Palladium-catalyzed oxidative activation of arylcyclopropanes

Article abstract of DOI:10.1021/ol062476e

(Diagram presented) Palladium chloride-catalyzed intramolecular activation of electroneutral cyclopropane derivatives results in cleavage of the cyclopropane ring followed by formation of heterocyclic derivatives. Phenols, carboxylic acids, and amide groups were considered as substituents ortho to the cyclopropane ring in this catalytic activation chemistry. The regioselectivity observed in the case of amide-containing substrates was different from that of carboxylic acid-containing substrates, ruling out simple cyclopropane isomerization followed by a Wacker oxidation as the mechanistic pathway.

Full text of DOI:10.1021/ol062476e

ORGANIC
LETTERS
2006
Vol. 8, No. 25
5829-5832
Palladium-Catalyzed Oxidative Activation
of Arylcyclopropanes
Zhi He and Andrei K. Yudin*
DaVenport Research Laboratories, Department of Chemistry,
UniVersity of Toronto, 80 St. George Street, Toronto, Canada, M5S 3H6
ayudin@chem.utoronto.ca
Received October 7, 2006
ABSTRACT
Palladium chloride-catalyzed intramolecular activation of electroneutral cyclopropane derivatives results in cleavage of the cyclopropane ring
followed by formation of heterocyclic derivatives. Phenols, carboxylic acids, and amide groups were considered as substituents ortho to the
cyclopropane ring in this catalytic activation chemistry. The regioselectivity observed in the case of amide-containing substrates was different
from that of carboxylic acid-containing substrates, ruling out simple cyclopropane isomerization followed by a Wacker oxidation as the mechanistic
pathway.
A cyclopropane ring can be found within the structures of
natural products such as curacin A, ambruticin, and hali-
cholactone, to name a few.1 Methods for the cyclopropane
ring construction have been thoroughly investigated.2 Al-
though synthetic applications of the “donor-acceptor” cy-
clopropanes are well precedented,3 the utility of “electro-
neutral” cyclopropanes in synthesis is far less established.4
Herein, we report a palladium chloride-catalyzed intramo-
lecular activation of electroneutral cyclopropane derivatives.
In terms of electronic structure, cyclopropanes are closer
to olefins than to other cycloalkanes. The orbitals of C-H
bonds in the simplest member of this class of compounds,
C3H6, have approximately 33% s-character, whereas those
of C-C bonds have 17% s-character.5 The electron-rich
nature of electroneutral cyclopropane rings manifests itself
in reactions with strong acids. Corner- and edge-protonated
cyclopropyl species have been postulated as intermediates.6
Attempts to activate C-C bonds in substituted cyclopropanes
with palladium catalysts have been made.7 The late transition
metals react with cyclopropanes when placed in their vicinity
by way of initial addition to the nearby olefin.8 The ring
expansion of highly reactive methylenecyclopropanes can
(5) Weigert, F. J.; Roberts, J. D. J. Am. Chem. Soc. 1967, 89, 5962.
(6) (a) Bodor, N.; Dewar, M. J. S. J. Am. Chem. Soc. 1971, 93, 6685.
(b) McKinney, M. A.; Smith, S. H.; Hempelman, S.; Gearen, M. M.;
Pearson, L. Tetrahedron Lett. 1971, 39, 3657. (c) Lee, C. C.; Vassie, S.;
Ko, E. C. F. J. Am. Chem. Soc. 1972, 94, 8931. (d) DePuy, C. H.; Andrist,
A. H.; Fuenfschilling, P. C. J. Am. Chem. Soc. 1974, 96, 948. (e) DePuy,
C. H.; Fuenfschilling, P. C.; Andrist, A. H.; Olson, J. M. J. Am. Chem.
Soc. 1977, 99, 6297. (f) Rood, I. D. C.; Klumpp, G. W. Tetrahedron Lett.
1983, 24, 4599. (g) Dewar, M. J. S.; Healy, E. F.; Ruiz, J. M. J. Chem.
Soc., Chem. Commun. 1987, 12, 943. (h) Koch, W.; Liu, B.; Schleyer, P.
v. R. J. Am. Chem. Soc. 1989, 111, 3479. (i) Burritt, A.; Coxon, J. M.;
Steel, P. J. J. Org. Chem. 1995, 60, 7670. (j) Frash, M. V.; Kazansky, V.
B.; Rigby, A. M.; van Santen, R. A. J. Phys. Chem. 1998, 102, 2232.
(7) (a) Albelo, G.; Rettig, M. F. J. Organomet. Chem. 1972, 42, 183.
(b) Albelo, G.; Wiger, G.; Rettig, M. F. J. Am. Chem. Soc. 1975, 97, 4510.
(c) Rettig, M. F.; Wilcox, D. E.; Fleischer, R. S. J. Organomet. Chem.
1981, 214, 261. (d) Parra-Hake, M.; Rettig, M. F.; Wing, R. M.; Woolcock,
J. C. Organometallics 1982, 1, 1478. (e) Ahmad, M. U.; Ba¨ckvall, J.-E.;
Nordberg, R. E.; Norin, T.; Stro¨mberg, S. J. Chem. Soc., Chem. Commun.
1982, 5, 321. (f) Wilhelm, D.; Ba¨ckvall, J.-E.; Nordberg, R. E.; Norin, T.
Organometallics 1985, 4, 1296. (g) Parra-Hake, M.; Rettig, M. F.; Williams,
J. L.; Wing, R. M. Organometallics 1986, 5, 1032.
(1) Donaldson, W. A. Tetrahedron 2001, 57, 8589.
(2) The Chemistry of the Cyclopropyl Group; Rappoport, Z., Ed.; Wiley:
Chichester, UK, 1987; Vol. 1.
(3) (a) Reissig, H.-U.; Zimmer, R. Chem. ReV. 2003, 103, 1151. (b) Yu,
M.; Pagenkopf, B. L. Tetrahedron 2005, 61, 321.
(4) In this paper, the term “electroneutral” refers to the cyclopropanes
that do not have carbon- or heteroatom-containing electron-withdrawing
and/or electron-donating substituents.
10.1021/ol062476e CCC: $33.50
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Published on Web 11/10/2006

Table 1. Palladium-Catalyzed Oxidative Activation of Arylcyclopropanesa
a Unless otherwise noted, the reactions were carried out using 0.5 mmol of starting material, 10 mol % of PdCl2(MeCN)2 as catalyst, and 1.0 equiv of
benzoquinone as oxidant in 5 mL of dioxane at 80 °C for 12 h. b Isolated yield with products ratio. c 30 mol % of PdCl2 and 2.0 equiv of CuCl2 were used.
d 10 mol % of PdCl2 and 2.0 equiv of CuCl2 were used. e Reaction was carried out at 100 °C for 24 h. f The product(s) presented in the table were the only
tractable organic compounds present in the reaction mixture upon completion.
be triggered by aminopalladation of the double bond leading
to R-palladated intermediates.9 These reactions proceed by
initial addition to the olefin rather than by direct activation
of the cyclopropane ring by the metal ion.
With a series of starting materials prepared using standard
cyclopropane chemistry,10 we explored PdII-catalyzed activa-
tion of arylcyclopropanes bearing heteroatom substituents
on the aromatic ring. Substituted carboxylic acids, amides,
and phenols were subjected to the PdII-catalyzed oxidation
conditions. We were pleased to observe that the cyclopropane
ring activation took place, and the corresponding lactones,
lactams, and ethers were formed in good yields (Table 1).
Dioxane was found to be superior to DMF, toluene, THF,
and DME as a solvent. Good yields were obtained with PdCl2
or PdCl2(MeCN)2 catalysts. Lower activity was observed
when PdBr2, PdI2, Pd(OAc)2, or Pd(TFA)2 was employed.
Copper(II) chloride was a good choice of oxidant for phenols
and acids; however, benzoquinone was superior to copper-
(II) chloride, PhI(OAc)2, oxone, and O2 as the oxidant in
the case of amides. A number of additives such as pyridine,
(8) Larock, R. C.; Yum, E. K. Tetrahedron 1996, 52, 2743.
(9) Nakamura, I.; Itagaki, H.; Yamamoto, Y. J. Org. Chem. 1998, 63,
6458.
(10) See Supporting Information.
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Org. Lett., Vol. 8, No. 25, 2006

Na2HPO4, Na2CO3, NaOAc, LiCl, and molecular sieves were
evaluated, but all of them slowed down catalytic turnover.
Scheme 2. Isotopic Labeling Experiments during Amide
Activation
Scheme 1. Proposed Mechanistic Pathway for Activation of
Arylcyclopropyl Acids
The R-methylstyrene derivative 12 (Scheme 1) was
detected by 1H NMR during the cyclization of 3a, suggesting
that a possible pathway in the case of carboxylic acid-
containing substrates is PdII-catalyzed isomerization of the
cyclopropane ring to the branched olefin followed by a
Wacker oxidation (Scheme 1, path I). This pathway is also
conceivable for the formation of phenol-containing arylcy-
clopropanes as well as for the formation of five-membered
ring lactams (5c, 6c, 8c, 9c, 10c) in the case of amide-
containing substrates. However, the formation of 3b can also
be explained by direct carboxypalladation followed by
â-hydride elimination and subsequent olefin isomerization
(Scheme 1, path II).11a The carboxypalladation is expected
to occur upon initial coordination of PdII to the more electron-
rich distal C-C bond of the arylcyclopropane.11b
23 in the reaction of phenylcyclopropane and H2O in the
presence of PdCl2 (eq 2). The acidic conditions would ensure
Interestingly, a different regioselectivity was observed in
the formation of six-membered ring lactams (5b, 6b, 8b, 9b)
in the case of amides. In an attempt to clarify the underlying
reasons, deuterium labeling experiments were carried out.
Deuterium incorporation was detected in positions 1 and 3
of the six-membered ring product when deuterated amide
14 was subjected to the reaction conditions (Scheme 2).12
This observation rules out simple cyclopropane-olefin
isomerization followed by Wacker oxidation as the reaction
pathway during PdII-promoted activation of amides. Fur-
thermore, when deuterated amide 22 (eq 1) was subjected
to the oxidation conditions, no deuterium incorporation was
detected.
that palladium release by protonation of the C-Pd bond is
the preferred reaction pathway. Accordingly, deuteration of
the C-Pd bond would account for the incorporation of
deuterium in positions 1 and 3.14i
Although a precise mechanistic picture has not been fully
established, it is clear that palladium-nitrogen coordination
is the key factor that accounts for different selectivities
observed during activation of acids and amides. The existence
of this interaction has been confirmed by 1H NMR through
An attack at the central carbon of the π-allyl complex in
the case of amides is consistent with our observations.13,14
This can also be supported by isolation of the π-allyl complex
(11) (a) For a recent example of â-alkoxy elimination in Wacker
chemistry, see: Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem.
Soc. 2005, 127, 17778. (b) For a detailed molecular orbital discussion of
phenylcyclopropane derivatives, see: Rademacher, P. Chem. ReV. 2003,
103, 933-975.
(13) For the formation of π-allyl complexes during metal-promoted
cyclopropane activation, see: (a) Tulip, T. H.; Ibers, J. A. J. Am. Chem.
Soc. 1979, 101, 9283. (b) Periana, R. A.; Bergman, R. G. J. Am. Chem.
Soc. 1984, 106, 7272.
(12) No deuterium incorporation into the ring-opened product was
detected in the case of the deuterated (COOD) derivative of acid 3a.
Org. Lett., Vol. 8, No. 25, 2006
5831

the low-field shift of the amide proton when amide 5a was
mixed with PdCl2 in dioxane-d8,10 whereas no coordination
was observed in the acid case. The interaction between
palladium and nitrogen is significantly suppressed in the case
of tert-butyl amide 7a and tertiary amide 26, which convert
to the branched olefins 7b (Table 1, entry 7) and 27 (eq 3),
respectively.
cyclopropane union may also prove to be of utility. Inves-
tigations along these lines are currently underway.
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council (NSERC), Canada Foundation
for Innovation (CFI), Ontario Research and Development
Challenge Fund (ORDCF), and Amgen for financial support.
Supporting Information Available: Experimental pro-
cedures and characterization data for all unknown com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL062476E
In summary, electroneutral cyclopropane rings can be
catalytically activated using PdCl2 to give heterocyclic
products. Interesting mechanistic trends have been uncovered,
pointing toward dependence of the cyclopropane activation
pathway on nearby substituents. Because of the wide
accessibility of electroneutral cyclopropanes, including a
range of chiral derivatives, one can anticipate benefits in
synthetic sequences that would rely on oxidative elaboration
of cyclopropanes. Just as palladium-olefin interactions have
served as a rich source of new reactions, the palladium-
(14) For nucleophilic attack on the central carbon of π-allyl palladium
complexes, see: (a) Hegedus, L. S.; Darlington, W. H.; Russell, C. E. J.
Org. Chem. 1980, 45, 5193. (b) Carfagna, C.; Galarini, R.; Musco, A. J.
Mol. Catal. 1992, 72, 19. (c) Hoffmann, H. M. R.; Otte, A. R.; Wilde, A.
Angew. Chem., Int. Ed. Engl. 1992, 31, 234. (d) Formica, M.; Musco, A.;
Pontellini, R. J. Mol. Catal. 1993, 84, 239. (e) Wilde, A.; Otte, A. R.;
Hoffmann, H. M. R. J. Chem. Soc., Chem. Commun. 1993, 615. (f) Castano,
A. M.; Aranyos, A.; Szabo´, K. J.; Ba¨ckvall, J.-E. Angew. Chem., Int. Ed.
Engl. 1995, 34, 2551. (g) Hoffmann, H. M. R.; Otte, A. R.; Wilde, A.;
Menzer, S.; Williams, D. J. Angew. Chem., Int. Ed. Engl. 1995, 34, 100.
(h) Aranyos, A.; Szabo´, K. J.; Castano, A. M.; Ba¨ckvall, J.-E. Organome-
tallics 1997, 16, 1058. (i) Organ, M. G.; Miller, M.; Konstantinou, Z. J.
Am. Chem. Soc. 1998, 120, 9283.
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