Diverse strategies toward indenol and fulvene derivatives: Rh-catalyzed C-H activation of aryl ketones followed by coupling with internal alkynes

Article abstract of DOI:10.1021/ja110650m

The synthesis of indenols and fulvenes was achieved through Rh-catalyzed C-H bond activation of simple and diverse aryl ketone derivatives and subsequent coupling with internal alkynes. The process was found to involve either an α or γ dehydration step, d

Full text of DOI:10.1021/ja110650m

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Diverse Strategies toward Indenol and Fulvene Derivatives:
Rh-Catalyzed C-H Activation of Aryl Ketones Followed by
Coupling with Internal Alkynes
Frederic W. Patureau, Tatiana Besset, Nadine Kuhl, and Frank Glorius*
Organisch-Chemisches Institut der Westf€alischen Wilhelms-Universit€at M€unster, Corrensstrasse 40, 48149 M€unster, Germany
S Supporting Information
b
and 2.1 equiv of Cu(OAc)2, PhCl, 120 °C, 16 h) led to coupl-
ing product indenol 1a in outstanding 99% isolated yield.8-10
ABSTRACT: The synthesis of indenols and fulvenes was
achieved through Rh-catalyzed C-H bond activation of
simple and diverse aryl ketone derivatives and subsequent
coupling with internal alkynes. The process was found to
involve either an R or γ dehydration step, depending on the
substrate disposition and representing diverse pathways
toward functionalized fulvenes.
Although in this case Cu(OAc)2 is not needed as a formal
oxidant (the transformation is redox neutral), its stoichiometric
presence was found essential for sufficient levels of reactivity.
Interestingly, using R1 = iPr under the same conditions did
not afford the R-dehydrated product that we had anticipated
(corresponding fulvene derivative) but rather indenol product
1b (66%), also when using harsher conditions (2.5 mol % Rh
precatalyst, 140 °C, 1,4-dioxane). Likewise, electron-withdraw-
ing phenones, even when bearing protons in potentially dehy-
drative positions, did not lead to the corresponding fulvene
derivatives but interestingly to the indenol products (1c-j) in
good to excellent yields. In contrast, electron-neutral and elec-
tron-rich phenones bearing protons in dehydrative positions
(R or γ) generally led to the corresponding fulvene derivatives, in
moderate to good yields (2a-h, 3a-f, 40-80% isolated yields).
In general, we found that the Hγ position dehydrates slightly
more easily than the HR position, allowing milder conditions and
providing higher yields. This is evident when comparing the
formation of 2a,b (= 3a,b) through the R- and the γ-route,
respectively (Scheme 1). Having established both routes provides
unique opportunities to regioselectively access fulvenes bearing
diverse functional groups. For example, fulvenes 2c-h are easily
accessible through the R-pathway but would involve serious
selectivity (and separation) issues through the γ-pathway, and
vice versa for 3c-f. In addition, our methodology tolerates halides
(1f,i,j, no debromination observed), strongly electron-withdrawing
groups (even phenones bearing two CF3 groups still afforded C-H
activation, 1d,h), strongly electron-donating groups (up to two
methoxy groups in 3c,d), andheterocyclic cores such as biologically
interesting indole derivatives (2c,d). Furthermore, the method is
highly regioselective when using unsymmetrical alkynes (1g,h,
3c-f).11 Even in the difficult case of an unsymmetrical 1,2-
diarylalkyne, the process still affords some regioselectivity (2g,h,
both regioisomers display an interesting axial chirality).12
ince their discovery by Thiele in 1900,1 fulvenes and their
S
derivatives have attracted much attention from generations of
scientists due to their unique properties in the fields of materials
science, organometallics and medicinal chemistry.2 They are
traditionally made by the condensation of cyclopentadienes onto
ketones, a method which is typically limited by the availability of
the cyclopentadienes, prepared from multistep procedures in
which regioselectivity and functional group tolerance are often
major difficulties (eq 1). Likewise, structurally related and
biologically relevant indenols also suffer from limited access, as
their preparation usually requires preactivation steps.3
In modern synthetic chemistry, C-C bond formation through
C-H activation reactions has gained importance because it
obviates the need for prior activation steps, a pivotal advantage
with respect to cost and waste reduction.4 The pioneering work
on the C-H activation of phenone derivatives,5 such as those
of Murai,5a Brookhart,5f Cheng,5j and others,5 and our recent work
on Rh-catalyzed C-H activation of acetophenones6 showed that
phenone substrates were suited for ortho C-H functionalization
reactions. Herein, we report diverse direct avenues into fulvene
and indenol synthesis through C-H activation/cyclization path-
ways (eqs 1, 2).
On the basis of previous reports by us and others,5-8 we
propose that the first step of the reaction is a cyclometalation,
followed by alkyne insertion and subsequent intramolecular
electrophilic attack of the carbonyl moiety (Scheme 2). Because
a catalytic amount of Cu(OAc)2 (typically 10 mol %) does not
suffice to provide more than a trace amount of product, it is likely
that one of the key roles of the Cu salt is to release the Rh catalyst
in a transmetalation event.13,14 Furthermore, intramolecular C-H
Engaging pivalophenone (R1 = tBu, Scheme 1), a privileged
C-H activation substrate,5b with 1,2-diphenylethyne7 under
optimized conditions (0.5 mol % [RhCp*Cl2]2, 2 mol % AgSbF6
Received: November 26, 2010
Published: January 25, 2011
r
2011 American Chemical Society
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Scheme 1. Rh C-H Activation of Phenones and Coupling
In conclusion, we have studied the Rh-catalyzed C-H activa-
tion of a representative set of phenone derivatives and their
subsequent coupling with internal alkynes and have developed a
suitable method for the comprehensive and selective preparation
of diversely functionalized indenol and fulvene derivatives. We
expect our method to be useful in the synthesis of 5-membered
carbocyclic ring-containing targets and perhaps in the inspiration
of novel and innovative transformations based on the C-H
activation of other phenone-like substrates.
with Internal Alkynes, Isolated Yieldsa
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental Section and
b
characterization details. This material is available free of charge
via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
glorius@uni-muenster.de
’ ACKNOWLEDGMENT
We thank the Alexander von Humboldt foundation (F.P.), the
Deutsche Forschungsgemeinschaft and the Alfried Krupp von
Bohlen und Halbach Foundation for generous financial support.
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a Reagents and conditions: (a) 1 mmol scale, 0.2 M for all entries. The
phenone/alkyne ratio varies from 1:1.2 to 1.2:1, depending on purifica-
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Scheme 2. Proposed Reaction Mechanism
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(9) See Experimental Section in the Supporting Information.
(10) Structurally reminiscent reactions using ketimines and Rh(I)
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(11) Combining R- and γ-strategies did not work out well under our
conditions:
(12) The chiral character of 2g and 2h was evidenced through chiral
HPLC measurements (ODH, hexane/iPrOH (99:1), 0.8 mL/min), see
ref 9.
(13) Replacement of the Cu salt with Mn(OAc)2 (no reaction) or
Cu(OTf)2 (decomposition) did not lead to the expected products.
(14) Furthermore, submitting already olefinated acetophenone 56 to
our optimized conditions led to neither the corresponding indenol 6 nor
to fulvene 7, leaving mostly unreacted starting material. This indicates
that 5 is not an intermediate of the reaction, thus excluding a Friedel-
Crafts-type electrophilic cyclization mechanism.
(15) Nevertheless, an indication that the electrophilic cyclization is a
critical step in the reaction can be deduced from the fact that 4-methoxy-
acetophenone and 4-methylacetophenone (poorly electrophilic
phenones) yield only 9% and 26%, respectively (2i,j), whereas analo-
gous 3-methylacetophenone yields 68% of the expected R dehydrated
product (2e,f).
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