Cooperative benzylic-oxyallylic stabilized cations: regioselective construction of α-quaternary centers in ketone-derived compounds

Article abstract of DOI:10.1039/c5sc01914a

We describe a novel reactivity of benzylic-stabilized oxyallyl cations towards regioselective construction of carbon quaternary centers. These synthetically useful intermediates were readily generated upon ionization of aryl substituted α-hydroxy methylenol ethers with catalytic, mild Bronsted acid. The emerging unsymmetrical oxyallyl cations were then directly captured by indoles and other nucleophiles with exquisite control of regioselectivity, predictably at the electrophilic carbon bearing the alkyl substituent to produce highly functionalized, value-added enol ethers.

Full text of DOI:10.1039/c5sc01914a

View Article Online
View Journal
Chemical
Science
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: N. S. Dange, J. R.
Stepherson, C. E. Ayala, F. R. Fronczek and R. Kartika, Chem. Sci., 2015, DOI: 10.1039/C5SC01914A.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/chemicalscience

Please do not adjust margins
Chemical Science
Page 1 of 7
View Article Online
DOI: 10.1039/C5SC01914A
Chemical Science
ARTICLE
Cooperative Benzylic-Oxyallylic Stabilized Cations: Regioselective
Construction of α-Quaternary Centers in Ketone-Derived
Compounds†
Received 00th January 20xx,
Accepted 00th January 20xx
Nitin S. Dange, Jacob R. Stepherson,‡ Caitlan E. Ayala,‡ Frank R. Fronczek,§ and Rendy Kartikaa
DOI: 10.1039/x0xx00000x
We describe a novel reactivity of benzylic-stabilized oxyallyl cations towards regioselective construction of carbon
quaternary centers. These synthetically useful intermediates were readily generated upon ionization of aryl substituted α-
hydroxy methylenol ethers with catalytic, mild Brønsted acid. The emerging unsymmetrical oxyallyl cations were then
directly captured by indoles and other nucleophiles with exquisite control of regioselectivity, predictably at the
electrophilic carbon bearing the alkyl substituent to produce highly functionalized, value-added enol ethers.
www.rsc.org/
Introduction
Scheme 1. Direct Nucleophilic Addition to Oxyallyl Cation
Oxyallyl cation is a reactive intermediate with profound
roles in many synthetic applications. It exhibits unique
reactivity due to the distribution of its electrophilic character
over three carbon atoms. For example, this species is
universally regarded as the participating intermediate in the
Nazarov cyclization,1 involving electrocylic ring closure of
divinyl ketone (Scheme 1), which could be intercepted via
2
facile processes, such as [4+3] cycloaddition1b, and [3+2]
cycloaddition,3 to expediently generate a variety of complex
molecular architectures. Recently, studies on the generation
of oxyallyl cations via acid or base-induced departure of a
leaving group at the α-carbon of ketone-derived compounds,
followed by immediate nucleophilic capture began to emerge
in the literature.4 These new bond-forming processes
successfully introduced various
α-functionalities that
otherwise would not have been feasible using classical
strategies. While these seminal reports largely employed
symmetrical systems, the use of unsymmetrical oxyallyl cations
2
appeared to be rather problematic, as addition of
nucleophiles to this intermediate had been shown to occur
competitively at both and ’ positions, producing a mixture
α
α
of regioisomers. Our group recently contributed a solution to
this fundamental problem.5 We discovered that simple
protection of oxyallyl cation
2
to the corresponding O-TBS
enabled a highly regioselective addition of indoles to
’-disubstituted silylenol ethers
variant
furnish
6
Driven by our interests in developing de novo synthesis of
quaternary carbon centers, our unique tactic in controlling
regioselectivity under exceedingly mild conditions encouraged
us to investigate a direct nucleophilic addition to much more
α
,
α
7.
complex unsymmetrical α,α’-disubstituted oxyallyl cations, viz.
9. In fact, the success of this novel chemistry would introduce
a powerful paradigm in the regioselective construction of an
α
-quaternary carbon center in ketone-derived compounds,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Chemical Science
Page 2 of 7
View Article Online
DOI: 10.1039/C5SC01914A
ARTICLE
Journal Name
which remain
a
significant synthetic challenge.6
While intermediate 15 by its electron-withdrawing character. To test
formation of quaternary centers via nucleophilic trapping of this hypothesis, we subjected methylenol ether analogue 12b
α,α’-disubstituted oxyallyl cations generated via Nazarov to identical conditions, and activation of this electron rich
cyclization are precedented,7 there are only a very few substrate was indeed complete in just one hour. Surprisingly,
examples on the use of unsymmetrical oxyallyl cations that the corresponding methylenol ether adducts were produced in
proceeded in
followed the assumption that ionization of disubstituted
hydroxy enol ether promoted by Brønsted acid in a non-polar selective.
medium should generate oxyallyl cation . Assuming that the
substituents in the and ’ positions are electronically
a
regioselective fashion.
Our hypothesis an essentially 1:1 mixture of regioisomers, indicating that
α-
addition of indole to the presumed oxyallyl cation 16 was not
8
9
α
α
dissimilar, we proposed that the ensuing nucleophilic addition Table 1. Screening Studies
to this reactive intermediate should proceed with a distinct
regioselective preference.
Results and Discussion
We commenced our investigation by rapidly assembling
model substrates 12a-12d in a divergent manner from 3-
methyl-cyclopentane-1,2-dione (Scheme 2). This commercially
available compound was subjected to an initial treatment with
TBSCl and imidazole to give silylenol ether 11a, or methyl
iodide and potassium carbonate to yield the methoxy variant
11b
. The residual ketone functionality in these adducts was
then either reduced with DIBAL to generate secondary alcohol
12a and 12b, or reacted with phenylmagnesium chloride to
afford tertiary alcohol substrates 12c and 12d
.
Scheme 2. Synthesis of Starting Materials 12a-12d
[a] Reaction concentration was based on starting material 12
[b] Isolated yield of products 13 or 14 after flash
chromatography. [c] The ratio of regioisomers was
determined by 1H NMR of the crude reaction mixture. [d]
Combined yield for both regioisomers as they were not
separable by flash chromatography. [e] The corresponding
ketones were isolated upon aqueous workup. [f] Starting
material 12d was never fully consumed.
.
OTBS
Me
HO
DIBAL
77%[a]
H
OTBS
Me
TBSCl,
imidazole
12a
O
OTBS
Me
11a
HO
PhMgCl
37%[a]
Ph
O
12d
OMe
O
Me
HO
H
DIBAL
76%[a]
Me
Me
Despite the complete loss of regioselectivity, we were
enthused to observe a possible formation of quaternary center
14. We subsequently incorporated an aromatic ring in the R2
OMe
MeI
K2CO3
12b
OMe
O
Me
11b
HO
PhMgCl
65%[a]
position via starting material 12c, believing that the α-phenyl
and ’-methyl substituents would provide sufficient electronic
Ph
α
12c
bias to differentiate the two electrophilic centers in
unsymmetrical oxyallyl cation 18 towards nucleophilic attack.
Indeed, exposure of substrate 12c to the activation conditions
afforded quaternary center 14 in 86% yield, remarkably as a
single regioisomer, where indole addition occurred exclusively
[a] Isolated yield over two steps after flash chromatography
With the availability of these crucial starting materials, we
then proceeded towards screening studies. As depicted in
Table 1, entries 1 and 2, we began by deliberately increasing
the catalyst loading to 50 mol% and the reaction concentration
to 0.2 M from the previously established conditions to
accelerate the reaction.5 We suspected that the TBS enol
ether moiety impeded the rate of reaction, perhaps through
destabilization of the emerging silyloxyallyl cation
at the α’-position (entry 4). Gratifyingly, reducing the catalyst
loading back to 10 mol% essentially furnished the same
product with an identical isolation yield and regioselectivity,
albeit with a slightly longer but manageable reaction time
(entry 5).
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Chemical Science
Page 3 of 7
View Article Online
DOI: 10.1039/C5SC01914A
Journal Name
ARTICLE
As indicated in entry 6, activation of starting material 12c Table 2. Scope of Indoles[a]
with 10 mol% pyridium tosylate produced the corresponding
indole adduct 14 in an essentially identical yield from that
obtained using catalytic pyridinium triflate. This result
suggested that the counter anion perhaps merely served as a
spectator in this methodology. Nevertheless, the quality of
our reaction appeared to be directly dependent on the acidity
of the catalysts. For instance, the use of stronger Brønsted
acids,8 such as CSA (entry 7) and triflic acid (entry 8) led to
significant decomposition of materials, thus leading to much
lower isolation yields of the target product. These studies also
demonstrated that free pyridine, liberated from pyridinium ion
catalyst upon ionization, did not play a role in controlling
regioselectivity,5 as addition of indole to starting material 12c
,
catalyzed by either CSA or triflic acid, also produced the
corresponding quaternary center 14 as a single regioisomer.
To further signify the role of O-methyl group in accelerating
the rate of reaction, we then exposed TBS enol ether variant
12d to the optimal reaction conditions. This compound, which
presumably proceeded to generate electron deficient
silyloxyallyl cation 17, severely lacked reactivity and in fact
failed to reach completion even after 110 hours of reaction
time (entry 9).
With these preliminary results in hand, our investigation
continued with a scope of indoles towards
of methylenol ether 19 (Table 2).9
α
’-quaternarization
Electron-donating
substituents, such as methyl and methoxy groups, produced
quaternary stereocenters 21b and 21c in 90% and 74% yields,
respectively. N-methyl indole was also a suitable nucleophile,
which afforded product 21d in 74% yield.
Halogen
substituents, such as 6-chloro and 5-bromo indoles, were
found robust under the optimized reaction conditions, leading
to formation of the corresponding methylenol ethers 21e and
21f in 75% and 85% yields, respectively. Electron-deficient
methyl-5-carboxylate indole furnished quaternary center 21g
in 68% yield despite a longer reaction time. Structurally
elaborate 5-methoxy-1H-benzo[g]indole was also found to [a] Isolated yield of products 21 or 22 after flash
produce the corresponding quaternary center 21h in near chromatography. [b] 1.1 equivalents of indole was employed.
quantitative yield.
This synthetic method was also applicable to analogous 6-
membered
corresponding
high yields as a single regioisomer despite the longer reaction 3, we proposed that ionization of either
time.10 Functionalization of starting material 20 with indole ether 23 or
’-hydroxy methylenol ether 24 with pyridinium
cleanly produced
’-indoyl product 22a in 80% yield.9 The use triflate should both generate methyloxyallyl cation 25, which
of electron donating 5-methoxyindole and halogenated 5- would be captured by indole, predictably at the ’-position, to
α
-hydroxy methylenol ether 20, which yielded the
’-quaternary center in methylenol ether 22 in positions, respectively, was then examined. As shown in Table
-hydroxy methylenol
The role of aromatic and alkyl substituents at the α and α’-
α
α
α
α
α
bromoindole furnished the corresponding methylenol ethers give the corresponding product 26. As illustrated in entries 1-
22b and 22c in 69% and 85%. The structure of compound 21c 6, various aromatic rings, such as electron-donating p-anisole
and 22b was conclusively confirmed by X-ray analysis.11 23a and p-toluene 23b, cleanly furnished
α’-indoyl adducts
Interestingly, electron deficient methylindole-5-carboxylate led 26a and 26b in 90% and 84% yields, respectively. Halogen
to an isolation of the resulting product 22d in modest 35% substituents, such as 4-fluorophenyl 23c and 4-chlorophenyl
yield.
We also explored the applicability of sterically 23d, were also tolerated to produce methylenol ethers 26c
congested 2-phenylindole and N-methyl indole, which led to and 26d in excellent yields. An aromatic heterocycle, such as
an installation of
yields.
α
’-quaternary center in 22e and 22f in good 3-methylthiophene 23e, furnished quaternary center 26e in
near quantitative yield. A larger aromatic system, such as the
2-napthyl group in 23f, was also found to be suitable in this
chemistry.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Chemical Science
Page 4 of 7
View Article Online
DOI: 10.1039/C5SC01914A
ARTICLE
Journal Name
Table 3. Scope of Aromatic and Alkyl Substituents
a) Isolated yield of products 26 after flash chromatography. b) The low yield was attributed to poor solubility of the product in most
organic solvents. c) Combined yield for both regioisomers. d) The major regioisomer was not assigned, as these compounds were not
separable by chromatography. e) The ratio of regioisomers was determined by 1H NMR of the crude reaction mixture.
Our investigation continued on with efforts to identify the
effect of various ’-alkyl substituents in this enol ether
As opposed to the methyl variant 12b (Scheme 1, entry 3),
α-phenyl substituted starting material 24e exclusively
α
functionalization reaction. As shown in Table 3, entries 7 and produced
8, allylic and aliphatic side chains 24a and 24b gave the quantitative yield. This astounding result strongly suggests
corresponding ’-indoyl enol ethers 26g and 26h, respectively, that the unusual benzylic-oxyallylic carbocation stabilization
α-phenyl-α’-indole 26k as a single regioisomer in
α
in excellent yields as a single regioisomer. The regioselectivity appeared to have cooperatively directed in these direct
induction in this methodology appeared to be sensitive to nucleophilic addition reactions.12 The involvement of the
simple modulation in the steric effect. For instance, a aromatic substituents in facilitating regioselectivity control was
significant erosion in regioselectivity was observed when further confirmed by the use of starting materials bearing
sterically encumbered isopropyl or isobutyl groups were isopropyl 23g and -isobutyl 23h (entries 12 and 13).
incorporated to the ’-position in starting materials 24c and Exposure of these substrates to the reaction conditions
24d The longer reaction time involving substrates 24b 24d produced the corresponding methylenol ether adducts 26l and
suggested that an increasing size of the alkyl substituents 26m with the indole addition occurring at the less sterically
α-
α
α
.
-
substantially impeded the rate of reaction.
congested methylated
α
’-carbon.
The observed
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Chemical Science
Page 5 of 7
View Article Online
DOI: 10.1039/C5SC01914A
Journal Name
ARTICLE
regioselectivity in these products, however, was rather consulted Mayr’s nucleophilicity parameters (N values)13 and
modest, suggesting that while steric influence readily offered extracted the N values of various substituted indoles, which
some degrees of regiochemical induction, these effects alone ranged from N = 2.2 for electron poor indoles to N = 7.2 for
were not sufficient in furnishing exclusive regioselectivity in electron rich indoles,13d as a reference. As illustrated in Table
the addition of nucleophiles to the putative oxyallyl cation 4, this strategy enabled us to identify that pyrrole (N = 4.6)
intermediates without reinforcement from the benzylic-type successfully reacted with starting materials 19 and 20 to afford
stabilization provided by aryl substituents.
the corresponding methylenol ethers 27a and 28a in 45% and
89% yields, respectively, although these reactions were rather
sluggish.13e In contrast, the use of much more nucleophilic 2,4-
dimethylpyrrole (N = 10.7) rapidly converted five-membered
methylenol ether 19 to the corresponding quaternary center
27b in 83% yield within 30 minutes.13f Azulene (N = 6.7), a
highly nucleophilic neutral aromatic hydrocarbon, was found
to react in this method and yielded methylenol ethers 27c and
28c as a single regioisomer.13h We were also able to
demonstrate the utility of 2-(trimethylsiloxy)furan (N = 7.2) in
this methodology.13c This nucleophile readily functionalized
starting material 19 to furnish stereochemically congested
Table 4. Scope of Nucleophiles
adduct 27d in 62% yield, surprisingly as
diastereomer.11
a
single
We recognized the challenge of using heteroatom-
centered nucleophiles to capture carbocations in Brønsted
acid catalyzed reactions due to the potentially reversible
ionization of the newly generated carbon-heteroatom bonds
promoted by the catalyst.12, 14 We explored the applicability of
such nucleophiles by initially focusing on alcohols.15
Interestingly, a reaction between α-hydroxy enol ether 19 and
methanol produced the corresponding methanol adduct 27e in
69% yield as a single regioisomer. While the use of 3-phenyl-1-
propanol afforded methylenol ether 27f in modest 39% yield,
the addition of this primary alcohol to six-membered substrate
20 formed quaternary center 28f in near quantitative yield. An
attempt to incorporate thiophenol was also successful to
produce the respective mercaptan adducts 27g and 28g in high
yields as a single regioisomer.
Scheme 3. Synthetic Applications of Methylenol Ethers
[a] Isolated yield of products 27 and 28 after flash
chromatography. [b] 50 mol% of pyridinium triflate was
added. [c] 1.1 equivalent of azulene was employed. [d] The
starting material was not fully consumed. [e] 4Å molecular
sieves were added.
While we and others have extensively utilized substituted
indoles in studies concerning a direct nucleophilic addition to
oxyallyl cations,4f, 4g, 5 there are only a few precedents on the
utility of other carbon and heteroatom nucleophiles in this
type of chemistry.4g,
4h
As a guideline for us to judiciously
select other potential carbon nucleophiles beyond indole, we
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
Chemical Science
Page 6 of 7
View Article Online
DOI: 10.1039/C5SC01914A
ARTICLE
Journal Name
Construction of these highly functionalized enol ethers University (LSU) College of Science and the Louisiana Board of
provided unique venue to access various structurally Regents through the PFUND Award (LEQSF-EPS(2015)-PFUND-
formidable quaternary center-containing molecular 395). C.E.A. thanks the Louisiana Board of Regents for the
architectures (Scheme 3). For example, treatment of Graduate Fellowship (LEQSF(2011-16)-GF-03). J.R.S. thanks
a
methylenol ether 21a to stoichiometric toluenesulfonic acid the Louisiana Board of Reagents for the Graduate Fellowship
monohydrate in THF at -20°C readily produced the (LEQSF(2014-19)-GF-02).
corresponding stereochemically elaborate ketone 29 in 73%
yield with 5.5:1 diastereoselection. Our ability to install two
Notes and references
aromatic substituents, each at the
α
ketone, while simultaneously introducing an
- and
α
’-positions of
-quaternary
α
‡
§
These authors contributed equally.
X-Ray Crystallographer
center, clearly demonstrated the strength of our methodology.
Methylenol ether 21a could also be subjected to palladium-
catalyzed hydrogenation. These conditions introduced a
stereotriad in methylated cyclopentanol 30 in a good yield
with a decent control of diastereoselectivity.
1. a) A. J. Frontier and C. Collison, Tetrahedron, 2005, 61, 7577-
7606; b) T. N. Grant, C. J. Rieder and F. G. West, Chem.
Commun., 2009, 5676-5688; c) W. Nakanishi and F. G. West,
Curr. Opin. Drug Discov. Dev., 2009, 12, 732-751; d) N.
Shimada, C. Stewart and M. A. Tius, Tetrahedron, 2011, 67,
5851-5870; e) T. Vaidya, R. Eisenberg and A. J. Frontier,
ChemCatChem, 2011, 3, 1531-1548.
2. a) A. G. Lohse and R. P. Hsung, Chem. Eur. J., 2011, 17, 3812-
3822; b) M. Harmata, Chem. Commun., 2010, 46, 8904-8922; c)
M. Harmata, Chem. Commun., 2010, 46, 8886-8903; d) D. A.
Foley and A. R. Maguire, Tetrahedron, 2010, 66, 1131-1175; e)
M. Harmata, Adv. Synth. Catal., 2006, 348, 2297-2306; f) M. A.
Battiste, P. M. Pelphrey and D. L. Wrightthl, Chem. Eur. J.,
2006, 12, 3438-3447; g) B. Niess and H. M. R. Hoffmann,
Angew. Chem. Int. Ed., 2005, 44, 26-29; h) I. V. Hartung and H.
M. R. Hoffmann, Angew. Chem. Int. Ed., 2004, 43, 1934-1949; i)
M. Harmata and P. Rashatasakhon, Tetrahedron, 2003, 59,
2371-2395; j) M. Harmata, Acc. Chem. Res., 2001, 34, 595-605.
3. a) E. H. Krenske, S. Z. He, J. Huang, Y. F. Du, K. N. Houk and R. P.
Hsung, J. Am. Chem. Soc., 2013, 135, 5242-5245; b) H. Li, R. P.
Hughes and J. Wu, J. Am. Chem. Soc., 2014, 136, 6288-6296; c)
H. Li, J. Wu, Synthesis-Stuttgart, 2015, 47, 22-33.
The indole ring in compound 21a could also be easily
protected without compromising the methylenol ether
functionality via treatment with LDA and acetic anhydride.
The resulting acetate-protected product 31 could be further
subjected to another diastereoselective transformation, such
as oxidation of the carbon-carbon double bond using m-
CPBA.16 Interestingly, this reaction cleanly produced
structurally intricate epoxide 32 with three contiguous
quaternary centers, in 80% yield as
a 5:1 mixture of
diastereomers. Similarly, the stereochemical identity of
compounds 29, 30, and 32 was confirmed by single crystal X-
ray diffraction.11 We were also able to oxidatively cleave the
carbon-carbon double bond in methylenol ether 31 using
RuCl3/NaIO4 to furnish 1,5-ketoester 33 17
.
In addition to the
generation an sp3-sp2 connectivity, chemoselective
α-
quaternarization of ester in the presence ketone are
challenging due to the subtle acidity differences between the
relevant α
-hydrogens.8
4. a) A. W. Fort, J. Am. Chem. Soc., 1962, 84, 2620-2625; b) K.
Freter, Liebigs Ann. Chem., 1978, 1357-1364; c) B. Föhlisch and
R. Joachimi, Chem. Ber., 1987, 120, 1951-1960; d) J. Leitich and
I. Heise, Eur. J. Org. Chem., 2001, 2707-2718; e) M. Harmata, C.
Huang, P. Rooshenas and P. R. Schreiner, Angew. Chem. Int.
Ed., 2008, 47, 8696-8699; f) Q. Tang, X. Chen, B. Tiwari and Y.
R. Chi, Org. Lett., 2012, 14, 1922-1925; g) M. N. V. Wal, A. K.
Dilger and D. W. C. MacMillan, Chem. Sci., 2013, 4, 3075-3079;
h) J. Luo, H. Zhou, J. W. Hu, R. Wang and Q. Tang, RSC Adv.,
2014, 4, 17370-17377.
Conclusions
In conclusion, we detailed a new method to generate benzylic-
oxyallylic stabilized carbocations under mild Brønsted acid
catalysis and discovered that the reactivity of these novel
intermediates could be harnessed towards a regioselective
construction of quaternary centers through a direct capture
with indoles and other high value nucleophiles. Overall, this
chemistry efficiently furnished highly functionalized enol
ethers that could be conveniently derivatized to other complex
molecular architectures. Detailed mechanistic investigations
on the origin of this unprecedented control of regioselectivity
are ongoing in our laboratory, and the results will be reported
in due course.
5. C. E. Ayala, N. S. Dange, F. R. Fronczek and R. Kartika, Angew.
Chem. Int. Ed., 2015, 54, 4641–4645.
6. a) Y. Liu, S.-J. Han, W.-B. Liu and B. M. Stoltz, Acc. Chem. Res.,
2015, 48, 740-751; b) C. M. Reeves, D. C. Behenna and B. M.
Stoltz, Org. Lett., 2014, 16, 2314-2317; c) P. Zhang, H. Le, R. E.
Kyne and J. P. Morken, J. Am. Chem. Soc., 2011, 133, 9716-
9719; d) J. T. Mohr, D. C. Behenna, A. M. Harned and B. M.
Stoltz, Angew. Chem. Int. Ed., 2005, 44, 6924-6927; e) W.-B.
Liu, C. M. Reeves, S. C. Virgil and B. M. Stoltz, J. Am. Chem.
Soc., 2013, 135, 10626-10629; f) J. Li and D. Lee, Chem. Sci.,
2012, 3, 3296-3301; g) A. Y. Hong, M. R. Krout, T. Jensen, N. B.
Bennett, A. M. Harned and B. M. Stoltz, Angew. Chem. Int. Ed.,
2011, 50, 2756-2760; h) D. C. Behenna, Y. Liu, T. Yurino, J. Kim,
D. E. White, S. C. Virgil and B. M. Stoltz, Nature Chem., 2012, 4,
130-133.
Acknowledgements
This material is based upon work supported by the National
Science Foundation under CHE-1464788.
We gratefully
acknowledge generous financial support from Louisiana State
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Chemical Science
Page 7 of 7
View Article Online
DOI: 10.1039/C5SC01914A
Journal Name
ARTICLE
7. a) Y.-K. Wu and F. G. West, Org. Lett., 2014, 16, 2534-2537; b) 14. a) S. E. Larson, J. C. Baso, G. L. Li and J. C. Antilla, Org. Lett.,
Y.-K. Wu, C. R. Dunbar, R. McDonald, M. J. Ferguson and F. G.
West, J. Am. Chem. Soc., 2014, 136, 14903-14911; c) Y. Kwon,
O. Scadeng, R. McDonald and F. G. West, Chem. Commun.,
2014, 50, 5558-5560; d) Y. Kwon, R. McDonald and F. G. West,
Angew. Chem. Int. Ed., 2013, 52, 8616-8619; e) Y.-K. Wu, R.
McDonald and F. G. West, Org. Lett., 2011, 13, 3584-3587; f) K.
Yaji and M. Shindo, Synlett, 2009, 2524-2528; g) D. Song, A.
Rostami and F. G. West, J. Am. Chem. Soc., 2007, 129, 12019-
12022; h) F. Dhoro, T. E. Kristensen, V. Stockmann, G. P. A. Yap
and M. A. Tius, J. Am. Chem. Soc., 2007, 129, 7256-7257; i) T.
2009, 11, 5186-5189; b) G. L. Li, F. R. Fronczek and J. C. Antilla,
J. Am. Chem. Soc., 2008, 130, 12216-12217; c) Y. Liang, E. B.
Rowland, G. B. Rowland, J. A. Perman and J. C. Antilla, Chem.
Commun., 2007, 4477-4479; d) E. B. Rowland, G. B. Rowland, E.
Rivera-Otero and J. C. Antilla, J. Am. Chem. Soc., 2007, 129,
12084-12085; e) G. B. Rowland, H. L. Zhang, E. B. Rowland, S.
Chennamadhavuni, Y. Wang and J. C. Antilla, J. Am. Chem. Soc.,
2005, 127, 15696-15697; f) M. Senatore, A. Lattanzi, S.
Santoro, C. Santi and G. Della Sala, Org. Biomol. Chem., 2011,
9, 6205-6207.
D. White and F. G. West, Tetrahedron Lett., 2005, 46, 5629- 15. Sterically bulky alcohols and nitrogen-centered nucleophiles
5632; j) F. Dhoro and M. A. Tius, J. Am. Chem. Soc., 2005, 127,
12472-12473.
8. F. G. Bordwell, Acc. Chem. Res., 1988, 21, 456-463.
were not tolerated in this methodology.
16. J. Carreras, M. Livendahl, P. R. McGonigal and A. M.
Echavarren, Angew. Chem. Int. Ed., 2014, 53, 4896-4899.
9. The use of 1.1 equivalents of indole resulted in a slighly lower 17. a) L. F. Silva, Jr., R. S. Vasconcelos and M. A. Nogueira, Org.
yield and longer reaction time.
Lett., 2008, 10, 1017-1020; b) M. C. Pierre, A. Tenaglia and M.
Santelli, Tetrahedron, 1998, 54, 14803-14810.
10. a) F. Johnson, Chem. Rev., 1968, 68, 375-413; b) R. W.
Hoffmann, Chem. Rev., 1989, 89, 1841-1860. We believed that
the lower reactivity of the six-membered substrates in this
methodology was most likely attributed by destabilization of
their corresponding six-membered oxyallyl cations due to the
more severe allylic strain that was readily introduced by the
smaller angles among the participating subsituents than those
from the analogous five-membered systems.
1
11. CCDC 1057457 contains the supplementary crystallographic
data for compound 21c.
CCDC 1057458 contains the
supplementary crystallographic data for compound 22b. CCDC
1057455 contains the supplementary crystallographic data for
compound 27d. CCDC 1057456 contains the supplementary
crystallographic data for compound 29. CCDC 1057460
contains the supplementary crystallographic data for
compound 30. CCDC 1057459 contains the supplementary
crystallographic data for compound 32. See Supporting
Information. These data can be obtained free of charge via
http://www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 879912, Union Road,
Cambridge CB879952 879951EZ, UK; fax: +879944 871223
336033.
12. R. Sanz, A. Martinez, D. Miguel, J. M. Alvarez-Gutierrez and F.
Rodriguez, Adv. Synth. Catal., 2006, 348, 1841-1845. The
extent of regioselectivity in the addition of nucleophiles to
unsymmetrical α,α’-disubstituted allylic cations under
Brønsted acid catalysis was unpredictable.
13. a) H. Mayr and A. R. Ofial, J. Phys. Org. Chem., 2008, 21, 584-
595; b) H. Mayr and A. R. Ofial, Pure Appl. Chem., 2005, 77,
1807-1821; c) H. Mayr, B. Kempf and A. R. Ofial, Acc. Chem.
Res., 2003, 36, 66-77; d) S. Lakhdar, M. Westermaier, F.
Terrier, R. Goumont, T. Boubaker, A. R. Ofial and H. Mayr, J.
Org. Chem., 2006, 71, 9088-9095; e) B. Kempf, N. Hampel, A. R.
Ofial and H. Mayr, Chem. Eur. J., 2003, 9, 2209-2218; f) T. A.
Nigst, M. Westermaier, A. R. Ofial and H. Mayr, Eur. J. Org.
Chem., 2008, 2369-2374; g) J. Ammer, C. Nolte and H. Mayr, J.
Am. Chem. Soc., 2012, 134, 13902-13911; h) M. Kedziorek, P.
Mayer and H. Mayr, Eur. J. Org. Chem., 2009, 1202-1206.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins