Pt-catalyzed pentannulations from in situ generated metallo-carbenoids utilizing propargylic esters

Article abstract of DOI:10.1021/ja053192c

A highly selective and efficient Pt-catalyzed pentannulation reaction beginning from propargylic esters is described. The key to this reaction is the use of a PtCl₂(PPh₃)₂/PhIO catalyst combination that allows the in situ

Full text of DOI:10.1021/ja053192c

Published on Web 08/19/2005
Pt-Catalyzed Pentannulations from In Situ Generated Metallo-Carbenoids
Utilizing Propargylic Esters
B. A. Bhanu Prasad, Francis K. Yoshimoto, and Richmond Sarpong*
Department of Chemistry, UniVersity of California, Berkeley, California 94720
Received May 16, 2005; E-mail: rsarpong@berkeley.edu
Scheme 1
Pentannulation of aromatic rings has emerged as an important
reaction in the arsenal of the synthetic organic chemist. Several
methods have been developed to achieve this transformation, most
notably, the Nazarov and Karpf-Drieding reactions, which form
1-indanones.1,2 These processes commonly employ either strong
protic or Lewis acids that eschew acid-labile functionality or require
prohibitively high temperatures. Alternatively, 2-indanones may be
prepared via C-H insertion from R-diazo ketone precursors, which
are not ideal substrates because of their acid-, photo-, and thermal-
lability.3 Due to these limitations, there remains a need for catalytic
Table 1. Optimization Studies
processes that effect pentannulations from readily available and
robust starting materials.4
We are interested in the synthesis of highly functionalized
indenes as intermediates in natural product synthesis and envisioned
a strategy that employs readily obtained propargylic esters for this
purpose (Scheme 1). The sequence would involve an initial,
potentially reversible metal-catalyzed 5-exo-dig cyclization of an
ester carbonyl (see 1) onto the alkyne to provide 2, followed by
C-O bond cleavage to afford the metallo-carbenoids 3a/b.5 At
this stage, preferential irreversible C-H insertion into the aryl
moiety of 3b would then yield 4.6
Over the past decade, increasing attention has been paid to the
activation of alkynes using transition metal complexes to generate
metallo-carbenoid intermediates.7,8 The reactivity of the resulting
metallo-carbenoid in the majority of these systems is found to be
heavily dependent on the identity of the metal. In this communica-
tion, we report the development of a pentannulation of propargylic
esters, which we believe proceeds via Pt-carbenoid intermediates.9
This methodology displays excellent generality and provides
efficient access to important substructures for complex molecule
synthesis.
Our studies began with propargylic acetate 5, easily prepared
from acetophenone in two steps (see Supporting Information). On
the basis of ample literature precedent6 for the generation of
metallo-carbenoids from alkynyl precursors, we examined the
reaction of several transition metal complexes with this substrate.
Various temperature (60-120 °C), solvent (1,2-dichloroethane,
MeCN, PhH, PhMe), and catalyst (IrCl(CO)(PPh3)2, RhCl(PPh3)3,
Pd(OAc)2, Rh2(OAc)4, Rh2(TFA)4, [RhCl(CO)2]2) combinations
resulted in either no discernible reaction, decomposition, or complex
mixtures of products, of which only trace amounts could be
attributed to 6,10 7a/b, and 8 (Table 1).
product ratio
entry
catalyst
additives
(6:7:8)b
1
2
3
4c
5
6
7
[RuCl2(CO)3]2
PtCl2
1:7:0
3:0:2
no reaction
>9:0:1
trace
4:0:1
>9:0:1
PtCl2(PPh3)2
PtCl2(PPh3)2
PtCl2(PPh3)2
PtCl2(PPh3)2
PtCl2(PPh3)2
air
p-benzoquinone
PhI(OAc)2
PhIO
a All reactions were run with 10 mol % catalyst loading and 20 mol %
additive. b Product ratios are based on integration of 1H NMR resonances.
c Reaction was allowed to cool to 23 °C every 3 h and analyzed by TLC,
which resulted in some exposure to air.
Pt metal center might modulate the reactivity of the catalyst and
perhaps improve selectivity. This notion led us to use commercially
available PtCl2(PPh3)2. Disappointingly, this catalyst led to a
complete recovery of starting material under the reaction conditions
(PhMe, 100 °C, 24 h, entry 3) when the reaction was left
undisturbed during this period. To our surprise, repeated exposure
of the reaction mixture to air (during TLC analysis) led to almost
exclusive formation of the desired indene product. On the basis of
a hypothesis that oxidation, presumably of the phosphine ligands
or metal, plays a key role in the generation of an active catalyst,
we studied the addition of several common oxidants (entries 5-7)
to the reaction mixture, from which iodosobenzene emerged as the
optimal reagent.13 As far as we know, this constitutes the first report
of the use of PtCl2(PPh3)2 to activate alkynes. As shown in Figure
1, the desired pentannulation products are easily obtained utilizing
our optimized reaction conditions (10 mol % of PtCl2(PPh3)2, 20
mol % of PhIO, 0.2 M in PhMe, 100 °C, 8 h). Methyl and ethyl
esters as well as acetate and benzoate propargylic esters readily
participate in this reaction. Substitution of other groups (e.g., alkyl,
phenyl, or silyl) for esters at the terminus of the alkyne did not
lead to productive reactivity, pointing to the necessity of an electron-
deficient alkyne for this transformation. Several substitution patterns
and aromatic and heteroaromatic nuclei are tolerated as substrates
and provide good yields of the desired products.
Interestingly, the use of [RuCl2(CO)3]2 as catalyst led to the
formation of 7a and 7b as major products (entry 1).11 It is important
to note that this catalyst, which was employed in a single, isolated
example of indene formation from a propargylic carboxylate by
Uemura et al.,9 proved to be unproductive for our desired
transformation. On the other hand, PtCl2 led to a significant increase
in the amount of the desired indene 6 along with diene 8 as the
major byproduct (entry 2).12 Despite this initial success, solvent,
temperature, and additive variations did not provide any noticeable
improvements. We reasoned that the introduction of ligands on the
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10.1021/ja053192c CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
of these transformations, unambiguously identify the catalytically
active species, and broaden the scope of these reactions are currently
ongoing and will be reported in due course.
Acknowledgment. The authors are grateful to UC Berkeley,
GlaxoSmithKline, and Eli Lilly for financial support, and Dr. H.
van Halbeek for extensive NMR assistance. We also thank the
Bartlett, Toste, Trauner, Bergman, Francis, and Ellman labs for
chemicals and pertinent discussions.
Supporting Information Available: Experimental details and
characterization data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
Figure 1. Pt-catalyzed cyclization of propargylic esters. For a full
description of reaction details, including the identity of propargylic ester
substrates, see Supporting Information. Products were obtained as a mixture
of olefin regioisomers (g17:3 ratio). In each case, the major product is
shown.
(1) For reviews, see: (a) Habermas, K. L.; Denmark, S. E.; Jones, K. L. Org.
React. 1994, 45, 1-158 (Nazarov). (b) Karpf, M.; Dreiding, A. S. HelV.
Chim. Acta 1979, 62, 852-865 (Karpf-Dreiding).
(2) For recent examples of 1-indanone synthesis, see: (a) Shintani, R.;
Okamoto, K.; Hayashi, T. J. Am. Chem. Soc. 2005, 127, 2872-2873. (b)
Yamabe, H.; Mizuno, A.; Kusama, H.; Iwasawa, N. J. Am. Chem. Soc.
2005, 127, 3248-3249.
We have also explored nonaromatic-based substrates; in one case,
a cyclopentadiene (18) is formed as the sole product from
propargylic acetate 17 in good yield (eq 1). In contrast, the related
substrate 19 yields 21b14 exclusively via a presumed allylic C-H
insertion, while 20 provides isomeric products 22a and 22b via
competitive formal allylic and vinylic insertion (eq 2).15
(3) For an example, see: Nakatani, K. Tetrahedron Lett. 1987, 28, 165-
166.
(4) For recent examples, see: (a) Nakamura, I.; Bajracharya, G. B.; Wu, H.;
Oishi, K.; Mizushima, Y.; Gridnev, I. D.; Yamamoto, Y. J. Am. Chem.
Soc. 2004, 126, 15423-15430.
(5) The C-O bond cleavage may not be a required step as the product may
be envisioned to arise directly from 2.
(6) Propargylic esters as substrates to access carbenes and metallo-carbenoids
have been previously proposed. See: (a) Frey, L. F.; Tillyer, R. D.; Ouellet,
S. G.; Reamer, R. A.; Grabowski, E. J. J.; Reider, P. J. J. Am. Chem. Soc.
2000, 122, 1215-1216. (b) Mamane, V.; Gress, T.; Krause, H.; Fu¨rstner,
A. J. Am. Chem. Soc. 2004, 126, 8654-8655. (c) Harrak, Y.; Bi-
aszykowski, C.; Benard, M.; Carlou, K.; Manetti, E.; Mourie´s, V.;
Dhimane, A.-L.; Fensterbank, L.; Malacria, M. J. Am. Chem. Soc. 2004,
126, 8656-8657.
(7) For a recent review, see: Nevado, C.; Echavarren, A. M. Synthesis 2005,
167-182.
(8) For seminal contributions, see: (a) Rautenstrauch, V. J. Org. Chem. 1984,
49, 950. (b) Mainetti, E.; Mourie´s, V.; Fensterbank, L.; Malacria, M.;
Marco-Contelles, J. Angew. Chem., Int. Ed. 2002, 41, 2132-2135.
(9) A single isolated example of indene synthesis from a propargylic
carboxylate via a Ru-carbenoid has been reported. See: Miki, K.; Ohe,
K.; Uemura, S. J. Org. Chem. 2003, 68, 8505-8513.
In a preliminary study to identify the active catalyst in these
reactions, we have undertaken a series of 31P NMR and preparative
experiments. NMR spectroscopic studies were performed in 1,2-
dichloroethane-d4 (1,2-DCE-d4),16 in which PtCl2(PPh3)2 was found
to be completely soluble. The starting complex displays an apparent
triplet centered at δ 15.7 (J ) 1836 Hz). Upon treatment with PhIO
at 100 °C, a signal that corresponds to OPPh3 (δ 28.4) as well as
other downfield signals (δ 37.9, 42.8, 43.9, and 72.2) was observed,
suggestive of further oxidation of the Pt-metal center. On the basis
of these findings, we were prompted to consider Pt(IV) catalysts
and additive combinations that might mirror our in situ generated
catalytic species.17 Thus, treatment of 5 with 10% PtCl4 as a catalyst
(0.2 M in PhMe, 100 °C, 5 h) results in a conversion to the desired
indene product 6 in 35% yield, along with several unidentified
byproducts. Interestingly, the addition of PPh3 (20 mol %)
completely inactivates the catalyst, resulting in no reaction.18 On
the other hand, introduction of 20 mol % of OPPh3 does not impart
any deleterious effects to the reaction and provides the desired
indene products in 42% isolated yield. These preliminary investiga-
tions suggest the possible intermediacy of a Pt(IV) species as the
active catalyst.19 Furthermore, our studies point to a clear advantage
in utilizing the moisture tolerant and robust PtCl2(PPh3)2 as a
precatalyst (compared to PtCl4) to effect a high-yielding conversion
of propargylic esters (e.g., 5) to highly functionalized pentannulated
compounds.
(10) Obtained as a 17:3 ratio of olefin isomers; major is shown. This mixture
was saponified to give the â-ketoester exclusively (see Supporting
Information).
(11) Optimization and mechanistic studies of this transformation are underway.
(12) For related precedent, see: Cariou, K.; Mainetti, E.; Fensterbank, L.;
Malacria, M. Tetrahedron 2004, 60, 9745-9755.
(13) Attempts to prepare a complex of PtCl2 and Ph3PO in situ in various
solvents did not lead to any improvements in yield as compared to PtCl2
alone. Other oxidants that were tried include NaIO4, I2, and NMO.
(14) A single diastereomer, established by nOe to be that shown (see Supporting
Information), was obtained.
(15) Recently, an elegant study describing the synthesis of nonaromatic
compounds related to eqs 1 and 2 was reported. See: Shi, X.; Gorin, D.
J.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 5802-5803. The insightful
mechanistic hypothesis put forth in this account cannot be ruled out for
the formation of 18, 21, or 22 and may also explain the formation of the
other pentannulated products. However, the formation of 21b (via 23 and
24), for example, would require a seemingly unlikely isomerization of
cyclopentadiene 21a to the diene 21b.
(16) Propargylic ester substrates are readily converted under our reaction
conditions in 1,2-DCE to the desired products, albeit in lower isolated
yields compared to reactions performed in PhMe.
(17) PtCl4 exhibits catalytic activity similar to that of PtCl2 and may even be
more efficient. See: (a) Fu¨rstner, A.; Stelzer, F.; Szillat, H. J. Am. Chem.
Soc. 2001, 123, 11863-11864. (b) Kobayashi, S.; Kakumoto, K.; Sugiura,
M. Org. Lett. 2002, 4, 1319-1322. (c) Pastine, S. J.; Youn, S. W.; Sames,
D. Org. Lett. 2003, 5, 1055-1058 and references therein.
(18) Presumably, PPh3 outcompetes the alkyne substrate for open coordination
sites on the metal center.
(19) The oxidation state of the active Pt species is still under investigation.
In conclusion, we have developed an efficient method for
pentannulation using in situ generated Pt-carbenoid intermediates
that arise from readily available propargylic esters. In addition, we
have demonstrated that PtCl2(PPh3)2 is a practical precatalyst to
effect these transformations. Further studies to probe the mechanism
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