Leaving group potential of a substituted cyclopentadienyl anion toward oxidative addition

Article abstract of DOI:10.1021/ol901598n

The facility with which a substituted cyclopentadienyl anion may function as a leaving group for palladium-catalyzed allylation reactions Is demonstrated. Reaction of several allylcyclopentadienyl substrates Is shown. Nucleophilic displacement of carbon w

Full text of DOI:10.1021/ol901598n

ORGANIC
LETTERS
2009
Vol. 11, No. 18
4108-4110
Leaving Group Potential of a
Substituted Cyclopentadienyl Anion
Toward Oxidative Addition
Ethan L. Fisher and Tristan H. Lambert*
Department of Chemistry, Columbia UniVersity, New York, New York 10027
tl2240@columbia.edu
Received July 13, 2009
ABSTRACT
The facility with which a substituted cyclopentadienyl anion may function as a leaving group for palladium-catalyzed allylation reactions is
demonstrated. Reaction of several allylcyclopentadienyl substrates is shown. Nucleophilic displacement of carbon with nitrogen is achieved
in the deallylation of allylpenta-p-acetylphenylcyclopentadiene with N-methylbenzylamine.
The ability of certain chemical species to function as leaving
groups (nucleofuges) is fundamental to all nucleophilic
substitution and elimination reactions (Figure 1).1 The
nucleofugal proficiency of a given species scales directly with
its capacity to accommodate two electrons from a hetero-
lytically cleaved bond. Because of this correlation, leaving
groups usually take the form of highly stabilized anions like
halides or sulfonates or neutral species such as water,
Figure 1. Leaving groups in organic chemistry.
alcohols, or amines. By the same token, carbon is not
commonly found to serve the role of leaving group,
especially for nucleophilic substitution reactions, due to the
general lack of C-C bond polarization and the normally high
instability of the resultant carbanions.2 In cases where a
carbon center does serve as a leaving group (e.g., retro-aldol,
haloform reaction), the nucleofugal electron pair is usually
stabilized via resonance or induction by more highly elec-
tronegative atoms. On the other hand, alternative carbon
moieties should be able to function as efficient leaving groups
provided their corresponding anions are rendered sufficiently
stable. Importantly, identification of a general carbon-based
leaving group scaffold could facilitate the invention of a
number of powerful new reaction methods involving nu-
cleophilic substitution or elimination mechanisms. Especially
intriguing is the fact that, in contrast to traditional leaving
groups such as the halides, carbon may be stereogenic,
leading to the possibility of inventing novel asymmetric
reactions using chiral nucleofugal carbon fragments. Moti-
vated by these possibilities, we have set as our goal the
identification of a versatile and efficient carbon leaving group
scaffold.
(1) Lepore, S. D.; Mondal, D. Tetrahedron 2007, 63, 5103.
(2) (a) Mencarelli, P.; Stegel, F. J. Org. Chem. 1985, 50, 5415. (b) Weiss,
R.; Huber, S. M.; Pu¨hlhofer, F. G. Eur. J. Org. Chem. 2005, 3530. (c)
Mattioli, M.; Mencarelli, P.; Stegel, F. J. Org. Chem. 1988, 53, 1087. (d)
Cardellicchio, C.; Fracchiolla, G.; Naso, F.; Tortorella, P.; Holody, W.;
Pietrusiewicz, K. M. Tetrahedron Lett. 1999, 40, 5773. (e) Cardellicchio,
C.; Iacuone, A.; Naso, F.; Tortorella, P. Tetrahedron Lett. 1996, 37, 6017.
(f) Bonesi, S. M.; Fagnoni, M.; Albini, A. Angew. Chem., Int. Ed. 2008,
47, 10022. (g) Garner, C. M.; Fisher, H. C. Tetrahedron Lett. 2006, 47,
7405.
In this regard, our attention has been drawn to cyclopen-
tadienyl (Cp) anions, which are readily available in achiral
10.1021/ol901598n CCC: $40.75
Published on Web 08/25/2009
 2009 American Chemical Society

Table 1. Optimization of Pd(0)-Catalyzed Nucleophilic
Displacement of a Cyclopentadienyl Aniona
entry
R
catalyst
mol %
time
24 h
15 min
40 min
90 min
24 h
% convn
Figure 2. Carbon as a leaving group.
1
2
3
4
5
Ph
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
--
20
20
10
5
<5
100
100
100
<5
p-AcPh
p-AcPh
p-AcPh
p-AcPh
and chiral forms3 and are highly tunable in regard to their
electronic properties.4 Importantly, the 6π-electron aromatic
character of Cp anions lends to them remarkably high
stability for carbanionic species. We were particularly
intrigued by the fact that ring substitution can further enhance
the stability of Cp anions to a remarkable extent,5 such that
the pKa values of their conjugate acids (cyclopentadienes)
are known as low as -11.6 The possibility of such
extraordinary carbanion stability led us to wonder whether
an appropriately substituted Cp fragment could serve as an
efficient leaving group for reaction processes such as
nucleophilic substitution (Figure 2).
--
a Conversion determined by 1H NMR using Bn2O as an internal standard.
loadings for this transformation could be decreased to 10 or
5 mol % without sacrificing yield and with reasonable scaling
of reaction time (entries 3 and 4). No reaction was observed
in the absence of palladium catalyst (entry 5).
The results shown in Table 1 demonstrate the capacity of
a cyclopentadienyl ring system to serve as a facile leaving
group for oxidative addition to an unstrained allylic
carbon-carbon bond. In comparison,12 it appears that the
Cp anion 2 is a more efficient leaving group than the
malonate anion8 and is comparable to a cyclic 1,3-
diketone.9a,c
To further examine this process, we have investigated the
transformations shown in Table 2.13 Thus allyl, methallyl,
and cinnamyl Cp substrates participate in the allyl transfer
reaction with good to high efficiency (entries 1-3). Interest-
ingly, the corresponding crotyl substrate was unreactive under
these conditions (entry 4). On the other hand, a crotonate
ester substrate was found to react efficiently and with no
complications arising from Michael addition (entry 5).
Cyclopentadienyl displacement with an alternative carbon
nucleophile in the form of an acetoacetic ester also proved
possible (entry 6). In accordance with the relative stabilities
of the corresponding Cp anions, allylpenta-p-acetylphenyl-
cyclopentadiene could be transformed to allylpentaphenyl-
cyclopentadiene with complete conversion and high isolated
yield (entry 7). Most interestingly, we found that a
carbon-carbonbondcouldbereplacedwithacarbon-nitrogen
bond with the use of N-benzylmethylamine as the nucleophile
and 50 mol % palladium catalyst (entry 8). The reaction in
this case appears to produce an equilibrium mixture of N-allyl
and C-allyl products.
As an initial investigation of this concept, we decided to
examine palladium-catalyzed allylation (Tsuji-Trost7 reac-
tion) using allylcyclopentadienes. Notably, the ability of
malonate8 and 1,3-diketone9 moieties to serve as leaving
groups for π-allyl palladium formation has been demon-
strated and thus provides a useful benchmark by which to
gauge the relative reactivity of Cp systems in this regard.10
In our initial experiments, we found that allylpentaphe-
nylcyclopentadiene 1 (R ) Ph) was unreactive to the sodium
salt of diethyl methylmalonate in the presence of 20 mol %
Pd(PPh3)4 in refluxing THF over prolonged periods of time
(Table 1, entry 1). On the other hand, allylpenta-p-acetylphe-
nylcyclopentadiene 1 (R ) p-AcPh)11 reacted quantitatively
under the same conditions in only 15 min to produce methyl
allyl malonate 3 along with the Cp anion 2 (entry 2). Catalyst
(3) For a review, see: Halterman, R. L. Chem. ReV. 1992, 92, 965.
(4) Rybinskaya, M. I.; Korneva, L. M. Russ. Chem. ReV. (Engl. Transl.)
1971, 40, 247.
(5) For example: (a) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
(b) Bordwell, F. G.; Drucker, G. E.; Fried, H. E. J. Org. Chem. 1981, 46,
632. (c) Laganis, E. D.; Lemal, D. M. J. Am. Chem. Soc. 1980, 102, 6633.
(6) (a) Webster, O. W. J. Am. Chem. Soc. 1966, 88, 3046. (b) Vianello,
R.; Maksic, Z. B. Tetrahedron 2005, 61, 9381.
(7) For recent reviews, see: (a) Lu, Z.; Ma, S. Angew Chem. Int. Ed.
2007, 47, 258. (b) Trost, B. M.; Lee, C. Catalytic Asymmetric Synthesis,
2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000; pp 593-649. (c)
Pfaltz, A.; Lautens, M. ComprehensiVe Asymmetric Catalysis; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Heidelberg, Germany, 1999;
pp 833-886.
As a demonstration of this point, we conducted the
following experiment. Thus, allylamine 7 was subjected to
penta-p-acetylphenylcyclopentadiene 6 in the presence of 50
mol % Pd(PPh3)4 and Cs2CO3 in refluxing THF (Figure 3).
(8) Nilsson, Y. I. M.; Andersson, P. G.; Ba¨ckvall, J.-E. J. Am. Chem.
Soc. 1993, 115, 6609.
(9) (a) Vicart, N.; Gore´, J.; Cazes, B. Tetrahedron 1998, 54, 11063. (b)
Bricout, H.; Carpentier, J.-F.; Mortreux, A. Tetrahedron Lett. 1997, 38,
1053. (c) Vicart, N.; Gore´, J.; Cazes, B. Synlett 1996, 850.
(10) Crabtree has reported the insertion of an iridium(I) complex to alkyl-
substituted cyclopentadienes. (a) Crabtree, R. H.; Dion, R. P. J. Chem. Soc.,
Chem. Commun. 1984, 1260 See also. (b) Crabtree, R. H. Chem. ReV. 1985,
85, 245.
(12) Ba¨ckvall reported that the equilibration of monoallylic malonates
required 24 h at 65 °C in THF (ref 8), while Cazes reported that conversion
of 2-allyl-2-methyl-1,3-cyclopentanedione to diethyl allylmalonate in the
presence of diethyl sodiomalonate and 5 mol % Pd(PPh3)4 in THF at 50 °C
required 2.5 h (refs 9a and 9c).
(11) For the synthesis of penta-p-acetylphenylcyclopentadiene: Lowack,
R. H.; Volhardt, K. P. C J. Organomet. Chem. 1994, 476, 25.
(13) No other allyl products were isolated which would account for the
loss of mass balance in these reactions.
Org. Lett., Vol. 11, No. 18, 2009
4109

Table 2. Optimization of Pd(0)-Catalyzed Nucleophilic
Displacement of a Cyclopentadienyl Aniona
Figure 3. Equilibration of the allyl amine substrate.
In conclusion, we have demonstrated that a suitably
substituted cyclopentadienyl moiety can function as a facile
leaving group for metal-catalyzed substitution reactions. We
believe that the broad electronic tunability and potential for
chirality of the Cp framework raise intriguing possibilities
for the development of a diverse menu of novel methodolo-
gies that rely on nucleofugal carbon expulsion. Currently,
we are examining the leaving group potential of the cyclo-
pentadienyl system in other contexts and exploring the
development of asymmetric methods that employ chiral
carbon leaving groups.
a Reactions were performed by adding a solution of the nucleophile
(1.5 equiv) and base (1.5 equiv) in THF to a solution of substrate (1 equiv)
and Pd(PPh3)4 (5 mol %) in THF (0.03 M final concentration) and heating
for the designated time. b 50 mol % Pd(PPh3)4 was used. c Yield determined
1
by H NMR with Bn2O as an internal standard.
Supporting Information Available: Experimental pro-
cedures and product characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
The result observed after 3 h was a 69:31 mixture of allyl
amine 7 and allyl Cp 1, a ratio identical to that observed
when 1 was treated with benzylmethylamine under the same
conditions (Table 2, entry 8). Presumably, the amine 7 is
sufficiently basic to deprotonate Cp 6 to generate ammonium
ion 8, which is then activated toward metal insertion.14
OL901598N
(14) Selected examples of palladium insertion to allyl amines: (a) Garro-
Helion, F.; Merzouk, A.; Guibe´, F. J. Org. Chem. 1993, 58, 6109. (b)
Murahashi, S.-I.; Imada, Y.; Nishimura, K. Tetrahedron 1994, 50, 453. (c)
Lemaire-Audoire, S.; Savignac, M.; Geneˆt, J. P. Tetrahedron Lett. 1995,
36, 1267.
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Org. Lett., Vol. 11, No. 18, 2009