Noncanonical cation-π cyclizations of alkylidene β-ketoesters: Synthesis of spiro-fused and bridged bicyclic ring systems

Article abstract of DOI:10.1021/acs.orglett.9b00094

Three cation-π cyclization cascades initiated at alkylidene β-ketoesters bearing pendent alkenes are described. Depending upon the alkene substitution pattern and the reaction conditions employed, it is possible to achieve selective synthesis of the three different types of products, including 1-halo-3-carbomethoxycyclohexanes, spiro-fused tricyclic systems, and [4.3.1] bridged bicyclic ring systems. All three reactions begin with 6-endo addition of an olefin to the alkylidene β-ketoester electrophile, followed by one of three different cation capture events.

Full text of DOI:10.1021/acs.orglett.9b00094

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Noncanonical Cation−π Cyclizations of Alkylidene β‑Ketoesters:
Synthesis of Spiro-fused and Bridged Bicyclic Ring Systems
Dylan E. Parsons and Alison J. Frontier*
Department of Chemistry, University of Rochester, 414 Huchison Hall, 100 Trustee Road, Rochester, New York 14611, United
States
S
* Supporting Information
ABSTRACT: Three cation−π cyclization cascades initiated at alkylidene
β-ketoesters bearing pendent alkenes are described. Depending upon the
alkene substitution pattern and the reaction conditions employed, it is
possible to achieve selective synthesis of the three different types of
products, including 1-halo-3-carbomethoxycyclohexanes, spiro-fused
tricyclic systems, and [4.3.1] bridged bicyclic ring systems. All three
reactions begin with 6-endo addition of an olefin to the alkylidene β-
ketoester electrophile, followed by one of three different cation capture
events.
corresponding β-ketoester and aldehyde. Experimentation
ascade reactions represent a powerful class of organic
Ctransformations that allow for the rapid construction of began with the treatment of substrate 1a with Lewis acid
promoters, as presented in Table 1. Exposing 1a to 1.1 equiv of
AlCl3 promotes cyclization at ambient temperature, affording a
1.7:1 mixture of halide 2a and spirocycle 4a (Table 1, entry 1).
Iron halide salts also are effective in promoting the trans-
formation, furnishing either halide 2a or 2b as the major
product (entries 2 and 3). The reactivity of Lewis acidic metal
halides can be enhanced through the addition of silver
hexafluoroantimonate (AgSbF6), which is thought to generate
a more cationic metal center through halide abstraction.15
Under these conditions, the formation of halide 2a is
suppressed (entries 4, 6, 7). Other metal halides such as
gold(III) chloride and magnesium bromide also promote the
reaction, although yields are lower than those observed in the
analogous iron(III)-promoted cascades.
Cyclization attempts were also carried out in the catalytic
regime. When the catalyst is prepared from equimolar amounts
of FeCl3 and AgSbF6 (loading = 10 mol %), only enone 3 is
observed (entry 6). Using a 1:3 ratio of iron to silver (10 mol
%/30 mol %), enone 3 dominates unless the reaction
temperature is increased to 60 °C, in which case spirocycle
4a is obtained (entry 7). On the other hand, AlCl3 is inefficient
as a catalyst; the reactions stall and produce a mixture of halide
2a with trace amounts of 3 along with unreacted starting
material (entry 8).
complex chemical frameworks from linear, achiral systems.
Enzyme-controlled cationic cascades are responsible for the
assembly of complex terpenoids,1 and synthetic chemists have
developed efficient sequences of cation−π cyclizations inspired
by these natural processes.2 In the laboratory, these cascade
carbocyclizations are initiated upon acidic activation of an
alkene,3,4 epoxide,5 acetal,6 or other carbonyl derivative,7 with
subsequent propagation or termination via intramolecular
capture by a neighboring alkene or aromatic π-system.8
Classically, polyene cyclizations are linear processes proposed
to occur through “anti-parallel addition and chairlike folding”2c
of a highly ordered intermediate, to deliver fused ring systems
in a stereocontrolled manner (Scheme 1, eq 1).9,2b In this
manuscript, we describe two novel cation−π cyclization
cascades that initiate at an alkylidene β-ketoester group
located in the middle of a linear polyene system, enabling
diastereoselective assembly of bridged and spiro-fused carbon
skeletons (Scheme 1, eqs 2 and 3).10 A third cyclization
pathway that terminates with diastereoselective capture of a
halogen ion is also described.
While α,β-unsaturated carbonyl derivatives can initiate
cation-olefin cyclizations,2a only a handful of examples have
been reported. These systems, which initially undergo 5-exo
(see Scheme 2) or 6-endo cyclization (vide infra) in most cases,
do not progress into a typical cation−π cyclization cascade.11
Rather, the reactions generate cationic intermediates that are
susceptible to hydride shift pathways (e.g., Scheme 2),12
rearrangements of the carbon skeleton,13 or intramolecular
capture by the enolate moiety.14
These results suggested that it should be possible to obtain
either the secondary halides 2 or the spirocycles 4, with good
selectivity through application of appropriate reaction con-
ditions. To test this hypothesis, we first carried out a series of
experiments designed to produce secondary halide derivatives
2a−m (Scheme 3). Stoichiometric amounts of iron halide salts
Our study focuses on the cation−π cyclization pathways of
type 1 substrates (Table 1), which contain an unactivated
olefin tethered to an alkylidene β-ketoester electrophile. These
are easily prepared through Knoevenagel condensation of the
Received: January 8, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00094
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Cation−π Cyclization Cascades for Synthesis of
Linear-Fused, Spiro-Fused and [4.3.1] Bridged Systems
Scheme 3. Synthesis of Secondary Halides 2
Scheme 2. 5-exo Cation-Olefin Cyclization/Hydride Shift
Sequence with Enone Electrophile
a
Reaction conditions: FeX3 (1.1 equiv), DCE (0.05 M), 0 °C, 1 h.
The E/Z ratio of the alkylidene β-ketoester precursors can be found in
Table 1. Lewis Acid Screening for Tandem Conjugate
b
c
a
the Supporting Information. AlCl3 used instead of FeCl3. AlI3
Addition/Nazarov
instead of FeCl3, −78 °C instead of 0 °C; DCE = dichloroethane.
differ at the stereogenic center at the α-position of the β-
ketoester, leading to the tentative structural assignment shown.
We next evaluated the versatility of the spirocyclization
pathway. The initial screen had indicated that indanones 4 can
be obtained using either stoichiometric or catalytic amounts of
an FeCl3/AgSbF6 mixture (Table 1, entries 4 and 7). For this
study, we exposed both electron-neutral and electron-rich aryl
alkylidene β-ketoesters to FeCl3, in combination with AgSbF6
(1:1 ratio or 1:3 ratio), as shown in Scheme 5. For most
electron-releasing substrates, the reaction can be achieved in
the catalytic regime (20 mol % FeCl3/AgSbF6; 1:1 ratio;
formation of 4b−e). Under these conditions, electron-neutral
1a produces 4a in only 17% yield. However, application of 1
equiv of FeCl3/AgSbF6 (1:3) generated 4a in 42% yield.
Spirocyclic pyrrole 4f could be prepared using AlCl3 (1 equiv).
The results described thus far involve substrates bearing a
pendent monosubstituted olefin. Experiments with substrates 5
(Scheme 6), bearing a 1,1-disubstituted alkene, revealed a
different cationic cyclization pathway. After some experimen-
tation,17 we found that subjection of 5c to catalytic FeCl3/
AgSbF6 (1:3 ratio) triggered smooth conversion to the [4.3.1]
bridged tricyclic system 6c in 70% yield (Table 2, entry 1).
Indeed, it was possible to catalyze the tandem cationic
cyclization at room temperature using several different Lewis
acidic transition metal reagents, with best results obtained
using metal halide salts with AgSbF6 as an additive (Table 2,
entries 1−5).17 While cyclization with the Cu(II) complex
c
b
entry
acid (equiv)
additive (equiv)
product ratio (SM :2:3:4)
1
2
3
AlCl3 (1.1)
FeCl3 (1.1)
FeBr3 (1.1)
FeCl3 (1.1)
FeCl3 (0.1)
FeCl3 (0.1)
FeCl3 (0.1)
AlCl3 (0.1)
−
−
−
0:1.7:0:1
0:4:1:0
2b only
4 only
2:1:4:0
3 only
d
4
5
AgSbF6 (1.1)
−
AgSbF6 (0.1)
AgSbF6 (0.3)
−
e
6
7
f
0:0:1:5
7:1 trace:0
8
a
Reaction conditions: Lewis acid (equiv as indicated), DCE (0.05
b
M), 25 °C, 24 h, 1a (as 5:1 mixture of E/Z isomers). SM = Starting
c
d
1
Material (1a). Ratio determined via H NMR analysis. 2 h, 0 °C.
e
f
Decomposition was observed. 60 °C; DCE = dichloroethane.
trigger the desired transformation, with both electron-neutral
and electron-rich aromatic substrates able to participate (2a−
f). Oxygen containing heteroaromatics are also viable
substrates, providing the desired products 2h−l. Aluminum
trichloride proves to be an effective promoter for nitrogen-
containing heteroaromatic precursors, affording 2g and 2m.
Finally, magnesium iodide and aluminum iodide are competent
promoters for preparation of the secondary iodide 2k. In highly
polarized systems,16 the Nazarov cyclization pathway is
dominant, with no participation from the pendent olefin (see
2n, Scheme 3).
Scheme 4. Halide 2d: Nature of Diastereomeric Mixture
The stereochemistry of the cyclohexanyl halides 2 can be
partially deduced using X-ray crystallographic analysis, along
with experimental results that provide corroborating data. The
two diastereomers (1:1 ratio) of 2d can be separated by
column chromatography. When either diastereomer is
subjected to basic conditions (Et3N, DCM), the 1:1 mixture
is again obtained (Scheme 4). This suggests that the isomers
B
DOI: 10.1021/acs.orglett.9b00094
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 5. Synthesis of Spirocyclic Systems 4
Table 2. Optimization of Cationic Cyclization Forming
a
[4:3:1] Bridged Systems 6c
entry
acid (equiv)
additive (equiv) T (°C) t (h) yield (%)
1
2
3
FeCl3 (0.05)
CuCl2 (0.1)
CuCl2 (0.1)
AgSbF6 (0.15)
AgSbF6 (0.2)
AgSbF6 (0.2)
HFIP (2)
rt
60
rt
1
2
0.5
70%
69%
68%
4
5
6
InCl3 (0.1)
AlCl3 (0.1)
HNTf2 (0.5)
AgSbF6 (0.3)
AgSbF6 (0.3)
−
rt
rt
0
0.5
1
1
61%
62%
17%
a
a
Reaction conditions: FeCl3 (0.2 equiv), AgSbF6 (0.2 equiv), DCE
DCE = dichloromethane.
b
(0.05 M), 60 °C, 2−4 h. FeCl3 (1 equiv), AgSbF6 (3 equiv), DCE
c
(0.05 M), 25 °C, 3 h. AlCl3 (1.1 equiv), DCE (0.05 M), 60 °C, 3 h;
pattern on the alkene and on the aromatic ring (Scheme 6).
Electron-rich aromatic rings readily cyclize to furnish 6a and
6b. In general, heteroaromatic systems also participate in the
cyclization, affording 6c−6g. Different substitution patterns on
the alkene are also tolerated, leading to the assembly of bridged
systems 6c and 6h−6m, with installation of an all-carbon
quaternary center at the bridgehead position. Comparing 6h−
6j, it appears that increased steric bulk correlates with a
decreased yield, presumably due to congestion during the
Friedel−Crafts step. In substrates with longer tethers, the
initial cation−π cyclization occurs, but the Friedel−Crafts
trapping does not, and the cationic intermediate decomposes
to a complex mixture of inseparable products. Substrates with
shorter tether lengths do not cyclize at all.
DCE = dichloroethane.
Scheme 6. Scope of Formal [5 + 2] Cycloaddition
Reactions
a
The different cationic cyclization reaction outcomes
observed in the formation of halides 2, spirocyclic indanones
4, and bridged [4.3.1] systems 6 can be rationalized as outlined
in Scheme 7.
All three pathways begin with nucleophilic attack of the
terminal carbon of the olefin onto the distal carbon of the
alkylidene β-ketoester (6-endo cyclization), facilitated by the
Scheme 7. Mechanistic Hypothesis
a
Reaction conditions: CuCl2 (0.1 equiv), AgSbF6 (0.2 equiv), DCE
(0.05 M), 60 °C, 2 h; DCE = dichloroethane.
required elevated temperatures (entry 2), addition of 2 equiv
of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) induced efficient
cyclization at ambient temperature (entry 3).18 Inefficient
cyclization is observed in protic acid (entry 6).
The copper(II) chloride/silver hexafluoroantimonate com-
bination (Table 2, entry 2) was chosen for examination of the
substrate scope (Scheme 6). The cationic cyclization of
aromatic alkylidene β-ketoesters 5 show a reasonably broad
substrate scope, especially with respect to the substitution
C
DOI: 10.1021/acs.orglett.9b00094
Org. Lett. XXXX, XXX, XXX−XXX

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Lewis acid catalyst. This cyclization generates the cationic
species CC1, an intermediate common to all three reaction
pathways.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: Alison.frontier@rochester.edu.
ORCID
When a type 1 substrate is treated with stoichiometric
amounts of a metal(III) halide, CC1 is trapped by the halide
anion in a highly diastereoselective manner, generating type 2
products. Halide addition in related cation−π cyclizations is
proposed to occur through a concerted mechanism, installing
the halide trans to the new C−C bond.19 The enolate is then
protonated to give products 2 as a 1:1 mixture of
diastereomers, epimeric at the α-position of the β-ketoester.
The spirocyclic products 4 are produced when intermediate
CC1 undergoes two sequential [1,2]-Wagner−Meerwein
hydride shifts (cf. Scheme 2),12 eventually generating stabilized
tertiary carbocation CC2, which undergoes Nazarov cycliza-
tion to give spirocycles 4 (cf. Scheme 1, eq 2). Consistent with
this mechanistic proposal, aryl enone 3 can be isolated if the
reaction is stopped before the cascade is complete.
Furthermore, if 3 is resubjected to the reaction conditions, it
cyclizes.
[4.3.1] Bridged bicyclic products 6 are formed when
intermediate CC1 engages in an intramolecular Friedel−Crafts
alkylation. This occurs when CC1 is a tertiary carbocation, and
the [1,2]-hydride shift pathway is disfavored relative to the
direct capture of the stabilized cation with the electron-rich
aromatic ring.
With these results, we demonstrate that alkylidene β-
ketoesters bearing pendent olefins can engage in three distinct
reaction pathways, each of which can be accessed with
complete selectivity. In two cases, a novel cationic cascade
converts a simple aromatic precursor into an unusual, three-
dimensional carbocyclic scaffold containing an all-carbon
quaternary center (i.e., 4 and 6). In the synthesis of spirocycles
4, two new C−C bonds are formed at the same carbon of the
reactant (i.e., the β-position of alkylidene β-ketoesters 1). In
the assembly of [4.3.1] bridged bicyclic systems 6, two new
C−C bonds are formed diastereoselectively, in a formal [5 + 2]
cyclization process.20 These cyclizations represent expansions
to the canon of cation-olefin and polyene cyclizations,
producing irregular patterns of ring fusions rather than the
typical, linear-fused polycyclic systems.
Alison J. Frontier: 0000-0001-5560-7414
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Science Foundation (CHE-
1565813) for funding this research. We also thank William W.
Brennessel (University of Rochester) for X-ray crystallography
and Kevin Well (University of Rochester Medical Center) for
high-resolution mass-spectrometric analysis.
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ASSOCIATED CONTENT
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* Supporting Information
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