Synthesis of 6-phenanthridinones and their heterocyclic analogues through palladium-catalyzed sequential aryl-aryl and N-aryl coupling

Article abstract of DOI:10.1021/ol0479949

(Chemical Equation Presented) 6-Phenanthridinones and their heterocyclic analogues were synthesized through a one-pot procedure based on consecutive Pd-catalyzed aryl-aryl and N-aryl coupling from iodoarenes ortho-substituted by electron-releasing substituents and amides of o-bromoarene- and heteroarenecarboxylic acids.

Full text of DOI:10.1021/ol0479949

ORGANIC
LETTERS
2004
Vol. 6, No. 25
4759-4762
Synthesis of 6-Phenanthridinones and
Their Heterocyclic Analogues through
Palladium-Catalyzed Sequential
Aryl−Aryl and N-Aryl Coupling
Raffaella Ferraccioli,*,† Davide Carenzi,† Ottavio Rombola`,‡ and Marta Catellani*,‡
CNR-Istituto di Scienze e Tecnologie Molecolari (ISTM), Dipartimento di Chimica
Organica e Industriale, UniVersita` di Milano, Via C. Golgi 19, 20133 Milano, Italy,
and Dipartimento di Chimica Organica e Industriale, UniVersita` di Parma,
Parco Area delle Scienze, 17/A, 43100 Parma, Italy
raffaella.ferraccioli@istm.cnr.it; marta.catellani@unipr.it
Received October 1, 2004
ABSTRACT
6-Phenanthridinones and their heterocyclic analogues were synthesized through a one-pot procedure based on consecutive Pd-catalyzed
aryl aryl and N-aryl coupling from iodoarenes ortho-substituted by electron-releasing substituents and amides of o-bromoarene- and
−
heteroarenecarboxylic acids.
We have recently reported a palladium-catalyzed one-pot
sequential reaction involving the aryl coupling of iodoarene
1, ortho-substituted by an electron-releasing group with
bromoarene 2, bearing an electron-withdrawing substituent.
The process is terminated by a Heck reaction (Scheme 1).1
In this paper, we further investigate the palladacycle-
catalyzed unsymmetrical aryl coupling reaction to obtain
nitrogen heterocycles in a one-pot sequence. To this purpose,
we wondered whether a suitable functional group such as
CONHR in the ortho position of the initial bromoarene 2
could undergo a different termination type intramolecularly
at the level of the intermediate 3, leading to 6-phenanthri-
dinones and their heterocyclic analogues 6 (Scheme 2, R1
) Me, Et, iPr, MeO; R2 ) H, Me, Bn; Ar: aryl or
heteroaryl).
conditions, Pd(OAc)2 as a catalyst, K2CO3 as a base,
norbornene in DMF at 105 °C,1 were unsuccessful (Table
1, entry 1) due to the interference of the amide group with
palladium.
This failure led us to make the hypothesis that suitable
tertiary phosphines could counteract the coordinating action
of the amide. We thus investigated the use of tertiary
arylphosphines as ligands for Pd(OAc)2 and Pd2(dba)3CHCl3
Scheme 1
However, our attempts to obtain 6a from the reaction of
1 (R1 ) Me) and 5a (R2 ) H) under the previously reported
† CNR-Istituto di Scienze e Tecnologie Molecolari.
‡ Universita` di Parma.
(1) Faccini, F.; Motti, E.; Catellani, M. J. Am. Chem. Soc. 2004, 126,
78-79.
10.1021/ol0479949 CCC: $27.50
© 2004 American Chemical Society
Published on Web 11/05/2004

Scheme 2
Scheme 3
in DMF and acetonitrile as a solvent. As shown in Table 1,
while TPP and P(o-tol)3 gave only modest yields of 6a, good
results were obtained with tri-2-furylphosphine (TFP) (entries
3 and 4). The latter was successfully employed by Lautens
for the ortho alkylation of palladacycles2 and by Buchwald
in Pd-catalyzed intramolecular arylation of amides.3
Table 1. Reaction of 1 (R1 ) Me) and 5a (R2 ) H) in the
Presence of K2CO3, Norbornene, Palladium Catalyst, and Ligand
in DMF or MeCNa
deinsertion, caused by the steric effect of the two ortho
substituents, affords intermediate 11 in which the CONH2
group is in a suitable position to afford an intramolecular
amidation3 of the biphenylylpalladium species leading to 6a.
This reaction achieves for the first time a consecutive
aryl-aryl and N-aryl coupling, leading to a phenanthridinone
derivative 6a in a one-pot sequence. In addition, it has been
extended to a variety of carboxamides of electron-poor and
electron-rich o-bromoheterocycles on one side and a variety
of iodides ortho-substituted with electron-releasing substit-
uents on the other (Scheme 2, Table 2).
The reactions of 1 (R1 ) Me) with 2-bromobenzamides
5a (R2 ) H, Me, Bn) proceeded with complete conversion
and good yields in DMF and acetonitrile at 105 and 85 °C,
respectively (entries 1-4). 3-Bromothiophene-2-carbox-
amides 5b (R2 ) Me, Bn) behaved analogously (entries
8-10). On the other side, DMF turned out to be the solvent
of choice with the heterocyclic amides 5c-f. For instance,
the reaction of 3-bromofurocarboxamide 5c with 1 (R1 )
Me) in MeCN gave palladium black precipitate and only 32%
conversion (entry 12), whereas, in DMF, it gave complete
conversion and 6c was isolated in 82% yield (entry 11).
Surprisingly, the reaction with the isomeric 2-bromofuran-
3-carboxamide 5d was less selective leading to 6d (48%
yield) along with a mixture of secondary unidentified
entry
catalyst
Pd(OAc)2
ligand
solvent, T (°C) 6a (%)b
1
2
3
4
5
6
7
8
9
DMF, 105
DMF, 85
traces
46
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3‚CHCl3 TFP
Pd2(dba)3‚CHCl3 TPP
Pd2(dba)3‚CHCl3 P(o-tol)3
TFP
TFP
TFP
TPP
TPP
P(o-tol)3
P(o-tol)3
DMF, 105
MeCN, 85
DMF, 105
MeCN, 85
DMF, 105
MeCN, 85
MeCN, 85
MeCN, 85
MeCN, 85
86
80
33
42
c
10d
74
57
19e
10
11
a Reactions of 1 (R1 ) Me, 1 mol equiv) and 5a (R2 ) H, 1 mol equiv)
were run in the presence of norbornene (1.1 mol equiv), K2CO3 (2 mol
equiv), Pd catalyst (5 mol %), and ligand if present (10 mol %) in DMF or
MeCN, 24 h. [1] ) [5a] ) 0.045 M. Unless otherwise indicated, conversion
of 5a was complete. b Isolated yield. c No product 6a formed; 1 and 5a
were present in a large extent in the crude (1H NMR analysis). d Recovery
of 5a ) 67%. e Recovery of 5a ) 30%.
The reaction proceeds as indicated in Scheme 3 (L ) TFP).
The o-iodotoluene 1 adds to palladium(0), giving complex
7. Norbornene insertion4 and subsequent ring closure through
C-H activation5 leads to palladacycle 9.6 Bromoamide 5a
then reacts with 9 (probably through oxidative addition
leading to palladium(IV) metallacycle, shown in brackets)
giving 10, which results from the attack of the aryl moiety
of 5 on the aromatic site of palladacycle 9. Norbornene
(4) (a) Li, C. S.; Cheng, C. H.; Liao, F. L.; Wang, S. L. Chem. Commun.
1991, 710-712. (b) Portnoy, M.; Ben-David, Y.; Rousso, I.; Milstein, D.
Organometallics 1994, 13, 3465-3479. (c) Catellani, M.; Mealli, C.; Motti,
E.; Paoli, P.;. Perez-Carreno, E.; Pregosin, P. S. J. Am. Chem. Soc. 2002,
124, 4336-4346.
(5) For examples of palladium-catalyzed C-H activation, see: (a)
Dyker,G. Angew. Chem., Int. Ed. 1999, 38, 1699-1712. (b) Karig, G.;
Moon, M. T.; Thasana, N.; Gallagher, T. Org. Lett. 2002, 4, 3115-3118.
(c) Huang, Q.; Fazio, A.; Dai, G.; Campo, M. A.; Larock, R. C. J. Am.
Chem. Soc. 2004, 126, 7460-7461.
(6) (a) Ca´mpora, J.; Palma, P.; Carmona, E. Coord. Chem. ReV. 1999,
193-195, 207-281. (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) Dyker, G. Chem. Ber. 1997, 130, 1567-1578.
(e) Ryabov, A. D. Chem. ReV. 1990, 90, 403-424. (f) Catellani, M.; Motti,
E.; Baratta, S. Organic Lett. 2001, 3, 3611-3614. (g) Catellani, M. Synlett
2003, 3, 298-313. (h) Motti, E.; Ippomei, G.; Deledda, S.; Catellani, M.
Synthesis 2003, 17, 2671-2678.
(2) (a) Lautens, M.; Piguel, S. Angew. Chem., Int. Ed. 2000, 39, 1045-
1046.
(3) For palladium-catalyzed N-arylation of amides, see: (a) Wolfe, J.
P.; Rennels, R. A.; Buchwald, S. L. Tetrahedron 1996, 52, 7525-7546.
(b) Yang, B. H.; Buchwald, S. L. Org. Lett. 1999, 1, 35-38. (c) Shakespeare,
W. C. Tetrahedron Lett. 1999, 40, 2035-2038. (d) Yin, J.; Buchwald, S.
L. Org. Lett. 2000, 2, 1101-1104. (e) Artamkina, G. A.; Sergeev, A. G.;
Beletskaya, I. P. Tetrahedron Lett. 2001, 42, 4381-4384.
4760
Org. Lett., Vol. 6, No. 25, 2004

Table 2. Synthesis of 6a
a Reaction conditions: 1 (1 mol equiv), 5 (1 mol equiv), K2CO3 (2 mol equiv), norbornene (1.1 equiv), Pd(OAc)2 (5 mol %), TFP (10 mol %), in MeCN
or DMF, 24 h. [1] ) [5] ) 0.045 M. Unless otherwise indicated, conversion of 5 was complete. b Isolated yield. c After 3 h, an extensive palladium black
precipitate was formed and the conversion of 5d was complete. d Conversion of 5b ) 97%. e Conversion of 5c ) 32%. f Crude was a complex mixture in
which 5e was present in very low concentration (1H NMR analysis). g Pd(OAc)2 (10 mol %), 1 (2 mol equiv). The reaction proceeded with 60% conversion
1
of 5f; yield of 6f was estimated by H NMR analysis of an inseparable mixture of 5f and 6f, ca. 2:3.
products (entry 13). 2-Bromofuran is reported to be quite
reactive in the presence of palladium complexes.7 As a
consequence, 2-bromofuran-3-carboxamide was involved in
competitive secondary reactions with loss of selectivity. A
similar behavior was observed with N-benzyl 2-bromonico-
tinamide, compound 6e-Br (R2 ) Bn) being formed in a
very small amount (entry 14). Interestingly, in the case of
3-pyridinecarboxamide, selectivity could be enhanced switch-
ing from the 2-bromo- to the less reactive 2-chloroderivative.
(7) Hooper, M. W.; Utsunomiya, M.; Hartwig, J. F. J. Org. Chem. 2003,
68, 2861-2873.
Org. Lett., Vol. 6, No. 25, 2004
4761

Thus, N-substituted 2-chloronicotinamides reacted with 1
giving 6e (R2 ) Me, Bn) in 55 and 63% yields, respectively
(entries 15 and 16). The reaction with 2-bromobenzothiophene-
3-carboxamide gave 6f with 60% conversion of 5f at 50 °C,
in DMF (entry 17). However, we were unable to isolate 6f
as a pure compound, separation from the starting amide being
difficult by both chromatography and crystallization. At
higher temperature (85 °C), conversion was complete, but
selectivity was low.
As previously reported, the presence of ortho electron-
donating substituents in the iodoarene 1 is needed to obtain
unsymmetrical aryl-aryl coupling.8 Accordingly, the reaction
of 5a (R2 ) Me) with aryl iodide 1 bearing Et, iPr, or OMe
as R1 led to 6a in fair to good yields (entries 5-7), final
amidation not being affected significantly by the substituent.
6-Phenanthridinones and their heterocyclic analogues are
bioactive compounds of current interest as antimicrobial,
antimalarial, insecticidal, antineoplastic, antidiuretic, and
antiarrhythmic agents, and a number of syntheses have been
developed so far to prepare them.9
In conclusion, we have developed a new method to obtain
6-phenanthridinones and heterocyclic condensed quinolones
6 based on consecutive palladium-catalyzed regioselective
aryl-aryl and N-aryl coupling of electron-rich o-iodoarenes
1 with o-bromobenzamides and/or their heterocyclic ana-
logues 5. Further investigation of this reaction is currently
underway.
Acknowledgment. We thank Consiglio Nazionale delle
Ricerche (CNR) and Ministero dell’Universita` e della Ricerca
Scientifica e Tecnologica (Cofinanziamento MIUR, Project
n.200303977774).
(8) Catellani, M.; Motti, E. New J. Chem. 1998, 22, 759-761.
(9) (a) Lewis, J. R. Nat. Prod. Rep. 1997, 14, 303-308. (b) Lee, Y. R.;
Kim, B. S.; Kweon, H. I. Tetrahedron 2000, 56, 3867-3874. (c) Koruznjak,
J. D.; Slade, N.; Zamola, B.; Pavelic, K.; Karminsky-Zamola, G. Chem.
Pharm. Bull. 2002, 50, 656-660. (d) Wu, M. J.; Lin, C. F.; Lu, W. D. J.
Org. Chem. 2002, 67, 5907-5912. (e) Koruznjak, J. D.; Grdisa, M.; Slade,
N.; Zamola, B.; Pavelic, K.; Karminsky-Zamola, G. J. Med. Chem. 2003,
46, 4516-4524. (f) Glover, B.; Harvey, K. A.; Liu, B., Sharp, M. J.;
Tymoschenko, M. F. Org. Lett. 2003, 5, 301-304. (g) Banwell, M. G.;
Lupton, D. W.; Ma, X.; Renner, J.; Sydnes, M. O. Org. Lett. 2004, 16,
2741-2744.
Supporting Information Available: Experimental pro-
cedures and characterization for compounds 5 and 6. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0479949
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Org. Lett., Vol. 6, No. 25, 2004