Leveraging the Halo-Nazarov Cyclization for the Chemodivergent Assembly of Functionalized Haloindenes and Indanones

Article abstract of DOI:10.1021/jacs.9b00198

In this report, we describe a halo-Prins/aryl halo-Nazarov cyclization strategy that employs readily available starting materials, inexpensive reagents, and convenient reaction procedures to generate functionalized haloindenes and indanones. The scope and

Full text of DOI:10.1021/jacs.9b00198

Article
Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
pubs.acs.org/JACS
Leveraging the Halo-Nazarov Cyclization for the Chemodivergent
Assembly of Functionalized Haloindenes and Indanones
Connor Holt, Georgios Alachouzos, and Alison J. Frontier*
Department of Chemistry, University of Rochester, 414 Hutchison Hall, 100 Trustee Road, Rochester, New York 14627-0216,
United States
*
S Supporting Information
ABSTRACT: In this report, we describe a halo-Prins/aryl
halo-Nazarov cyclization strategy that employs readily available
starting materials, inexpensive reagents, and convenient
reaction procedures to generate functionalized haloindenes
and indanones. The scope and limitations of the method are
outlined, demonstrating that aromatic systems readily react
under mild, catalytic conditions when this strategy is
implemented. Furthermore, we present both experimental and computational data supporting the notion that cyclizations of
3-halopentadienyl cationic intermediates are more kinetically accessible, as well as more thermodynamically favorable, than
cyclizations of the analogous 3-oxypentadienyl cationic systems. The energetic advantage imparted by the halo-Nazarov
cyclization design was found to be especially valuable in the cyclizations of arylallyl cationic intermediates, which require
disruption of aromaticity.
INTRODUCTION
Scheme 1. Oxy-Nazarov and Halo-Nazarov Cyclization
Processes
■
The Nazarov cyclization of dienones has been the subject of
extensive research since its discovery in the middle of the last
1
century. Early research was driven by the desire to capitalize
upon the exquisite stereocontrol offered in this electro-
2
3
cyclization reaction. More recently, advances in catalysis,
4
the ability to launch into subsequent cationic cascades, and
the advent of enantioselective cyclization methods have vastly
5
expanded the synthetic utility of this reaction. However, the
cyclization of aryl enones (rather than dienones; Scheme 1, eq
3
) is not as well-developed or versatile, despite extensive
6
−8
studies on the topic.
Presumably, the difficulty can be
traced to the energetic cost required to disrupt aromaticity of
9
cationic intermediate C en route to cation C′. Cyclizations of
aryl enones to indanones are commonly accomplished under
10,11
9a,12
strongly Lewis acidic
or superacidic conditions
or by
using other catalyst systems capable of generating a high
13
energy dicationic intermediate. In many cases, an α chelating
group is also required to stabilize the cationic com-
1
0d,13a,b,14
15
plex
or to help bias the substrate toward cyclization.
Recently, we became disillusioned with dienones as Nazarov
cyclization precursors for a number of reasons. These reactants
tend to degrade upon prolonged storage, and their synthesis is
typically a multistep endeavor. In addition to the practical
shortcomings of working with these compounds, our
experimental studies led us to suspect that an oxygen
substituent at the 3-position of the cation (see A)
compromises reactivity as well. Seeking a replacement for
both dienones and 3-oxypentadienyl cationic intermediates like
A, we began to explore a “halo-Nazarov cyclization” manifold.
We reasoned that halopentadienyl cation B should be less
stable than oxypentadienyl cation A and, therefore, more
reactive as a cyclization intermediate (Scheme 1, eqs 1 and 2).
Computational modeling estimates that the barrier for
cyclization of a type B 3-halopentadienyl cation is ∼8 kcal/
mol lower than cyclization of a type A 3-oxypentadienyl cation
Received: January 11, 2019
©
XXXX American Chemical Society
A
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Journal of the American Chemical Society
vide infra), which is in agreement with our proposed
Article
(
profile. The activation barrier for cyclization of haloarylallyl
cation H is predicted to be approximately 10 kcal/mol lower
than the barrier for oxyarylallyl cation G, and the Nazarov
cyclization is about 15 kcal/mol more energetically favorable.
Remarkably, the calculations predict that the cyclization of J is
actually exothermic by 0.5 kcal/mol.
Accessing the Halo-Nazarov Precursor. Experimental
studies were also conducted to examine the cyclization
behavior of type H and J halo arylallyl cationic intermediates
and to expand the scope of our previously reported halo-Prins/
halo-Nazarov “carbonyl pinch” strategy. To that end, when
arenyne 1a is coupled with benzaldehyde (PhCHO) in the
presence of triflic acid (TfOH) and tetrabutylammonium
bromide (TBAB), 2b is furnished in 77% yield as the E isomer
(Scheme 3). The structure of 2b and incorporation of the
nucleophilic halide was determined unambiguously by X-ray
crystallographic analysis. Using tetrabutylammonium iodide
hypothesis.
Over the years, isolated examples of the halo-Nazarov
cyclization have been disclosed, although the transformation is
often described as an intramolecular Friedel−Crafts aryla-
1
6
tion. We have recently developed cationic cascades that
capitalize upon this halo-Nazarov cyclization to afford complex
17
halocyclopentenes (e.g., Scheme 1, eq 2), and prior to this
recent work, only five studies have focused on the generation
and cyclization of halo-pentadienyl cationic intermediates.
Interestingly, cyclopentenones, not halocyclopentenes, were
17a
18
isolated in all five cases.
These observations inspired us to explore a halo-Nazarov
strategy for the preparation of substituted haloindenes and
offered the tantalizing possibility that the same strategy could
be applied for the preparation of indanones. The studies
described herein demonstrate that intermediate D (Scheme 1,
eq 4) is an easily accessible, highly reactive intermediate that is
not only useful for the synthesis of haloindenes but can also
serve as a conduit to provide synthetic access to indanones at a
lower energetic cost (Scheme 1).
(
TBAI) as the halide source gives similar results; however,
using tetrabutylammonium chloride (TBAC) results in
incomplete conversion and decomposition despite extended
reaction times. Therefore, TBAB and TBAI were selected as
optimal nucleophilic halide sources for subsequent studies.
Arenynes 1b and 1c also react with benzaldehyde to form
five- and seven-membered rings, respectively, as a mixture of
E/Z isomers. The yields for 2d, 2e, and 2g range from 70 to
73%, similar to the yields observed for formation of six-
membered rings. Notably, use of TBAB results in incomplete
RESULTS AND DISCUSSION
■
Ab initio density functional theory (DFT) calculation studies
were conducted to examine the impact of the heteroatom
substituent at the 3-position on the electrocyclization step.
First, we calculated reaction barriers and thermodynamics for
the cyclization of the 3-oxypentadienyl cation E, 3-
bromopentadienyl cation F, and 3-iodopentadienyl cation I
Scheme 3. Alkynyl Halo-Prins Scope: Halide, Tether
19−22
using the M06-2x/Def2TZVP level of theory (Scheme 2).
Length, and Aryl Substitution
Scheme 2. DFT Results for the Nazarov Electrocyclization
of Oxy-, Bromo-, and Iodopentadienyl and Arylallyl
a
Cationic Intermediates at the M06-2x/Def2TZVP Level
a
All values presented are in kcal/mol.
The results predict that substituting bromine (F) for oxygen
(
E) would lead to an 8 kcal/mol reduction in activation
energy, and the Nazarov cyclization would be 12 kcal/mol
more energetically favorable. Substituting iodine (I) is even
more advantageous, providing a 9 kcal/mol reduction in
activation energy, while the Nazarov cyclization would be 13
kcal/mol more favorable. Performing the same calculations for
arylallyl cations G, H, and J results in a similar energetic
a
See the Supporting Information for a scheme showing the prepared
b
1
arenynes. Yield based on percent (%) conversion from crude H
NMR data. Reaction was approximately 50% complete after 24 h
c
d
(
see the SI). Reaction was warmed from 0 °C to ambient
temperature. E/Z refers to the ratio of double-bond isomers as
1
determined by H NMR analysis.
B
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conversion to 2f, while TBAI triggers efficient conversion to 2g
in good yield. In general, tether length does not impact
reaction rate or yield, and in the cases of 2d,e, there is no sign
chloroacetaldehyde dimethyl acetal in the presence of
FeBr3 results in a moderate yield of 2w after 21 h.
25
As expected, ketone substrates react more slowly toward
cyclization. However, cyclic and acyclic aliphatic ketones
participate in the reaction with moderate yields and reaction
times. Spirocyclic adducts 2x and 2y are isolated from
reactions using the dimethyl ketal of cyclohexanone, and
cyclization using phenylacetone as the carbonyl partner gives
23
of competing oxonia-Cope rearrangement.
Additional experiments were then conducted to examine
how the electronics of the aromatic partner influence this
cyclization. Subjecting benzofuran arenyne 1d to the reaction
conditions affords product 2h efficiently in 81% yield, and 2i
can be produced in 60% yield with a slightly longer reaction
time. The yield and reaction rate are excellent for both 2j and
2
z, which contains a tertiary stereogenic center. Notably,
neither acetophenone nor its α-methoxystyrene analogue react
under the optimized conditions, and mostly starting material is
recovered. Taken together, the results in Scheme 4 establish
aldehydes, acetals, ketones, and ketals as viable carbonyl
partners in the alkynyl halo-Prins reaction.
2
k with −OMe in the para position, presumably due to
enhanced nucleophilicity of the alkyne. A moderate yield is
observed for 2l; however, the yield of 2m is improved with use
of TBAI. Electron-deficient aromatic partners dramatically
increase the reaction time, but the yields of both 2n and 2o are
satisfactory.
Inducing the Halo-Nazarov Cyclization by Ionization.
With halo-Prins adducts in hand, we turned our attention to
the awaited aryl halo-Nazarov cyclization. We envisioned
inducing ionization of the cyclic ether moiety with an acidic
promotor in order to reveal the necessary 3-halosubstituted
arylallyl cation. After some optimization (vide infra), 20 mol %
For carbonyl partners, the substrate scope demonstrates that
both electron-deficient (2p) and electron-rich (2q−r)
aromatic aldehydes are tolerated (Scheme 4). These
conditions translate smoothly to branched, chained, and cyclic
aliphatic aldehydes (2s−v), although longer reaction times are
required to reach full conversion. While the E isomer is
observed exclusively in most cases, product 2s is formed in a
triflimide (Tf NH) in hexafluoroisopropanol (HFIP) solvent
2
was selected for exploring the substrate scope. Scheme 5
Scheme 5. Substrate Scope: Halo-Nazarov Cyclization to
Functionalized Haloindenes
2
0:1 mixture of E/Z isomers. Gratifyingly, acetals and ketals
also participate in the reaction, demonstrating that protected
aldehydes and ketones can be used directly in the alkynyl halo-
Prins cyclization. Benzaldehyde dimethyl acetal leads to 2b in
7
0% yield, and product 2u can be synthesized from
propionaldehyde or its diethyl acetal in 73% and 64% yield,
respectively. Unfortunately, only mixed acetal intermediates
are isolated in experiments in which the acetal bears an
electron-withdrawing group at the α position. Even after
24
extensive experimentation, these intermediates could not be
induced to cyclize. However, the reaction of 1a and
Scheme 4. Alkynyl Halo-Prins Scope of Carbonyl Coupling
Partners
a
b
Yield based on recovered Z isomer. Yield based on recovered E and
c
Z isomer. Reaction conducted in dichloromethane (DCM) at 0 °C
d
instead of HFIP solvent. Yield based on consumption of E isomer.
e
f
Reaction conducted in DCM at 0 °C with 20 mol % HFIP. A 3:1
a
b
Reaction conducted at 15 °C. Reaction conducted using FeBr in
mixture of regioisomers was observed (see the SI). d.r. refers to the
3
1
dichloromethane (DCM) at 0 °C. E/Z refers to the ratio of double-
bond isomers as determined by H NMR analysis.
diastereomeric ratio as determined by H NMR analysis. r.r. refers to
the regioisomeric ratio as determined by H NMR analysis.
1
1
C
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demonstrates that a variety of functionalized haloindenes are
expediently accessed in moderate to excellent yield from the
prepared halo-Prins products. In testing 2a−c under the
optimized reaction conditions, the highest yield of 82% is
observed with the bromine analogue 2b, although all three
ionization/cyclization events occurred within minutes to afford
Scheme 6. Examination of Different Aromatic Partners
4
a−c (Scheme 5). Ionization of substrates bearing only a two-
carbon tether proved more challenging with iodine at the 3-
position as formation of 4e is slow and inefficient. However,
the cyclization rate and yield of this system is greatly improved
with bromine (4d). The identity of the halogen had no
significant effect on formation of 4f or 4g. An increase in yield
is observed when the more electron-rich aromatic system of 2i
is cyclized to 4i, but only ketone 3a is isolated from cyclization
of 2h (vide infra). In some cases, regioisomers are observed by
1
H NMR analysis due to rotation of the aromatic ring prior to
26
a
b
the electrocyclization event. However, the para isomer is
always observed to be the major isomer (≥3:1) in comparison
to the ortho isomer (see 4s and 4s′).
Reaction warmed from 0 °C to ambient temperature. Reactions
were conducted with only bromine as the halogen. d.r. refers to the
diastereomeric ratio as determined by H NMR analysis at the newly
1
formed stereocenters of the indanone.
Haloindenes with a range of substituents at the stereogenic
center of the ring are also simple to prepare using this strategy
Furthermore, this observation is in line with our computational
predictions described in Scheme 2.
(
Scheme 5). The reaction is effective for substrates containing
both electron-rich and -poor aromatic substituents, although
the rate of cyclization is affected (compare reaction time for
formation of 4j vs 4k). Cyclization of halo-Prins products
containing alkyl substituents gives branched (4m), cyclic (4n),
and linear (4o,p) alkyl-substituted haloindenes with good
yields and reaction times. Unfortunately, no reaction occurs
when 2w is subjected to the reaction conditions and starting
material is recovered. Furthermore, attempts to ionize 2x in
HFIP produce complex mixtures, while using 20 mol % HFIP
in DCM with compound 2y results in very slow, but ultimately
clean, ionization and cyclization to Nazarov products 4s and
This two-step alkynyl halo-Prins/halo-Nazarov sequence was
also successfully carried out on a gram scale with no loss in
efficiency (Scheme 7), and the HFIP solvent can easily be
recovered by rotary evaporation to reuse in subsequent
27
reactions. Most notably, the catalyst loading can be reduced
from 20 to 5 mol % with no significant reduction in reaction
time. At a loading of only 5 mol % Tf NH, this large-scale halo-
2
Nazarov reaction is complete in only 8 min at 0 °C, and the
yield of 4b is 99% with no purification required after removal
of HFIP solvent.
4
s′ in good overall yield. Most promisingly, this method is also
Scheme 7. Gram-Scale Alkynyl Halo-Prins/Halo-Nazarov
Reaction Sequence
capable of the efficient generation of an all-carbon quaternary
stereocenter within the haloindene moiety as ionizing 2z under
the optimized conditions results in 4r in less than 10 min in
9
1% yield. Furthermore, while the halo-Nazarov cyclization is
successful for 3-substituted electron-rich aromatics, we were
also interested in the effects of different substitution patterns
and changes in the electronics of the aromatic partner (Scheme
6
).
When 2j (Scheme 3) is subjected to the optimized
conditions for haloindene formation, aryl enone 3b is the
major product observed in 65% yield. However, conducting
the halo-Nazarov with 2k results in the cyclized dihydropyran
(
2
DHP) adduct 3d as the major product with indanone 3c in
3% yield (vide infra). This observation suggests that the
choice of halogen is capable of altering selectivity for cyclized
products with less activated aromatics. This effect is also
observed for Prins products bearing an electron-neutral
aromatic partner. Attempts to cyclize 2l result in recovery of
starting material with only trace amounts of desired product by
crude H NMR analysis despite warming the reaction to
ambient temperature. When the halogen is switched to iodine
Reactivity of E and Z Halo-Prins Products toward
Electrocyclization. Exposure of halo-Prins product 2d (1.9:1
E/Z ratio, see Scheme 3) to the standard reaction conditions
revealed an unexpected difference in reactivity between the E
and Z isomers (Scheme 8). Compound 2d reacts to afford a
3.1:1 ratio of 4d and (Z)-2d after 10 min (78% combined
yield). However, when (Z)-2d is resubjected to the reaction
conditions, only trace amounts of 4d are observed, along with
aryl enone 3g (64% yield), after warming to ambient
temperature and stirring for 7 h.
1
as in 2m, haloindene 4u is efficiently formed in 84% yield after
1
5 min (Scheme 6). Both halo-Prins products containing
electron-deficient aromatic partners 2n and 2o result in
conversion to aryl enones 3e and 3f with no observable
cyclization products. In general, the reactivity of the halo
arylallyl cation can be modulated by choice of halogen in cases
where cyclization may involve less reactive aromatics.
The mechanism proposed for the halo-Prins/halo-Nazarov
synthetic sequence begins with condensation of the arenyne
alcohol and carbonyl partner, generating an oxocarbenium
D
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Scheme 8. Halo-Nazarov Cyclization of Prins Adduct 2d
the E/Z mixture of compound 2f to generate 4f in 94% yield
(
Scheme 5) suggests that the E/Z ratio is inconsequential in
this case as both isomers react to form a single product.
Accessing Indanones Directly from the Halo-Prins
Products. During the development of the protocol for
synthesis of haloindenes, we occasionally observed the
unexpected formation of indanone products. After some
experimentation, we found that halo-Prins adduct 2b can be
converted to either haloindene 4b or undergo cyclization/
hydrolysis to afford indanone 3h with judicious choice of
catalyst (Scheme 10). Treatment of 2b with 20 mol % TfOH
31
in wet HFIP yields 64% of 3h as an 11:1 mixture of
diastereomers. Thin-layer chromatographic (TLC) analysis
during the reaction indicates that 4b forms initially and
undergoes conversion to 3h as the reaction progresses.
1
E/Z refers to the ratio of double-bond isomers as determined by H
NMR analysis.
Replacing TfOH with Tf NH (20 mol %) in dried HFIP
solvent furnishes 4b, along with <10% of 3h judging by H
NMR analysis of the crude reaction mixture. When this
mixture is resubjected to the reaction conditions in wet HFIP
at room temperature, 4b is almost completely converted to
indanone 3h in 24 h (Scheme 10).
2
1
2
8
intermediate (Scheme 9). Intramolecular attack of the alkyne
onto the oxocarbenium electrophile occurs, and the
intermediate vinyl cation is captured by the nucleophilic
halide. For six-membered ring formation, only one alkene
diastereoisomer is observed. For five- and seven-membered
ring formation, addition of halide across the alkyne is less
stereoselective, and both E and Z diastereomers are observed.
Subsequent ionization of these E and Z isomers is presumed to
Scheme 10. Synthesis of Haloindene and Indanone from
Prins Product 2b
2
0b
generate cation U and cation S, respectively.
We
hypothesize that this ionization/cyclization sequence works
so well because the HFIP solvent both enhances the acidity of
the promoter and stabilizes the cationic intermediates that are
1
7,29
generated.
Scheme 9. Mechanistic Overview of the Halo-Prins and
Halo-Nazarov Reaction Sequence
a
b
Dried over 4 Å molecular sieves for at least 24 h. Reagent-grade
c
HFIP that was not dried over molecular sieves. Monitored by TLC.
No isolated yield obtained. d.r. refers to the diastereomeric ratio as
1
determined by H NMR analysis at the newly formed stereocenters of
the indanone.
We then set out to determine whether this protocol could
represent a general approach to indanone synthesis. When
selected halo-Prins adducts 2 are exposed to the hydrolytic
cyclization conditions, smooth ionization/cyclization/hydrol-
ysis occurs, delivering indanones 3i−k in 44−73% yield with
>
20:1 d.r. in all cases (Scheme 11).
These representative examples demonstrate that indanone
The geometry of the cationic intermediate U (generated
from the E isomer) places the cation in direct proximity to the
formation is facile with alkyl or aryl substituents as well as
different tether lengths. Interestingly, the hydrolytic cyclization
of 2z affords 3k in 44% yield along with 31% of DHP
byproduct that arises from cyclization/dehydration of 2z
(structure assigned by X-ray crystallographic analysis; see the
SI).
20b,30
aryl ring for electrocyclization.
This U configuration is
also apparent in the crystal structure of 2b. On the other hand,
the intermediate S (from ionization of the Z isomer) must
undergo isomerization to achieve productive orbital overlap for
electrocyclization to occur. In most of the halo-Prins reactions
reported in Schemes 3 and 4, the E isomer is the only one
isolated. In these cases, we imagine that the ionization
generates only the U cation, which cyclizes without
complication. However, in the case of 2d, ionization of the
E/Z mixture generates both U- and S-configured cationic
intermediates. The U cation cyclizes smoothly to produce 4d,
but the S cation suffers hydrolysis after extended reaction
times, with formation of aryl enone 3g. However, ionization of
Furthermore, 3a is the only major product observed upon
cyclization of 2h, even when the conditions optimal for
1
haloindene formation are employed (Scheme 5). H NMR
analysis of 3a also contains traces of its dihydropyran
derivative. Experiments are currently ongoing to elucidate
the factors controlling the distribution of products in these
cyclizations and how they relate to substrate structure.
To return to the computational data presented in Scheme 2,
it is important to point out that calculations performed by our
E
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Scheme 11. Synthesis of Indanones via Hydrolytic Halo-
Nazarov Cyclization of Selected Halo-Prins Adducts 2*
cyclization of type 2 substrates is more efficient and, most
importantly, occurs under milder conditions than the
cyclizations of aryl vinyl ketones such as 5. In fact, the mild
conditions and efficient nature of this halo-Nazarov cyclization
enables formation of functionalized haloindenes in a cationic,
one-pot cascade reaction (Scheme 13). While the overall rate
is slower, the efficiency of this one-pot sequence is greatly
improved compared to the two-step process (47% yield over
two steps vs 58% in one step for 4c) and demonstrates the
robust nature of the aryl halo-Nazarov reaction. Overall,
simple, prochiral building blocks are coupled together to
3
efficiently generate two C−C bonds, a stereogenic sp center,
and one C−X bond for further synthetic elaboration.
Scheme 13. One-Pot Cationic Cascade to Haloindene 4c
*
a
General conditions: TfOH (20 mol %), wet HFIP, 0 °C. Vinyl
iodide 2g used instead. Room temperature was required for hydrolysis
to be observed. The relative stereochemistry was determined by 1D-
NOE experiments (see the SI). Yield includes a small amount of
DHP that was observed by H NMR analysis (see the SI). d.r. refers
b
c
1
1
to the diastereomeric ratio as determined by H NMR analysis at the
newly formed stereocenters of the indanone. r.r. refers to the
1
regioisomeric ratio as determined by H NMR analysis.
group and others indicate that cyclizations of arylallyl cations
are thermodynamically disfavored, often endothermic by >15
12d
kcal/mol due to the loss of aromaticity.
It is therefore
remarkable that conversion of H to H′ is estimated to be
nearly thermoneutral, despite the requisite disruption of
aromaticity, and even more surprising that cyclization of J to
J′ is predicted to be exothermic. To assess the validity of this
CONCLUSIONS
■
In summary, experimental and computational studies were
carried out to evaluate the validity of our aryl halo-Nazarov
design concept. The results described indicate that 3-halo
cationic intermediates are more kinetically accessible, and their
electrocyclizations more thermodynamically favorable, than the
oxy-Nazarov analogues. Consequently, aromatic substrates are
readily engaged in electrocyclizations through this lower
energy pathway. Additionally, this “carbonyl pinch” strategy
facilitates construction of two C−C bonds and a C−X bond
from readily available precursors while generating function-
alized haloindenes in only two steps. Moreover, this protocol
enables the diastereoselective synthesis of indanones directly
from the halo-Prins products describedoffering a mild,
convenient alternative to the Nazarov cyclization of aryl
enones.
32
computational prediction, we elected to prepare aryl enone 5
in order to compare its cyclization behavior to the analogous
halo-Nazarov system (Scheme 12). When 5 is subjected to
TfOH, no reaction is observed after 16 h at 0 °C and only
starting material is recovered. In contrast, halo-Prins adduct
2
m ionizes and undergoes efficient hydrolytic halo-Nazarov
cyclization in only 45 min at 0 °C, yielding 72% of indanone 3l
with >20:1 d.r.
To our delight, these findings are consistent with the
computational predictions presented in Scheme 2, and these
results support our assertion that ionization and subsequent
Scheme 12. Experimental Comparison of Oxy-Nazarov and
Halo-Nazarov Cyclizations of Arylallyl Cations
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.9b00198.
■
*
S
X-ray data collection (PDF)
X-ray data for compound 2b (CIF)
X-ray data for compound 3k′ (CIF)
X-ray data for compound 4b (CIF)
Experimental details (PDF)
Spectra of obtained compounds (PDF)
a
AUTHOR INFORMATION
Corresponding Author
*E-mail: alison.frontier@rochester.edu.
Reaction conditions: TfOH (20 mol %), wet HFIP, 0 °C. d.r. refers
■
1
to the diastereomeric ratio as determined by H NMR analysis at the
newly formed stereocenters of the indanone.
F
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ORCID
examples of enantioselective cyclizations of aryl enones have been
reported.
Connor Holt: 0000-0002-0228-2254
Georgios Alachouzos: 0000-0002-3058-2246
Alison J. Frontier: 0000-0001-5560-7414
(6) On the other hand, several methods for cyclization of electron-
rich heteroaryl enones have been developed: (a) Malona, J. A.;
Colbourne, J. M.; Frontier, A. J. A General Method for the Catalytic
Nazarov Cyclization of Heteroaromatic Compounds. Org. Lett. 2006,
Notes
8
, 5661−5664. (b) Wu, Y.-K.; Niu, T.; West, F. G. Construction of α-
The authors declare no competing financial interest.
amido-indanones via formal allenamide hydroacylation-Nazarov
cyclization. Chem. Commun. 2012, 48, 9186−9188. (c) Takeda, T.;
Harada, S.; Nishida, A. Catalytic Asymmetric Nazarov Cyclization of
Heteroaryl Vinyl Ketones through a Crystallographically Defined
Chiral Dinuclear Nickel Complex. Org. Lett. 2015, 17, 5184−5187.
ACKNOWLEDGMENTS
■
1
We are grateful to the National Science Foundation (CHE-
565813) for funding this research. We thank Dr. William W.
(d) Wang, G.-P.; Chen, M.-Q.; Zhu, S.-F.; Zhou, Q.-L. Enantiose-
Brennessel for performing X-ray crystallographic analysis of 2b,
lective Nazarov cyclization of indole enones cooperatively catalyzed
3
k′, and 4b, and we thank Kevin Welle for performing high-
by Lewis acids and chiral Brønsted acids. Chem. Sci. 2017, 8, 7197−
resolution mass spectrometry of all newly reported com-
pounds. Finally, we thank Dr. Brendan Mort (CIRC,
University of Rochester) and Dr. Harry Stern (CIRC,
University of Rochester) for their advice regarding the setup
of an uplink for DFT calculations.
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