)3 + 5% dppp CH3CN and toluene (1:1) 110
2.5% Pd2(dba)3 + 5% dppp CH3CN and toluene (1:1) 110
2.5% Pd2(dba)3 +5% dppp CH3CN and toluene (1:1) 110
2.5% Pd2(dba)3 + 5% dppp CH3CN and toluene (1:1)
2.5% Pd2(dba)3 + 5% dppp CH3CN
2.5% Pd2(dba)3 + 5% dppp toluene
CH3CN and toluene (1:1) 110
CH3CN and toluene (1:1) 110
56
22
30
A novel convenient approach for the construction of indolo-
[1,2-f]phenanthridine was developed from the reaction of
arynes with 1-(2-bromophenyl)-1H-indole in the presence
of palladium catalyst.
76
58c
31d
46
80
80
110
80
54
2
43
trace
10 2.5% Pd2(dba)3 + 5% dppp DME
11 2.5% Pd2(dba)3 + 5% dppp THF
Phenanthridine heterocycles are of interest in many aspects.
They not only widely occur in natural products,1 but they also
show a broad spectrum of biological activities and unusual
pharmacological properties that make them suitable for antine-
oplastic applications.2 In addition, the high-charge mobility of
this heterocyclic system provides pronounced photoconducting
and photovoltaic properties, which are key features in the field
of dye lasers and electroluminescence.3 Much attention has been
focused on the efficient synthesis of phenanthridines over recent
decades, and a variety of methods have been developed.4
Although these methods provide reliable routes for the prepara-
tion of phenanthridines, most of them require multistep syntheses
and strictly anhydrous conditions. The development of direct
and efficient procedures for these classes of compounds has been
the target of synthetic organic chemistry.
67
a Reaction conditions: 1-(2-bormophenyl)-5-methylindole (0.5 mmol),
o-trimethylsilyl phenyltriflate (0.5 mmol), CsF (1.5 mmol), CH3CN:toluene
) 3:3 mL, external temperature, 24 h. b HPLC yield using 1,10-phenan-
throline as the internal standard. c Reaction time was 12 h. d Reaction time
was 6 h.
of aryne catalyzed by palladium was reported in 1998,6 and
subsequent studies demonstrated that the cocyclizations of
arynes with a variety of alkynes,7 diynes,8 allyl derivatives,9
allenes,10 CO2,11 and CO12 could be performed in the presence
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* To whom correspondence should be addressed. Phone: +86-571-
87953253. Fax: +86-571-87951512.
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S. B. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 9836-9841. (c) Bach, S.;
Talarek, N.; Andrieu, T.; Vierfond, J.-M.; Mettey, Y.; Galons, H.; Dormont,
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10.1021/jo070625g CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/08/2007
J. Org. Chem. 2007, 72, 5431-5434
5431

TABLE 2. Scope of the Annulation Reactiona
a Reaction conditions: derivatives of indole (0.5 mmol), o-trimethylsilyl phenyltriflate (0.5 mmol), CsF (1.5 mmol), Pd2(dba)3‚CHCl3 (2.5 mol %), dppp
(5 mol %), CH3CN:toluene ) 3:3 mL, 110 °C (external temperature), 24 h. b Isolated yield.
of transition-metal catalysts. More recently, Liu et al. have
shown that the coupling reaction between the two reactive
substrates, an aryne and an organopalladium species, can be
carried out to generate the cross-coupling products.13 Herein,
we report a mild and highly efficient route for the synthesis of
indolo[1,2-f]phenanthridine from arynes and 1-(2-bromophenyl)-
1H-indoles catalyzed by palladium complex under mild condi-
tions. This reaction process involves the palladium-catalyzed
carboannulation of arynes.
(Scheme 1).14 This straightforward method offered the possibil-
ity of preparing a wide range of substituted 1-(2-bromophenyl)-
1H-indoles.
The reaction of 1-(2-bormophenyl)-5-methylindole and ben-
zyne, which was generated from in-situ elimination of o-
trimethylsilyl phenyltriflate by CsF, was first studied using a
catalytic amount of Pd(PPh3)4 as the catalyst in a mixture of
1:1 CH3CN and tolune at 110 °C for 24 h. The annulation
product of 11-methylindolo[1,2-f]phenanthridine was isolated
in 56% yield (Table 1, entry 1). With Pd2(dba)3‚CHCl3 as
catalyst, the reaction was dependent on the auxiliary phosphine
ligands. In the absence of phosphine ligand, the annulation
The key starting compounds of 1-(2-bromophenyl)-1H-indoles
were accessed via a Hartwig-Buchwald C-N coupling reaction
(10) Hsieh, J. C.; Rayabarapu, D. K.; Cheng, C. H. Chem. Commun.
2004, 532-533.
(13) (a) Liu, Z. J.; Zhang, X. X.; Larock, R. C. J. Am. Chem. Soc. 2005,
127, 15716-15717. (b) Jayanth, T. T.; Jeganmohan, M.; Cheng, C.-H.
Chem. Commun. 2006, 894-896. (c) Liu, Z. J.; Larock, R. C. J. Org. Chem.
2007, 72, 223-232.
(14) Klapars, A.; Antilla, J. C.; Huang, X. H.; Buchwald, S. L. J. Am.
Chem. Soc. 2001, 123, 7727-7729.
(11) Yoshida, H.; Fukushima, H.; Ohshita, J.; Kunai, A. J. Am. Chem.
Soc. 2006, 128, 11040-11041.
(12) (a) Chatani, N.; Kamitani, A.; Oshita, M.; Fukumoto, Y.; Murai, S.
J. Am. Chem. Soc. 2001, 123, 12686-12687. (b) Sato, T.; Niino, H.; Yabe,
A. J. Am. Chem. Soc. 2003, 125, 11936-11941.
5432 J. Org. Chem., Vol. 72, No. 14, 2007

SCHEME 2
product was produced in poor yield (Table 1, entry 2). The use
of PPh3 afforded more annulation product (Table 1, entry 3),
and the yield was improved to 76% when using dppp (1,3-bis-
(diphenylphosphino)propane) as the phosphine ligand (Table 1,
entry 4). Shortening the reaction time and decreasing the reaction
temperature led to the lower yields (Table 1, entries 5-7). The
choice of solvent was crucial for the success of the reaction,
and the mixture of 1:1 CH3CN and tolune was superior to other
solvents such as CH3CN, toluene, DME, and THF alone (Table
1, entries 8-11).
The reaction scope and limitations were investigated, and the
results are summarized in Table 2. The reaction of 1-(2-
bromophenyl)-5-methoxy-1H-indole and 1-(2-bromophenyl)-6-
methoxy-1H-indole with o-trimethylsilyl phenyltriflate pro-
ceeded smoothly under the catalytic conditions to give the
corresponding annulated products in high isolated yields (Table
2, entries 1-2). Employment of 1-(2-bromophenyl)-4-methyl-
1H-indole and 1-(2-bromophenyl)-5-methyl-1H-indole as sub-
strates resulted in 78% and 72% yields, respectively (Table 2,
entries 3-4). However, when 1-(2-bromophenyl)-1H-indole
(Table 2, entry 5) was used as the starting material, only a 61%
yield was obtained (Table 2, entry 5). Clearly, the electron-
donating substitutes on phenyl ring were beneficial to the
annulation reaction. On the other hand, the indoles with electron-
withdrawing substitutes on phenyl ring also worked well in this
annulation reaction (Table 2, entries 6-7). Dimethylbenzyne
was successfully employed in this annulation process, and
moderate to high yields were obtained (Table 2, entries 8-12).
Good fluorescence quantum yields were observed for the above
new compounds (see Supporting Information).
activation to generate the palladacycle B, which reacts with the
aryne to afford intermediate C. The subsequent reductive
elimination yields the final product and regenerates the Pd(0)
catalyst. One other possible pathway, which is closely related
to the one proposed by Liu and Larock,13c is that the arylpal-
ladium intermediate A reacts with the aryne to afford intermedi-
ate D. The following intramolecular C-H activation generates
the palladacycle C, which affords the final product via the
reductive elimination.
In conclusion, we have demonstrated a palladium-catalyzed
annulation reaction by aryne and 1-(2-bromophenyl)-1H-indoles,
which allows an efficient synthesis of indolo[1,2-f]phenanthri-
dine under mild conditions and in good yields. Further studies
to elucidate the reaction mechanism and to extend the scope of
the reaction are in progress.
Experimental Section
Representative Procedure for the Reaction of 1-(2-Bro-
mophenyl)indole with Benzyne. 1-(2-Bromophenyl)indole (136
mg, 0.5 mmol), CsF (228 mg, 1.5 mmol), Pd2(dba)3‚CHCl3 (13
mg, 0.0125 mmol), and dppp (10 mg, 0.025 mmol) were placed in
an oven-dried flask. CH3CN (2 mL) and toluene (2 mL) were added
under N2. o-(Trimethylsilyl)phenyl triflate (149 mg, 0.5 mmol) in
CH3CN (1 mL) and toluene (1 mL) was added dropwise. After the
completion of the addition, the reaction mixture was allowed to
react at 110 °C for 24 h. Then, the reaction mixture was cooled to
room temperature and was filtered through a pad of cellite. The
filtrate was distilled under reduced pressure, and the product was
obtained by flash chromatography on a silica gel column.
T2-5 Indolo[1,2-f]phenanthridine. 1H NMR (400 MHz, CDCl3,
TMS) δ 8.56 (d, J ) 8.4 Hz, 1 H), 8.39 (d, J ) 8.4 Hz, 1 H), 8.34
On the basis of these experiments, the following plausible
mechanism for this useful phenanthridine synthesis was pro-
posed (Scheme 2). The Pd(0) complex first undergoes the
oxidative addition15 with 1-(2-bromophenyl)-1H-indole to give
the arylpalladium intermediate A, followed by the C-H
(15) (a) Zeni, G.; Larock, R. C. Chem. ReV. 2006, 106, 4644-4680. (b)
Kirchhoff, J. H.; Netherton, M. R.; Hills, I. D.; Fu, G. C. J. Am. Chem.
Soc. 2002, 124, 13662-13663. (c) Hills, I. D.; Netherton, W. R.; Fu, G. C.
Angew. Chem., Int. Ed. 2003, 72, 5749-5752. (d) Barrios-Landeros, F.;
Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 6944-6945.
J. Org. Chem, Vol. 72, No. 14, 2007 5433

(d, J ) 8 Hz, 1 H), 8.24 (m, 1 H), 8.15 (m, 1 H), 7.84 (d, J ) 7.6
Hz, 1 H), 7.59 (t, J ) 7.6 Hz, 1 H), 7.50 (m, 2 H), 7.36 (m, 3 H),
7.28 (s, 1 H); 13C NMR (100 MHz, CDCl3) δ 136.0, 135.2, 133.9,
130.3, 128.7, 128.2, 127.8, 126.8, 126.1, 124.1, 124.0, 123.0, 122.4,
122.1, 122.0, 121.8, 121.0, 116.3, 114.2, 96.2. HRMS (ESI) calcd
for C20H13N: [M + H]+ 268.1121; found, 268.1113. Yellow
powder, mp 140-142 °C.
116.1, 114.1, 95.1, 20.2, 19.8. HRMS (ESI) calcd for C22H17N:
[M + H]+ 296.1434; found, 296.1425. Yellow powder, mp 103-
105 °C.
Acknowledgment. We thank the support of Natural Science
Foundation of China (No. 20571063).
T2-12 6,7-Dimethylindolo[1,2-f]phenanthridine. 1H NMR (400
MHz, CDCl3, TMS) δ 8.51 (d, J ) 8.4 Hz, 1 H), 8.38 (d, J ) 6.8
Hz, 1 H), 8.24 (d, J ) 8.0 Hz, 1 H), 7.90 (s, 1 H), 7.82 (s, 1 H),
7.54 (t, J ) 8.0 Hz, 1 H), 7.39 (m, 2 H), 7.32 (t, J ) 7.8 Hz, 1 H),
7.17 (m, 1 H), 2.39 (s, 3 H), 2.37 (s, 3 H); 13C NMR (100 MHz,
CDCl3) δ 137.1, 136.7, 135.6, 135.4, 133.7, 130.4, 127.9, 124.62,
124.59, 123.8, 123.6, 122.9, 122.7, 122.1, 121.54, 121.52, 120.7,
Supporting Information Available: The experimental proce-
dure and spectroscopic data (1H NMR, 13C NMR, and HRMS) for
the products. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO070625G
5434 J. Org. Chem., Vol. 72, No. 14, 2007