Palladium-promoted cascade reactions of isonitriles and 6-iodo-N-propargylpyridones: synthesis of mappicines, camptothecins, and homocamptothecins.

Article abstract of DOI:10.1021/ol026408d

Ambient-temperature reactions of electron-rich aryl isonitriles with substituted 6-iodo-N-propargylpyridones in the presence of silver carbonate and palladium acetate produce 11H-indolizino[1,2-b]quinolin-9-ones in good to excellent yield. Experimental ev

Full text of DOI:10.1021/ol026408d

ORGANIC
LETTERS
2002
Vol. 4, No. 19
3215-3218
Palladium-Promoted Cascade Reactions
of Isonitriles and
6-Iodo-N-propargylpyridones: Synthesis
of Mappicines, Camptothecins, and
Homocamptothecins
Dennis P. Curran* and Wu Du
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
curran@pitt.edu
Received June 21, 2002
ABSTRACT
Ambient-temperature reactions of electron-rich aryl isonitriles with substituted 6-iodo-N-propargylpyridones in the presence of silver carbonate
and palladium acetate produce 11H-indolizino[1,2-b]quinolin-9-ones in good to excellent yield. Experimental evidence suggests that the process
occurs though organopalladium rather than radical intermediates. It is applied to synthesis analogues of mappicine and camptothecin, including
the silatecans DB-67 and DB-91 (homo-DB-67).
Cascade radical reactions of aryl and alkenyl isonitriles have
emerged as powerful tools for the synthesis of quinolines,
indoles, and other heterocycles.1 These reactions typically
involve addition of a radical to an isonitrile to give an imidoyl
radical, followed by one or more subsequent radical additions
or cyclizations. In contrast, while transition-metal-mediated
additions to isonitriles are well-known, most such processes
result in direct 1,1-addition of a reagent to the isonitrile
carbon,2 and the possibility for making heterocycles3 by
cascade processes involving the isonitrile nitrogen substit-
uents has not often been exploited.
4,5 camptothecin 5,6 and homocamptothecin 6,7 and we have
made several hundred analogues of these molecules by
cascade radical annulations in recent years.8 Many of these
camptothecin and homocamptothecin analogues are potent
(2) (a) Murakami, M.; Kawano, T.; Ito, H.; Ito, Y. J. Org. Chem. 1993,
58, 1458. (b) Murakami, M.; Masuda, H.; Kawano, T.; Nakamura, H.; Ito,
Y. J. Org. Chem. 1991, 56, 1. (c) Murakami, M.; Kawano, T.; Ito, Y. J.
Am. Chem. Soc. 1990. 112, 2437. (d) Berk, S. C.; Grossman, R. B.;
Buchwald, S. L. J. Am. Chem. Soc. 1993, 115, 4912. (e) Tamao, K.;
Kobayashi, K.; Ito, Y. J. Am. Chem. Soc. 1988, 110, 1286. (f) Otsuka, S.;
Nakamura, A.; Yashida, T. J. Am. Chem. Soc. 1969, 7196. (g) Ohe, K.;
Matsuda, H.; Ishihara, T.; Ogoshi, S.; Chatani, N.; Murai, S. J. Org. Chem.
1993, 58, 1173. (h) Ishiyama, T.; Oh-e, T.; Miyaura, N.; Suzuki, A.
Tetrahedron Lett. 1992, 33, 4465.
(3) (a) For synthesis of indole from 2,6-dimethylphenyl isonitrile, see:
Jones, W. D.; Kosar, W. P. J. Am. Chem. Soc. 1986, 108, 5640. (b) For
synthesis of poly(2,3-quinoxaline), see: Ito, Y.; Ihara, E.; Murakami, M.
J. Am. Chem. Soc. 1990, 112, 6446. (c) Marcaccini, S.; Torroba, T. Org.
Prep. Proced. Int. 1993, 25, 141.
Cascade radical reactions of aryl isonitriles 1 and 6-iodo-
N-propargylpyridones 2 typically provide 11H-indolizino-
[1,2-b]quinolin-9-ones 3 in about 40-60% yield in a single
step (Scheme 1).4 This ring system is the core of mappicine
(4) (a) Curran, D. P.; Liu, H. J. Am. Chem. Soc. 1991, 113, 2127. (b)
Curran, D. P.; Ko, S.-B.; Josien, H. Angew. Chem., Int. Ed. Engl. 1995,
34, 2683. (c) Curran, D. P.; Liu, H.; Josien, H.; Ko, S.-B. Tetrahedron
1996, 52, 11385. (d) Josien, H.; Ko, S.-B.; Bom, D.; Curran, D. P. Chem.
Eur. J. 1998, 4, 67. (e) Josien, H.; Curran, D. P. Tetrahedron 1997, 53,
8881.
(1) (a) Ryu, I.; Sonoda, N.; Curran, D. P. Chem. ReV. 1996, 96, 177. (b)
Kobayashi, Y.; Fukyuama, T. J. Heterocycl. Chem. 1998, 35, 1043. (c)
Camaggi, C. M.; Leadrini, R.; Nanni, D.; Zanardi, G. Tetrahedron 1998,
54, 5587. (d) Lenoir, I.; Smith, M. L. J. Chem. Soc., Perkin Trans. 1 2000,
641.
10.1021/ol026408d CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/20/2002

the attendant toxicity issues and separation problems,10 is
far from ideal for large scale synthesis. We report herein a
palladium-catalyzed process that provides 11H-indolizino-
[1,2-b]quinolin-9-ones from the same two precursors as the
tandem radical process. The new process already func-
tions well for small-scale preparations, and the results form
the basis for the development of a practical large-scale
method.
Scheme 1
p-Methoxyphenylisonitrile 8a and N-propargylpyridone 9a
were chosen as substrates for an initial survey of reaction
conditions because the target product 10a from this reagent
pair has a substitution pattern similar to that of DB-67 7.
Treatment of 8a and 9a with 10% Pd(OAc)2, 20% Ph3P, and
Et3N in MeCN at 80 °C gave only traces of the product 10a
as assayed by TLC analysis against an authentic sample
(Scheme 2). In follow-up reactions, we varied the Pd
anticancer agents, and one of the most promising new
compounds, DB-67 7, is currently in preclinical develop-
ment.9
Scheme 2
catalysts, ligands, solvents, temperatures, and bases.11 We
learned that a phosphine ligand was not needed for the
reaction. Toluene was found to be a suitable solvent, and
the reaction occurred at room temperature. Addition of a base
proved helpful, and among the bases tried, Ag2CO3 proved
to be the best.
While the generality and simplicity of the cascade radical
addition approach are nearly ideal for discovery chemistry,
the reliance on stoichiometric quantities of tin reagents, with
In a typical reaction, 1 equiv of 9a, 1.5 equiv of Ag2CO3,
and 20% Pd(OAc)2 were mixed in toluene, and then 2 equiv
of isonitrile 8a was slowly added at room temperature. A
clean transformation occurred, and after 20 h, a mixture of
product 10a and starting iodopyridone 9a in a 3:1 ratio was
obtained. Various attempts to push the reaction to completion
were not successful. Although excess isonitrile was used,
(5) (a) Govindachari, T. R.; Ravindranath, K. R.; Viswanathan, N. J.
Chem. Soc., Perkin Trans. 1 1974, 1215. (b) Pendrak, I.; Wittrock, R.;
Kingsbury, W. D. J. Org. Chem. 1995, 60, 2912. (c) Pirillo, A.; Verotta,
L.; Gariboldi, P.; Torregiani, E.; Bombardelli, E. J. Chem. Soc., Perkin
Trans. 1 1995, 583.
(6) The Camptothecins: Unfolding their Anticancer Potential; Liehr, J.
G., Giovanella, B. C., Verschraegen, C. F., Eds. Ann. N.Y. Acad. Sci. 2000,
922.
(7) Lavergne, O.; Lesueur-Ginot, L.; Rodas, F. P.; Kasprzyk, P. G.;
Pommier, J.; Demarquay, D.; Prevost, G.; Ulibarri, G.; Rolland, A.; Schiano-
Liberatore, A.-M.; Harnett, J.; Pons, D.; Camara, J.; Bigg, D. C. H. J. Med.
Chem. 1998, 41, 5410.
(8) (a) de Frutos, O.; Curran, D. P. J. Comb. Chem. 2000, 2, 639. (b)
Luo, Z. Y.; Zhang, Q. S.; Oderaotoshi, Y.; Curran, D. P. Science 2001,
291, 1766. (c) Zhang, W.; Chen, C. H.-T.; Luo, Z.; Curran, D. P. Submitted
for publication. (d) Curran, D. P.; Josien, H.; Bom, D.; Gabarda, A. E.;
Du, W. Ann. N.Y. Acad. Sci. 2000, 902, 112. (e) Gabarda, A.; Du, W.;
Isarno, T.; Tangirala, R. S.; Curran, D. P. Tetrahedron, in press.
(9) Bom, D.; Curran, D. P.; Kruszewski, S.; Zimmer, S. G.; Thompson
Strode, J. ; Kohlhagen, G.; Du, W.; Chavan, A. J.; Fraley, K. A.; Bingcang,
A. L.; Latus, L. J.; Pommier, Y.; Burke, T. G. J. Med. Chem. 2000, 43,
3970.
1
its presence was not detected in the H NMR spectrum of
the product mixture obtained after removing insoluble
materials. Once the reaction had stopped, addition of more
isonitrile or Pd catalyst alone did not result in further
conversion.
The reaction was finally driven to completion by a simple
recycle process. After filtration to remove insoluble material
(10) (a) Baguley, P. A.; Walton, J. C. Angew. Chem., Int. Ed. Engl. 1998,
37, 3073. (b) Studer, A.; Amrein, S. Synthesis, 2002, 835.
(11) Du, W. Ph.D. Thesis, University of Pittsburgh, 2002.
3216
Org. Lett., Vol. 4, No. 19, 2002

and evaporation of the solvent, the crude product was simply
resubjected to the same conditions with reduced Pd catalyst
loading (10%). After an additional 20 h, workup and
purification by flash chromatography gave the polycyclic
quinoline 10a in 83% isolated yield. This product was
identical to an authentic sample prepared under the ditin
photolysis conditions.
The standard procedure with a single recycle was then
applied to different iodo-N-propargylpyridones and substi-
tuted isonitriles, and the results of these experiments are
summarized in Table 1. The substituent on the isonitrile
proceeding through the usual free-radical addition mecha-
nism.12 To provide additional evidence that radicals are not
involved, we conducted the competition experiments shown
in Scheme 3. Under palladium conditions, pyridone 9a re-
Scheme 3
Table 1. Polycyclic Quinolines Prepared by
Palladium-Promoted Cascade Reactions of para-Substituted
Isonitriles and Iodopyridones
isonitrile 8
(R2, R3)
iodopyridone 9
quinoline 10
(yield, %)a
acts with p-methoxyphenylisonitrile 8a (Scheme 2) but not
2,6-diethylphenylisonitrile 8f. Under radical conditions
(Me3SnSnMe3, benzene, sunlamp photolysis, 60-70 °C), 9a
reacts with both isonitriles; reaction with 8a gives 10a in
81% yield while reaction with 8f gives a 0.9/1 mixture of
regioisomers 11 and 12 in 79% yield.13 We rationalized that
if radicals were generated during a competition experiment
then a mixture of three products should result. Indeed, a
competitive experiment with 8a and 8f (4 equiv) promoted
by irradiation with UV light (25 °C) in the presence of
Me3SnSnMe3 produced 10a, 11, and 12 in a 7/1/2 ratio in
60% combined yield. In contrast, a competitive reaction
under the palladium conditions but with benzene as the
solvent to mimic the radical reaction gave a complex mixture
containing 10a (20% yield) but not 11 or 12. These results
suggest that radicals are not involved in the palladium
process.
On the basis of the information provided by the model
substrates, the reaction was then applied to camptothecin and
mappicine analogues. p-Methoxyphenylisonitrile 8a reacted
with iodopyridone (S)-13 to give camptothecin analogue (S)-
14 in 62% yield, and p-benzyloxyphenyl isonitrile 8b reacted
with iodopyridone rac-15 to give mappicine analogue rac-
16 in 53% yield (Scheme 4).
entry
(R1)
1
2
3
4
5
6
8a (4-MeO)
8b (4-BnO)
8c (4-Me2N)
8d (4-Me)
8c (4-Me2N)
8e (3,4-diOMe)
9b (TES)
9a (TBS)
9c (TMS)
9a (TBS)
9d (tBu)
9a (TBS)
10b (66)
10c (92)
10d (67)
10e (41)b
10f (41)
10g (83)
a Isolated yield after flash chromatography. b Yield determined by 1H
NMR analysis, 40% of the starting iodopyridone was also present.
played an important role in the success of the reaction.
Various electron-rich alkoxy (8a,b,e) and amino (8c) iso-
nitriles gave good to excellent yields (entries 1-3), while
p-tolyl isonitrile 8d (entry 4) gave lower yield (41%) along
with unreacted starting material 9a (40%). Reaction of 3,4-
methylenedioxyisonitrile 8e with 9a gave a single regio-
isomeric teracycle 10g (83%). The same regioisomer 10g
was produced under standard ditin photolysis conditions but
in only about half the yield. Both silyl and tert-butyl groups
(entry 5) are acceptable on the terminus of the propargyl
groups; however, an attempt to react a terminally unsubsti-
tuted propargyl pyridone failed to provide the product.
Phenylisonitrile and isonitriles with electron-withdrawing
groups only gave traces of tetracyclic products (results not
shown). We also tested N-propargylchloropyridones and
bromopyridones (not shown) but found that these were much
less reactive.
(12) For examples of palladium-promoted or -initiated radical reactions,
see: (a) Curran, D. P.; Chang, C.-T. Tetrahedron Lett. 1990, 31, 933. (b)
Ryu, H.; Kreimerman, S.; Araki, F.; Nishitani, S.; Oderaotoshi, Y.; Minakata,
S.; Komatsu, M. J. Am. Chem. Soc. 2002, 124, 3812.
(13) Full details of radical reactions with 2,6-disubstituted aryl isonitriles
will be described separately. Du, W.; Curran, D. P. Manuscript in
preparation.
The need for electron-rich isonitriles provides circumstan-
tial evidence that the palladium-mediated reaction is not
Org. Lett., Vol. 4, No. 19, 2002
3217

Scheme 4
Figure 1. Possible series of steps involving organopalladium
intermediates.
To illustrate the practical utility of this process, we
prepared DB-67 (7) and its homolog DB-91 (17).14 Isonitrile
8b reacted under the standard conditions with iodopyridones
13 and 188e to give 19 and 20 in 70% and 82% yield (Scheme
5). Treatment of 19 and 20 with TFA and thioanisole
species, possibly already ligated to one or more isonitriles,
inserts into the C-I bond of the iodopyridine to give 21.
Subsequent 1,1-addition to an isonitrile to give 22, followed
by intramolecular addition to the triple bond, gives a
vinylpalladium species 23. This species could cyclize by
oxidative addition to an ortho CH bond followed by reductive
elimination of a palladium hydride15a or by addition to the
aromatic ring (or electrocyclization) followed by palladium
hydride elimination.15b Reaction of the so-formed palladium
hydride species with the base regenerates the starting low-
valent palladium species (not shown). Silver carbonate may
also ionize one or more of the palladium iodide intermediates.
In conclusion, we have developed a new Pd-promoted
cascade reaction of electron-rich isonitriles and applied this
to synthesis of polycyclic quinolines. While the reaction does
not currently exhibit the scope of the cascade radical
annulation with respect to the isonitrile substituent, it is
convenient to conduct on small scale and produces some of
the most important classes of camptothecin and homocamp-
tothecin analogues in better yields than the radical process.
Further improvements in reaction conditions including reduc-
ing the amount of palladium and eliminating the recycle
could result in a practical large-scale process.
Scheme 5
Acknowledgment. We thank the National Institute of
Health for supporting this work. W.D. thanks the University
of Pittsburgh for a Mellon Predoctoral Fellowship. We thank
Drs. David Bom, Oscar de Frutos, and Thomas Isarno for
preparing some intermediates used in this work.
removed the benzyl ether protective group to give the desired
products 7 and 17 in 75% and 61% yield. These yields are
superior to those obtained on a small scale for the radical
photolysis conditions. In addition, purification is easier, and
the difficulties posed by scaling up the photolytic radical
reactions should not be encountered in the palladium-
promoted reactions.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The mechanism of the palladium-catalyzed reaction is not
clear at this point. We speculate (Figure 1) that a palladium
OL026408D
(14) Bom, D.; Curran, D. P.; Chavan, A. J.; Kruszewski, S.; Zimmer, S.
G.; Fraley, K. A.; Burke, T. G. J. Med. Chem. 1999, 42, 3018.
(15) (a) Roesch, K. R.; Larock, R. C. J. Org. Chem. 2001, 66, 412. (b)
Dang, H.; Garcia-Garibay, M. A. J. Am. Chem. Soc. 2001, 123, 355.
3218
Org. Lett., Vol. 4, No. 19, 2002