Expeditious synthesis of phenanthridines from benzylamines via dual palladium catalysis

Article abstract of DOI:10.1021/ol102509n

A method for the synthesis of phenanthridines from benzylamines and aryl iodides which uses a dual palladium-catalyzed process is developed. The domino sequence ends via an intramolecular amination and an oxidative dehydrogenation. No protecting group or

Full text of DOI:10.1021/ol102509n

ORGANIC
LETTERS
2010
Vol. 12, No. 24
5692-5695
Expeditious Synthesis of
Phenanthridines from Benzylamines via
Dual Palladium Catalysis
´
Giovanni Maestri, Marie-He´le`ne Larraufie, Etienne Derat, Cyril Ollivier,
Louis Fensterbank,* Emmanuel Lacoˆte,* and Max Malacria*
UPMC UniV Paris 06, Institut Parisien de Chimie Mole´culaire (UMR CNRS 7201),
4 place Jussieu, C. 229, 75005 Paris, France
louis.fensterbank@upmc.fr; emmanuel.lacote@upmc.fr; max.malacria@upmc.fr
Received October 16, 2010
ABSTRACT
A method for the synthesis of phenanthridines from benzylamines and aryl iodides which uses a dual palladium-catalyzed process is developed.
The domino sequence ends via an intramolecular amination and an oxidative dehydrogenation. No protecting group or prefunctionalization of
the amine is required, and the process uses dioxygen as the terminal oxidant.
Palladium-catalyzed cascades involving direct C-H bond
activation have emerged as powerful tools for rapid access
to complex polycyclic structures because they bypass the
prefunctionalizations required for the traditional cross-
coupling methods.1 In this context, the addition of norbornene
as cocatalyst pioneered by Catellani gives access to catalytic
sequences uniquely suited to selective sequential bond
forming.2 New syntheses of polycyclic frameworks from
simple substrates are thus easily accessible.3 Yet, despite the
variety of possibilities offered by Pd/norbornene catalysis,
the introduction of a C-amination step in a cascade has been
limited to anilines.4
Reasoning that some Pd(II) complexes could also catalyze
oxidative dehydrogenations to generate alkenes,6 we felt that a
(2) (a) Catellani, M.; Fagnola, M. C. Angew. Chem., Int. Ed. Engl. 1994,
33, 2421–2422. (b) Amatore, C.; Catellani, M.; Deledda, S.; Jutand, A.;
Motti, E. Organometallics 2008, 27, 4549–4554. For other recent repre-
sentative examples of high oxidation state Pd-reactions, see: (c) Kalyani,
D.; Satterfield, A. D.; Sanford, M. S. J. Am. Chem. Soc. 2010, 132, 8419–
8427. (d) Ball, N. D.; Kampf, J. W.; Sanford, M. S. J. Am. Chem. Soc.
2010, 132, 2878–2779. (e) Powers, D. C.; Ritter, T. Nature Chem. 2009, 1,
302–309. (f) Tsujihara, T.; Takenaka, K.; Onitsuka, K.; Hatanaka, M.; Sasai,
H. J. Am. Chem. Soc. 2009, 131, 3452–3453. (g) Thirunavukkarasu, V. S.;
Parthasarathy, K.; Cheng, C.-H. Angew. Chem., Int. Ed. 2008, 47, 9462–
9465. (h) Reddy, B. V. S.; Reddy, L. R.; Corey, E. J. Org. Lett. 2006, 8,
3391–3394. (i) Alexanian, E. J.; Lee, C.; Sorensen, E. J. J. Am. Chem. Soc.
2005, 127, 7690–7691. For reviews specifically on Pd(IV) catalysis, see:
(j) Sehnal, P.; Taylor, R. J. K.; Fairlamb, I. J. S. Chem. ReV. 2010, 110,
824–889. (k) Mun˜iz, K. Angew. Chem., Int. Ed. 2009, 1, 9412–9423.
(3) Recent examples: (a) Catellani, M.; Motti, E.; Della Ca, N. Acc.
Chem. Res. 2008, 41, 1512–1522. (b) Gericke, K. M.; Chai, D. I.; Bieler,
N.; Lautens, M. Angew. Chem., Int. Ed. 2009, 48, 1447–1451. (c) Zhao,
Y.-B.; Mariampillai, B.; Candito, D. A.; Laleu, B.; Li, M. Z.; Lautens, M.
Angew. Chem., Int. Ed. 2009, 48, 1849–1852.
We report herein an example of such a domino reaction.
It allows the protecting-group free rapid assembly of phenan-
thridines, which are attractive targets because of their
established significant bioactivities,5 from single aryls and
an amine (Scheme 1).
(4) (a) Della Ca, N.; Sassi, G.; Catellani, M. AdV. Synth. Catal. 2008,
350, 2179–2181. (b) Thansandote, P.; Chong, E.; Feldman, K.-O.; Lautens,
M. J. Org. Chem. 2010, 75, 3495–3498. (c) Martins, A.; Mariampillai, B.;
Lautens, M. Top. Curr. Chem. 2010, 292, 1–33. For reviews on Pd-catalyzed
C-aminations, see: (d) Jiang, L.; Buchwald, S. L. Metal Catalyzed Cross-
Coupling Reactions, 2nd ed.; de Meijere, A., Diederich, F., Eds.; Wiley-
VCH: Weinheim, 2004. (e) Hartwig, J. F. Synlett 2006, 1283–1294.
(1) (a) Ackermann, L.; Rube´n, V.; Anant, R. K. Angew. Chem., Int. Ed.
2010, 49, 9792–9826. (b) Lyons, T. W.; Sanford, M. S. Chem. ReV. 2010,
110, 1147–1169. (c) Chiusoli, G. P.; Catellani, M.; Costa, M.; Motti, E.;
Della Ca, N.; Maestri, G. Coord. Chem. ReV. 2010, 254, 456–469. (d)
Alberico, D.; Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107, 174–238.
10.1021/ol102509n  2010 American Chemical Society
Published on Web 11/17/2010

Scheme 1. One-Pot Strategy to Phenanthridines
Table 1. Formation of Phenanthridines from Benzylaminesa
combination of the latter reaction with Pd/norbornene-mediated
formations of N-containing heterocycles could drive the reactiv-
ity of unprotected benzylic amines directly toward the formation
of phenanthridines. To the best of our knowledge, the
Catellani-Lautens coupling reaction has never been associated
with another metal-mediated reaction in a dual catalytic process.
We selected 2-iodotoluene and 2-bromobenzylamine as
representative reagents. Those were reacted in the presence of
palladium acetate (5 mol %) and norbornene (1 equiv) as
cocatalysts in DMF at 130 °C. The conversion was low (10%),
and only dihydrophenanthrine 1a was obtained in 6% yield
(Table 1, entry 1). Addition of triphenylphosphine proved
beneficial, yielding 53% of 1a and 12% of the desired
phenanthridine 2a (entry 2). Lowering the norbornene amount
to 50 mol % increased the relative ratio of 2a, albeit at the
expense of conversion beyond that point (entries 3 and 4).
This suggested that the excess norbornene in the initial
stages of the reaction led to norbornyl-containing byproducts
with reactive iodides.7 We thus decided to keep a slight
excess of the aryl iodide over the bromobenzylamine as some
of it might be consumed in side reactions. Phenanthridinine
2a is formed via dehydrogenation of 1a, which requires a
sacrificial olefin to accept the dihydrogen. Part of the
norbornene is most probably also consumed for the aroma-
tization of 1a. If its initial amount drops too low, none is
available for further catalysis. Addition of 3 equiv of
norbornene at 90% conversion resulted in an increased ratio
of 2a (1a/2a ) 1:4, entry 5).8
conv.
conv.
yield
yield
entry
norbornene
Ar-Ib
Ar-Brb
(%) 1ac
(%) 2ac
1d
2
3
1 equiv
1 equiv
0.5 equiv
0.25 equiv
0.5 + 3 equiv
0.5 equiv
10
95
99
55
99
99
7
70
95
45
95
95
6
53
58
20
17
-
-
12
27
24
65
85
4
5
6e
a Reaction conditions: Pd(OAc)2 (0.013 mmol), PPh3 (0.026 mmol),
norborn., Cs2CO3 (0.6 mmol), Ar-I (0.29 mmol), Ar-Br (0.26 mmol) in
DMF (6 mL) at 130 °C under argon until Pd black precipitation (24-48
h). b Determined by GC. c 1H NMR yield using MeNO2 as internal standard.
d Without PPh3. e O2 added after full conversion.
induction of oxygen via a balloon at the end of the reaction
(evidenced by precipitation of Pd black) allowed us to get
rid of any trace of 1a. In a typical experiment, 1.1 equiv of
2-iodotoluene was reacted with 2-bromobenzylamine in the
presence of 5 mol % of Pd(OAc)2, 10 mol % of triph-
enylphosphine, and 50 mol % of norbornene in DMF at
130 °C under argon for 36 h. Then, after addition of O2, the
reaction mixture was kept overnight at the same temperature.
Phenanthridine 2a was obtained in 85% yield (entry 6).
Good results were obtained with electron-donating sub-
stituents, whether alkyl (entries 1-3) or alkoxy (entries 4-5).
Benzo[c]phenanthridines were also prepared in high yields
(entries 5 and 6). On the other hand, iodides bearing electron-
withdrawing groups at the ortho position led to moderate to
poor yields (Table 2, entries 8 and 9). This reflects previous
results on similar reactions.1c,9 As before, omission of the
oxygen resulted in phenanthridine/dihydrophenanthridine
mixtures.
Addition of more norbornene after full conversion did not
change the product ratio. We finally found that simple
(5) (a) Phillips, S. D.; Castle, R. N. J. Heterocycl. Chem. 1981, 18, 223–
232. (b) Makhey, D.; Gatto, B.; Yu, C.; Liu, A.; Liu, L. F.; LaVoie, E. J.
Bioorg. Med. Chem. 1996, 4, 781–791. (c) Ishikawa, T. Med. Res. ReV.
2001, 21, 61–72. (d) Denny, W. A. Curr. Med. Chem. 2002, 9, 1655–1665.
(e) Bernardo, P. H.; Wan, K.-F.; Sivaraman, T.; Xu, J.; Moore, F. K.; Hung,
A. W.; Mok, H. Y. K.; Yu, V. C.; Chai, C. L. L. J. Med. Chem. 2008, 51,
6699–6710. (f) Hu, J.; Zhang, W.-D.; Liu, R.-H.; Chuan, Z.; Shen, Y.-H.;
Li, H.-L.; Liang, M.-J.; Xu, X.-K. Chem. BiodiVersity 2006, 3, 990–995.
(g) Cappelli, A.; Arnzini, M.; Vomero, S.; Mennuni, L.; Makovec, F.;
Doucet, E.; Hamon, M.; Bruni, G.; Romeo, M. R.; Menziani, M. C.; Langer,
T. J. Med. Chem. 1998, 41, 728–741. (h) Kock, I.; Heber, D.; Weide, M.;
Wolschendorf, U.; Clement, B. J. Med. Chem. 2005, 48, 2772–2777. (i)
Nakanishi, T.; Suzuki, M.; Saimoto, A.; Kabasawa, T. J. Nat. Prod. 1999,
62, 864–867.
Diversely 6-substituted phenanthridines were obtained with
excellent yields from both secondary R-methylbenzylamine
(Table 3, entries 1-3) and dibenzylamine derivatives (entries
8 and 9). Aromatic substituents of different electronic and steric
properties did not disrupt the reaction, which proved much more
tolerant of substitution of the benzylamine part (entries 4-7)
than it was of substitution of the iodide partner. Electron-
donating and -withdrawing groups worked equally well, inde-
pendently of the substitution on the other partner. Again, this
is in agreement with both previous findings3a,9 and the proposed
reaction mechanism (vide infra). Note that our method is
thus suitable for the synthesis of fluorinated phenanthridines.
(6) (a) Trost, B. M.; Metzner, P. J. J. Am. Chem. Soc. 1980, 102, 3572–
3577. (b) Bercaw, J. E.; Hazari, N.; Labinger, J. A. J. Org. Chem. 2008,
73, 8654–8657. (c) Muzart, J. Chem. Asian J. 2006, 1, 508–515.
(7) Della Ca, N.; Maestri, G.; Catellani, M. Chem.sEur. J. 2009, 15,
7850–7853.
(8) Diphenylethane was detected in the reaction mixture when stilbene
was added at the start of the reaction. This further proves that a metal-
catalyzed transhydrogenation reaction is involved.
(9) (a) Faccini, F.; Motti, E.; Catellani, M. J. Am. Chem. Soc. 2004,
126, 78–79. (b) Motti, E.; Faccini, F.; Ferrari, I.; Catellani, M.; Ferraccioli,
R. Org. Lett. 2006, 8, 3967–3970
.
Org. Lett., Vol. 12, No. 24, 2010
5693

Table 2. Effect of Substituents on the Aryl Iodide Partner
Table 3. Effect of Substituents on the Aryl Bromide Partner
a Conditions: see Table 2. b Without O2, the phenanthr./dihydrophenanthr.
ratio was 1:2 (same combined yield).
a Conditions: see Table 1. An O2 balloon is introduced after the
appearance of Pd black and the reaction left overnight at 130 °C. b Without
O2, the phenantr./dihydrophenanthr. ratio was 1:2 (same combined yield).
An alternative pathway relies on a transmetalation involv-
ing two Pd(II) species (blue path).14 We could not completely
rule out this mechanism, although it could hardly account
for the observed selectivity in our coupling sequence.
Transmetalation among complex C and an arylpalladium(II)
species would likely result in large amounts of (unobserved)
homocoupling byproducts,3a,7,9b due to the higher reactivity
of aryl iodides vs bromides.
On the other hand, the selective formation of the desired
compound derives from a faster reaction of the bromoben-
zylamine on complex C relative to the aryl iodide. At a
higher temperature, the smaller bromide might overcome its
inherent lower reactivity and certainly benefit from chelation
to compete successfully with the bulkier iodide at the
sterically congested center.
A tentative mechanism is depicted in Scheme 2. The ortho-
substituted aryl iodide first oxidatively adds to Pd(0) to give
intermediate Pd(II) complex A,10 which inserts norbornene
into the aryl-Pd bond to generate B.11 Arene C-H activa-
tion12 delivers palladacycle C.13 This latter intermediate may
react with the aryl bromide possibly affording Pd(IV)
complex D, in analogy to observations made for ortho
alkylations (red path),2b in which the amine moiety likely
completes the Pd(IV) coordination sphere.
(10) (a) Fitton, P.; Rick, E. A. J. Organomet. Chem. 1971, 28, 287–
291. (b) Roy, A. H.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 13944–
13945. (c) Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314–321.
(11) (a) Horino, H.; Arai, M.; Inoue, N. Tetrahedron Lett. 1974, 647–
650. (b) Li, C.-S.; Cheng, C.-H.; Liao, F.-L.; Wang, S.-L. Chem. Commun.
1991, 710–712. (c) Portnoy, M.; Ben-David, Y.; Rousso, I.; Milstein, D.
Organometallics 1994, 13, 3465–3479. (d) Catellani, M.; Mealli, C.; Motti,
E.; Paoli, P.; Perez-Carreno, E.; Pregosin, P. S. J. Am. Chem. Soc. 2002,
124, 4336–4346.
Reductive elimination forms biphenyl derivative E. Since
the norbornyl moiety remains bonded, the steric hindrance
in complex E causes norbornene to be eliminated to F,2a,1c
which undergoes the final intramolecular amination step from
the amine and generates dihydrophenanthridine 1.
(12) (a) Beletskaya, I. P.; Cheprakov, A. V. J. Organomet. Chem. 2004,
689, 4055–4082. (b) Catellani, M.; Chiusoli, G. P. J. Organomet. Chem.
1988, 346, C27–C30. (c) Liu, C.-H.; Li, C.-S.; Cheng, C.-H. Organome-
tallics 1994, 13, 18–20. (d) Gorelsky, S.; Lapointe, D.; Fagnou, K. J. Am.
Chem. Soc. 2008, 130, 10848–10849.
(14) (a) Ca`rdenas, D. J.; Mart`ın-Matute, B.; Echavarren, A. M. J. Am.
Chem. Soc. 2006, 128, 5033–5044. For variant involving a Pd(0)/Pd(II)
aryl cooperative activation of an Ar substrate, see: (b) Grushin, V. V.;
Marshall, W. J. J. Am. Chem. Soc. 2006, 128, 4632–4641.
(13) (a) Dyker, G. Angew. Chem., Int. Ed. 1999, 38, 1699–1712. (b)
Kakiuchi, F.; Chatani, N. AdV. Synth. Catal. 2003, 345, 1077–1101. (c)
Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439–2463.
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Org. Lett., Vol. 12, No. 24, 2010

Scheme 2. Proposed Reaction Mechanism
Phenanthridine 2 is formed in the presence of dioxygen
(or a sacrificial olefin), which presumably both regenerates
a Pd(II) species to switch from one catalytic cycle to the
other and acts as the hydrogen scavenger in the dehydroge-
nation step.6b
The isolated 1a was not oxidized after 24 h at 130 °C in
DMF/base under argon without any source of palladium. If
dioxygen but no palladium complex was present, then
oxidation occurred, but was much slower, confirming the
role of the latter in the oxidation step.6c We also added an
olefin after full conversion, i.e., when no more ArX was
present in solution to regenerate a Pd(II) species. This did
not favor dehydrogenation and thus tends to confirm that
this step is catalyzed by Pd(II).
When norbornene was omitted, low conversions were
achieved, and only traces of Ullmann-type coupled biphenyl
derivatives were observed. This rules out the possibility that
the reaction proceeds via initial amination of the iodide
followed by intramolecular ring closure. The ortho-substitu-
ent on the aryl iodide is necessary to trigger biaryl formation
rather than attack of a second aryl halide at the norbornyl
site of palladacycle C.15,1c
tionalization of substrates or the presence of protecting
groups, which impact their atom economy. From that
perspective also our method compares well to the reported
methods.
In conclusion, we have developed a new method for the
expeditious synthesis of phenanthridines from benzylamines
and aryl iodides, by successfully coupling a palladium/
norbornene cocatalyzed domino sequence ending via an
intramolecular amination with an oxidative dehydrogenation.
Acknowledgment. We thank UPMC, CNRS, IUF, and
the Re´gion Ile-de-France. G.M. is on leave from the
Universita` di Parma (Italy), which is acknowledged for
financial support. We warmly thank Prof. M. Catellani
(Università di Parma, Italy) for helpful discussions. Technical
assistance was generously offered by FR 2769.
Supporting Information Available: Experimental pro-
cedure, characterization data, and NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL102509N
As phenanthridines form a well-known class of molecules
with biological properties,5 many protocols for the synthesis
of these compounds have been reported.16 Even if some of
these methods are efficient, they usually require prefunc-
(16) Pd-catalyzed approaches to phenanthridines: (a) Candito, D. A.;
Lautens, M. Angew. Chem., Int. Ed. 2009, 48, 6713–6716. (b) Gerfaud, T.;
Neuville, L.; Zhu, J. Angew. Chem., Int. Ed. 2009, 48, 572–577. (c) Della
Ca, N.; Motti, E.; Mega, A.; Catellani, M. AdV. Synth. Catal. 2010, 352,
1451–1454. (d) Shabashov, D.; Daugulis, O. J. Org. Chem. 2007, 72, 7720–
7725. (e) Siddiqui, M. A.; Snieckus, V. Tetrahedron Lett. 1988, 29, 5463–
5466.
(15) Catellani, M.; Chiusoli, G. P. J. Organomet. Chem. 1985, 286, C13–
C16
.
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