Palladium-mediated synthesis of phenanthridines: The first report of palladium insertion into imidoyl selenides

Article abstract of DOI:10.1055/s-2008-1078246

Imidoyl phenyl selenides have been shown to be precursors to phenanthridines, when treated with Pd(PPh₃)₄ under reflux in toluene in the presence of a base, giving reasonable yields. It is proposed that insertion of palladium into th

Full text of DOI:10.1055/s-2008-1078246

LETTER
2169
Palladium-Mediated Synthesis of Phenanthridines: The First Report of
Palladium Insertion into Imidoyl Selenides
S
ynthesis of Phenanthrid
.ines Russell Bowman, Jessica E. Lyon, Gareth J. Pritchard*
Department of Chemistry, Loughborough University, Loughborough, Leicestershire, LE11 3TU, UK
Fax +44(1509)223925; E-mail: G.J.Pritchard@lboro.ac.uk
Received 2 June 2008
We wish to dedicate this paper to mark Professor Sir Jack E. Baldwin’s 70th birthday.
ical methods,11 Bischler–Napieralski reactions,12 reduc-
tion of phenanthridones,13 routes using Pd catalysis,14 and
other methods.15 Our present route to phenanthridines 1
involves the Pd-mediated formation of one of the C–C
Abstract: Imidoyl phenyl selenides have been shown to be precur-
sors to phenanthridines, when treated with Pd(PPh3)4 under reflux
in toluene in the presence of a base, giving reasonable yields. It is
proposed that insertion of palladium into the C–Se bond is followed
by cyclisation onto a phenyl ring and subsequent aromatisation by bonds of the pyridine nucleus from imidoyl selenides 2,
elimination of HPdSePh.
which in turn can be synthesised from the corresponding
amides 3. The amides 3 are readily prepared from the ar-
omatic acid chlorides and commercially available 2-ami-
nobiphenyl 4 (Scheme 1).
Key words: heterocycles, palladium, phenanthridines, imidoyl sel-
enides, cyclisations
We have an interest in the development of new methods
to synthesise heterocyclic systems; including radical,1 or-
ganometallic,2 and condensation of reactive electrophilic
systems.3 Additionally, we are using novel palladium
chemistry as an approach to polycyclic heterocyclic mo-
tifs. We now wish to report a new Pd-mediated route to
phenanthridines.
Ph
SePh
N
N
R
R
1
2
Ph
O
Ph
Palladium plays an important role in aromatic heterocy-
clic synthesis.4,5 There is a large number of precursors
available for the palladium-catalysed construction of het-
erocyclic rings; including aryl and vinyl halides or corre-
sponding triflates, and compounds with suitably located
Ar–H bonds. It is therefore an important challenge to find
novel alternatives to simplifying existing synthetic routes
and allowing rapid access to unusual systems. We have
previously used imidoyl selenides [PhSeC(R)=N-] as im-
idoyl radical precursors to synthesise indoles and quino-
lines.6 During the investigation, we became interested in
using imidoyl selenides as starting materials for Pd-medi-
ated reactions,5,6 analogous to the insertion of Ni(0) into
C–Se bonds and their use in the synthesis of stereodefined
alkenes.7 To our knowledge, there is a single study in the
literature that reports the insertion of Pd(0) into C–Se
bonds,8 but there are no reports of insertion of Pd(0) into
the C–Se bond of imidoyl selenides.
N
H
NH2
R
3
4
Scheme 1 Proposed synthesis of phenanthridines 1
O
Cl
Ph
Et3N, CH2Cl2
0 °C to r.t.
R
O
+
Ph
N
H
R
3a–g
NH2
4
1) COCl2, CH2Cl2
cat. DMF, r.t.
2) (PhSe)2, THF
K-Selectride, r.t.
Ph
SePh
In order to explore the idea of using imidoyl selenides as
precursors for Pd(0)-mediated reaction we have initially
chosen to trap the imidoyl palladium species [PhSe-
PdC(R)=N-] with a phenyl group to give a phenanthridine
ring system. The phenanthridines showed an interesting
range of biological activities.9 They can be prepared by a
number of methods including, anionic ring closure,10 rad-
N
R
2a–g
Scheme 2 Preparation of the imidoyl selenides
The required amides 3 were prepared by standard proce-
dures from 2-aminobiphenyl 4 and an aryl acid chloride in
reasonable yields (Scheme 2, Table 1). The amides 3 were
converted into the appropriate a-chloroimines by treat-
ment with phosgene and catalytic DMF.16 The required
potassium salt of phenyl selenide was prepared in situ by
SYNLETT 2008, No. 14, pp 2169–2171
2
2
.0
8
.2
0
0
8
Advanced online publication: 31.07.2008
DOI: 10.1055/s-2008-1078246; Art ID: D19008ST
© Georg Thieme Verlag Stuttgart · New York

2170
W. R. Bowman et al.
LETTER
reduction of diphenyl diselenide with K-Selectride® and
added directly to the unpurified a-chloroimines to give the
imidoyl selenides 2 (Scheme 2, Table 1).1a,6 The imidoyl
selenides 2 were either used crude or after purification by
crystallisation, or rapid chromatography. Some hydrolysis
took place upon both silica and alumina chromatography.
Ph
N
SePh
Pd(PPh3)4
Et3N, toluene,
reflux, 48 h
N
R
2a–g
1a–g
R
Scheme 3 Palladium-mediated preparation of phenanthridines
Table 1 Results of the Preparation of Imidoyl Selenides
Table 2 Results of Palladium-Mediated Synthesis of Phenan-
thridines
Entry
R
Yield of amide 3 Yield of selenide 2
(%)
52
64
59
70
64
61
77
(%)
54
44
66
51
60
62
60
1
2
3
4
5
6
7
H
1
R
Yield of phenanthridines (%)
Me
1a
1b
1c
1d
1e
1f
H
24
38
47
39
46
22
48
t-Bu
OMe
Cl
Me
t-Bu
OMe
Cl
NMe2
CF3
NMe2
CF3
1g
A representative range of 4-substituted aryl acid chlorides
was used to prepare the amides 3 in order to observe the
electronic effect on the insertion of palladium into the Se–
C bond of the imidoyl selenides 2 (Table 2). With a range
of imidoyl selenides 2 in hand we explored conditions for
the Pd-mediated cyclisation to phenathridines 1. A large
range of conditions have been reported for palladium-
catalysed reactions.5 In order to limit the number of vari-
ables in the preliminary reactions we have only used the
readily available Pd(PPh3)4 as the palladium source.
action without the base gave no reaction or significantly
reduced yield. Attempts to cyclise the a-chloroimines,
precursors of the imidoyl selenides, under all conditions
have failed to give any signs of the phenanthridines in our
hands to date.
Mechanistically, we propose insertion of a Pd(0) species
into the carbon–selenium bond followed by carbopallada-
tion on to the phenyl ring. This intermediate then under-
goes rearomatisation with the loss of HPdSePh to give the
phenanthridine system (Scheme 4).
The parent imidoyl selenide (R = H) 2a was first subject-
ed to a range of reaction conditions in the presence of 10%
Pd(PPh3)4 and excess triethylamine. No reactions took
place at either room temperature or at reflux in CH2Cl2,
THF, or MeCN. Complex mixtures were observed when
the reactions were carried out at 80 °C in DMF or chlo-
robenzene. However, when the reaction was carried out at
80 °C in toluene a trace of the desired phenanthridine 1a
was detected in the 1H NMR spectrum of the crude mix-
ture. Encouraged by this result the reaction was carried
out at reflux in toluene for 48 hours, which gave a 10%
isolated yield. A further improved yield was seen when
we increased the amount of palladium to 0.4 equivalents.
With these conditions in hand, the range of imidoyl sele-
nides 2a–g previously prepared were treated with
Pd(PPh3)4 (0.4 equiv) and excess triethylamine in toluene
at reflux for 48 hours, to successfully produce the respec-
tive phenanthridines 1a–g (Scheme 3, Table 2).17
SePh
Ph
N
Ph
Pd
SePh
Pd(PPh3)2
N
R
R
SePh
R
Pd
– HPdSePh
R
N
N
Scheme 4 Proposed mechanism of palladium-mediated cyclisation
We are pleased with these initial results and a wider range
of targets is currently under investigation using imidoyl
selenides and Pd-mediated conditions. We are also look-
ing at optimising the reaction conditions.
The phenanthridines 1a–g were isolated in synthetically
useful yields, which are currently unoptimised. The elec-
tronic effect of the substitution on the aromatic ring (R)
did not appear to affect the reaction. Carrying out the re-
Synlett 2008, No. 14, 2169–2171 © Thieme Stuttgart · New York

LETTER
Synthesis of Phenanthridines
2171
(10) (a) Lysén, M.; Kristensen, J. L.; Vedsø, P.; Begtrup, M. Org.
Lett. 2002, 4, 257. (b) Pawlas, J.; Begtrup, M. Org. Lett.
2002, 4, 2687. (c) Lysén, M.; Madden, M.; Kristensen, J. L.;
Vedsø, P.; Zøllner, C.; Begtrup, M. Synthesis 2006, 3478.
(11) Leardini, R.; Tundo, A.; Zanardi, G. Synthesis 1985, 107.
(12) (a) Mamalis, P.; Petrow, V. J. J. Chem. Soc. 1950, 703.
(b) Buu-Hoï, N. P.; Jaquignon, P.; Long, C. T. J. Chem. Soc.
1957, 505.
References and Notes
(1) For example, see: (a) Bowman, W. R.; Fletcher, A. J.;
Lovell, P. J.; Pedersen, J. M. Synlett 2004, 1905.
(b) Bowman, W. R.; Fletcher, A. J.; Potts, G. B. S. J. Chem.
Soc., Perkin Trans. 1 2002, 2747. (c) Bowman, W. R.;
Cloonan, M. O.; Krintel, S. L. J. Chem. Soc., Perkin Trans. 1
2001, 2885.
(2) Christie, S. D. R.; Davoile, R. J.; Elsegood, M. R. J.; Fryatt,
R.; Jones, R. C. F.; Pritchard, G. J. Chem. Commun. 2004,
2474.
(3) For example, see: (a) Baldwin, J. E.; Pritchard, G. J.;
Rathmell, R. E. J. Chem. Soc., Perkin Trans. 1 2001, 2906.
(b) Adlington, R. M.; Baldwin, J. E.; Catterick, D.;
Pritchard, G. Chem. Commun. 1997, 1757. (c) Baldwin,
J. E.; Fryer, A. M.; Pritchard, G. J. Bioorg. Med. Chem. Lett.
2000, 10, 309.
(13) Narasimham, N. S.; Chandrachood, P. S. Tetrahedron 1981,
37, 825.
(14) (a) Shabashov, D.; Daugulis, O. J. Org. Chem. 2007, 72,
7720. (b) Xie, C.; Zhang, Y.; Huang, Z.; Xu, P. J. Org.
Chem. 2007, 72, 5431. (c) Shou, W.-G.; Yang, Y.-Y.;
Wang, Y.-G. J. Org. Chem. 2006, 71, 9241.
(15) Patra, P. K.; Suresh, J. R.; Ila, H.; Junjappa, H. Tetrahedron
1998, 54, 10167.
(16) Newcomb, M.; Esker, J. L. Tetrahedron Lett. 1991, 32,
1035.
(4) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic
Chemistry; Pergamon: Oxford, 2000.
(17) Typical Procedure for the Synthesis of Phenanthridines
To a mixture of Pd(PPh3)4 (83 mg, 0.072 mmol) and Et3N
(0.13 ml, 0.90 mmol) was added the imidoyl selenide 2e (80
mg, 0.18 mmol) in toluene (2 mL). The mixture was refluxed
for 48 h, and after cooling to r.t., H2O (10 mL) was added.
The reaction mixture was extracted with CH2Cl2 (2 × 10
mL). The combined organic phases were washed with a sat.
aq solution of NaHCO3 (10 mL), brine (10 mL), dried
(MgSO4), filtered, and the solvent removed under reduced
pressure. The crude product was further purified by column
chromatography (neutral alumina, 20% CH2Cl2 in hexane)
to yield the desired 6-(4-chlorophenyl)phenanthridine (1e,
24 mg, 46%) as colourless crystals; mp 152–154 °C (Lit.11
mp 160–161 °C). IR (KBr): 2924, 1608, 1485, 1361, 1091,
829, 752, 721 cm–1. 1H NMR (400 MHz, CDCl3): d = 7.54 (2
H, m, ArH), 7.64 (1 H, m, ArH), 7.70 (3 H, m, ArH), 7.77 (1
H, m, ArH), 7.88 (1 H, m, ArH), 8.06 (1 H, dd, J = 0.8, 8.4
Hz, ArH), 8.23 (1 H, dd, J = 1.2, 8.4 Hz, ArH), 8.63 (1 H, dd,
(5) Tsuji, J. Palladium Reagents and Catalysts; Wiley:
Chichester, 2004.
(6) (a) Pedersen, J. M.; Bowman, W. R.; Elsegood, M. R. J.;
Fletcher, A. J.; Lovell, P. J. J. Org. Chem. 2005, 70, 10615.
(b) Bowman, W. R.; Fletcher, A. J.; Pedersen, J. M.; Lovell,
P. J.; Elsegood, M. R. J.; Hernández López, E.; McKee, V.;
Potts, G. B. S. Tetrahedron 2007, 63, 191.
(7) For example, see: (a) Silveira, C. C.; Santos, P. C. S.; Braga,
A. L. Tetrahedron Lett. 2002, 43, 7517. (b) Silveira, C. C.;
Cella, R.; Vieira, A. S. J. Organomet. Chem. 2006, 691,
5861. (c) Martynov, A. V.; Potapov, V. A.; Amosova, S. V.;
Makhaeva, N. A.; Beletskaya, I. P.; Hevesi, L.
J. Organomet. Chem. 2003, 674, 101. (d) Okamura, H.;
Miura, M.; Kosugi, K.; Takei, H. Tetrahedron Lett. 1980,
21, 87.
(8) Toyofuku, M.; Fujiwara, S.-i.; Shin-ike, T.; Kuniyasu, H.;
Kambe, N. J. Am. Chem. Soc. 2005, 127, 9706.
(9) For example, see: (a) Li, D.; Zhao, B.; Sim, S.-P.; Li, T.-K.;
Liu, A.; Liu, L. F.; LaVoie, L. F. Bioorg. Med. Chem. 2003,
11, 521. (b) Lynch, M. A.; Duval, O.; Sukhanova, A.; Devy,
J.; MacKay, S. P.; Waigh, R. D.; Nabiev, I. Bioorg. Med.
Chem. Lett. 2001, 11, 2643. (c) Ishikawa, T. Med. Res. Rev.
2001, 21, 61.
J = 1.6, 8.4 Hz, ArH), 8.72 (1 H, d, J = 8.4 Hz, ArH). 13
C
NMR (100 MHz, CDCl3): d = 122.0 (ArCH), 122.4 (ArCH),
123.8 (ArC), 125.0 (ArC), 127.2 (ArCH), 127.3 (ArCH),
128.5 (ArCH), 128.7 (2 × ArCH), 129.0 (ArCH), 130.4
(ArCH),130.7 (ArCH), 131.1 (2 × ArCH), 133.5 (2 × ArC),
134.9 (ArC), 143.8 (ArCCl), 160.0 (ArC=N). LRMS–FAB:
m/z (%) = 290 (67) [M + H+], 289 (38), 176 (22), 155 (24),
154 (100), 138 (25), 137 (48), 136 (61). HMRS: m/z calcd
for C19H13NCl: 290.0736; found: 290.0732.
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