Divergent reaction pathways of a cationic intermediate: Rearrangement and cyclization of 2-substituted furyl and benzofuryl enones catalyzed by iridium(III)

Article abstract of DOI:10.1021/ja111317q

In contrast to 2-substituted pyrrole enones, furyl and benzofuryl enones do not undergo the Nazarov electrocyclization. Instead, these furyl and benzofuryl enones exhibit unusual rearrangement sequences in the presence of catalytic amounts of [IrBr(CO)(DIM)((R)-(+)-BINAP)](SbF₆)₂ (1; DIM = diethylisopropylidene malonate) and AgSbF₆ (1:1). A 1,2-H shift followed by intramolecular Friedel-Crafts alkylation leads to synthetically valuable cyclohexanones with furanylic quaternary centers. The electrophilicity of 1 is essential for this rearrangement.

Full text of DOI:10.1021/ja111317q

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Divergent Reaction Pathways of a Cationic Intermediate:
Rearrangement and Cyclization of 2-Substituted Furyl and Benzofuryl
Enones Catalyzed by Iridium(III)
Tulaza Vaidya, Gerald F. Manbeck, Sylvia Chen, Alison J. Frontier,* and Richard Eisenberg*
Department of Chemistry, University of Rochester, Rochester, New York 14627, United States
S Supporting Information
b
Table 1. Cyclization with 2-Substituted Pyrrole and Furyl
Enonesa
ABSTRACT: In contrast to 2-substituted pyrrole enones,
furyl and benzofuryl enones do not undergo the Nazarov
electrocyclization. Instead, these furyl and benzofuryl en-
ones exhibit unusual rearrangement sequences in the pre-
sence of catalytic amounts of [IrBr(CO)(DIM)((R)-(þ)-
BINAP)](SbF6)2 (1; DIM = diethylisopropylidene mal-
onate) and AgSbF6 (1:1). A 1,2-H shift followed by
intramolecular Friedel-Crafts alkylation leads to syntheti-
cally valuable cyclohexanones with furanylic quaternary
centers. The electrophilicity of 1 is essential for this
rearrangement.
entry
X
R
catalysta
product (% yield)
1
2
3
4
NH
NH
O
cyclobutyl
cyclobutyl
iPr
Sc(OTf)3/LiClO4
1/AgSbF6
I (61%)b
I (71%)b
II (69%)
II (<10%)
1/AgSbF6
O
iPr
Sc(OTf)3/LiClO4
a Reaction conditions: Sc(OTf)3 (10 mol %)/LiClO4 (1 equiv) or 1 (10
mol %)/AgSbF6 (10 mol %), 80 °C, DCE or CD3NO2. b See ref 3q.
he Nazarov cyclization1 of polarized divinyl or aryl vinyl
T
ketones2 to form densely functionalized cyclopentenones
has been achieved with a number of catalysts.2,3 The reaction
proceeds via the formation of a pentadienyl cation intermediate
that undergoes electrocyclization. Complex 1, which is activated
by bromide abstraction using AgSbF6 to generate a tricationic d6
iridium species, is able to effect cyclization in some of the most
unreactive molecules.3q The Nazarov cyclization of heteroaro-
matic enones of type A has been previously achieved using
catalytic Sc(OTf)3 and a stoichiometric amount of LiClO4.3d
The reaction is efficient for indole and pyrrole (e.g., Table 1,
entry 1), but the analogous furyl and benzofuryl enones do not
undergo similar cyclizations.3d The difficulty associated with
these cyclizations prompted us to examine the effect of tricationic
1/AgSbF6 on potential furan and benzofuran substrates of type
A. The study described in this communication reveals that furans
and benzofurans of type A follow a fundamentally different
reaction pathway than pyrroles, indoles, and thiophenes of type
A when subjected to iridium(III) catalyst 1.
π-electron Nazarov electrocyclization.3d,3p,3q Instead, cyclohex-
anone II, which contains a new quaternary carbon at the furanylic
position, was the only product observed (>99% conversion as
1
determined by H NMR spectroscopy). In comparison, the
reaction of 2 with Sc(OTf)3/LiClO4 gave a complex mixture
of products, and cyclohexanone II was present only in small
amounts (entry 4).
The unusual and selective reaction sequence observed when
furanyl enone 2 was exposed to Ir(III) complex 1 encouraged us
to investigate this transformation further. The scope of the
cyclization was explored with a variety of 2-substituted furyl
and benzofuryl enones (Table 2). The enone substrates were
prepared in excellent yields using either oxidoalkylidenation of
alkynes4 or Knoevenagel condensation.3d,5
Reactions could be run at 80 °C but were most efficient at
100 °C. Furyl enone 2 furnished 3 at 100 °C in 8 h (Table 2, entry
1). Benzofuranyl enone 4 (R = iPr) rearranged to 5 within 2 h
with an excellent yield of 92% (entry 2). A methyl substituent at
the 5-position of the furan ring in 6 (R = iPr) had a parallel effect
on the reaction time (entry 3). An extension of the reaction scope
to cyclic precursors 8, 10, 12, and 14 resulted in the formation of
[5,5]- and [5,6]-spirocyclic scaffolds 9, 11, 13, and 15 in high
yields (70-83%; entries 4-7).
While enones with cyclohexyl and cyclopentyl side chains
formed spirocyclic cyclohexanones, cyclobutyl substrates 16 and
i
When 2 (R = Pr; Table 1, entry 3) was treated with 1 and
Received: December 15, 2010
Published: February 15, 2011
AgSbF6, a cyclization occurred, but it was not the expected four-
r
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Table 2. Cyclization with 2-Substituted Furyl and Benzofuryl
Enonesa
Table 3. Cyclization Followed by Decarboxylationa
a Reaction conditions: (i) Cyclization: 100 °C, 1 (10 mol %), AgSbF6
(10 mol %), CD3NO2 (0.1 M), minimum light. (ii) Decarboxylation:
DABCO (0.5 equiv), toluene (0.1 M), H2O (0.1 equiv), reflux.
b Cyclization time for >99% conversion as determined using 1H NMR
spectroscopy. c Isolated yields over two steps. d Cyclization required 20
mol % 1 and 20 mol % AgSbF6.
18 rearranged to form tetrasubstituted double bonds in 17 and
19 without further reaction even at elevated temperatures
(entries 8 and 9). In contrast, the 2-substituted pyrrole enone
with R = cyclobutyl undergoes simple Nazarov cyclization
(Table 1, entry 2).3q Cyclopropyl and n-propyl variants (20
and 21) did not show the same reactivity (entries 10 and 11).
Benzofuryl dienone 22 underwent an unexpected six-π-elec-
tron ring closure to provide cycloheptenone 23 (entry 12). This
is particularly interesting when viewed in the context of previous
studies exploring the reactivity of vinyl dienyl ketones, in which
Nazarov-type four-π-electron electrocyclization has been the
only reaction observed.2a,3q Cyclization of the analogous furyl
substrate 24 was not observed (entry 13).
A subsequent endeavor to cyclize furyl or benzofuryl enones
with more elaborate side chains led to the isolation of cyclohex-
anones with new quaternary stereocenters (Table 3). Enones 25
and 27 generated their respective furyl and benzofuryl cyclohex-
anones in a diastereomeric ratio of 1:1. Quantitative decarbox-
ylation of the product mixture using 1,4-diazabicyclo[2.2.2]-
octane (DABCO) afforded 26 and 28, respectively (entries 1
and 2). Enones 29 and 31 with phenyl-containing side chains
furnished hydride migration products 30 and 32 (entries 3 and
4). Enone 33 (R = tBu) underwent a 1,2-methyl shift to afford 34
upon decarboxylation (entry 5).
A mechanistic rationale for this Ir(III)-catalyzed rearrange-
ment is outlined in Scheme 1. The catalysis is initiated with the
displacement of the malonate from 1 and bidentate coordination
of B to form pentadienyl cation C.3b A 1,2-hydride shift from the
pendant side chain occurs, generating tertiary carbocation D.
The formation of D induces an intramolecular Friedel-Crafts
alkylation6 at the 3-position of the furyl ring, leading to oxyallyl
cation E. Subsequent elimination provides enolate F, and pro-
tonation forms the metal-bound species G. A product-substrate
a Reaction conditions: 100 °C, 1 (10 mol %), AgSbF6 (10 mol %),
CD3NO2 (0.1 M), minimum light. b Reactions were monitored using 1H
NMR spectroscopy until >99% conversion was achieved. c Isolated yields.
d Cyclization was performed at 80 °C. e Decomposition of substrate.
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Scheme 1. Divergent Reaction Pathways of the Pentadienyl
Cation Intermediate with Iridium(III)
Scheme 2. Cyclization of a Deuterated Variant of 2
branched alkyl chains are known to experience a 1,2-hydride shift
upon treatment with protic acid and generate carbocation-
trapped products.7
In conclusion, we have reported a novel rearrangement
sequence involving a 1,2-H shift and a Friedel-Crafts alkylation
sequence of 2-substituted furyl and benzofuryl enones using the
electrophilic Ir(III) complex 1. Pentadienyl cation intermediate
C generated from heteroaryl vinyl ketones (Scheme 1) suffers a
hydride shift rather than undergoing Nazarov electrocyclization.
We are aware of only one transformation related to this one: a
1,2-H shift/Friedel-Crafts alkylation of indoles.8 The sequence
represents an efficient method for the preparation of furan- and
benzofuran-fused cyclohexanone ring systems with quaternary
centers, which are motifs found in various bioactive molecules.9
Detailed studies of the mechanism and efforts directed toward
achieving asymmetric Ir(III) catalysis are ongoing and will be
reported in due course.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental details, prepara-
b
tion and characterization of new compounds, and data from DFT
calculations. This material is available free of charge via the
Internet at http://pubs.acs.org.
exchange step through η1-coordinated Ir(III) species H3b fur-
nishes furyl- or benzofuryl-fused cyclohexanone J.
Density functional theory (DFT) calculations [B3LYP with
the 6-31G(d) basis set for C, H, O, N, and P and the LANL2DZ
basis set for Ir] were performed on coordinated 2 as C or D. The
energy of D was found to be 1.11 kcal/mol lower than that of C;
this supports the mechanism, which invokes carbocation stability
as a driving force for the hydride shift. Conversely, the tertiary
carbocation of the pyrrole analogue is 1.72 kcal/mol higher in
energy than the cyclopentadienyl carbocation, and only the
Nazarov product is obtained. The gap between the highest
occupied orbital with significant electron density on the furan
3-position and the lowest unoccupied orbital with contributions
from the cationic carbon is 5.17 eV (HOMO-3 to LUMOþ1) for
C and 2.65 eV (HOMO to LUMOþ1) for D (see the Supporting
Information).
’ AUTHOR INFORMATION
Corresponding Author
frontier@chem.rochester.edu; eisenberg@chem.rochester.edu
’ ACKNOWLEDGMENT
We thank the National Science Foundation (Grants CHE-
0556225 and CHE-0849892) for funding this work. T.V. thanks
the University of Rochester for the Elon Huntington Hooker
Fellowship. We are grateful to Prof. Joseph Dinnocenzo, Dr. Jie
Huang, Dr. John Malona, and Dr. Abdallah Bitar for valuable
discussions and Dr. Alice Bergmann (SUNY Buffalo) for high-
resolution mass spectrometry.
Other experiments conducted during the study were consis-
tent with the proposed carbocationic mechanism. Benzofuran or
furan 21 has an unbranched alkyl chain that provides no
opportunity for the formation of a tertiary carbocation, and no
cyclization was observed (Table 2, entry 11). In comparison, 33
with a branched alkyl chain underwent a 1,2-methyl shift to form
a tertiary carbocation and subsequent cyclization product 34
(Table 3, entry 5). Similarly, compounds 16 and 18 underwent
an alkyl shift with ring expansion, consistent with an intermediate
carbocation similar to D, although the subsequent cyclization was
not observed (Table 2, entries 8 and 9). To further probe the
viability of the proposed 1,2-H migration, cyclization with a
deuterated variant of 2 (2-d1) was examined (Scheme 2). A 1,2-
deuteride shift from the isopropyl chain of 2-d1 to form 3-d1 was
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