Ring-opening hydroarylation of monosubstituted cyclopropanes enabled by hexafluoroisopropanol

Article abstract of DOI:10.1039/c8sc02126k

Ring-opening hydroarylation of cyclopropanes is typically limited to substrates bearing a donor-acceptor motif. Here, the transformation is achieved for monosubstituted cyclopropanes by using catalytic Br?nsted acid in hexafluoroisopropanol (HFIP) solvent, constituting a rare example where such cyclopropanes engage in intermolecular C-C bond formation. Branched products are obtained when electron-rich arylcyclopropanes react with a broad scope of arene nucleophiles in accord with a simple S_N1-type ring-opening mechanism. In contrast, linear products are obtained when cyclopropylketones react with electron-rich arene nucleophiles. In the latter case, mechanistic experiments and DFT-calculations support a homo-conjugate addition pathway.

Full text of DOI:10.1039/c8sc02126k

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Ring-opening hydroarylation of monosubstituted cyclopropanes
enabled by hexafluoroisopropanol
Received 00th January 20xx,
Accepted 00th January 20xx
Edward Richmond,a Jing Yi,a Vuk D. Vuković,a Fatima Sajadi,b Christopher N. Rowley*b and Joseph
Moran*a
DOI: 10.1039/x0xx00000x
Ring-opening hydroarylation of cyclopropanes is typically limited to substrates bearing a donor-acceptor motif. Here, the
transformation is achieved for monosubstituted cyclopropanes by using catalytic Brønsted acid in hexafluoroisopropanol
(HFIP) solvent, constituting a rare example where such cyclopropanes engage in intermolecular C–C bond formation.
Branched products are obtained when electron-rich arylcyclopropanes react with a broad scope of arene nucleophiles in
www.rsc.org/
accord with
a simple SN1-type ring-opening mechanism. In constrast, linear products are obtained when
cyclopropylketones react with electron-rich arene nucleophiles. In the latter case, mechanistic experiments and DFT-
calculations support a homo-conjugate addition pathway.
Typical Cyclopropane Hydroarylation: Donor-Acceptor Systems3
Introduction
Ar
EWG
EDG EWG
EWG
EWG
LA (cat.)
Ar
Cyclopropanes are readily accessed substrates whose strain-
release ring opening gives rise to highly functionalized
products.1 The ring-opening hydroarylation of cyclopropanes
installs an aryl moiety and a hydrogen atom in a 1,3-
relationship. Thus far, it has mostly been described for so-
called donor-acceptor cyclopropanes, a class of cyclopropanes
that are highly tractable synthetic precursors due to the
presence of electron-donating and electron-withdrawing
groups arranged in a 1,2-relationship.2,3 Intermolecular ring-
opening hydroarylation can also occur in cyclopropanes
bearing two geminal acceptor groups, but only for indoles
under ultra-high pressure (13,000 atm) conditions.4,5 Catalytic
EDG
H
■ cyclopropane polarisation through synergistic EDG/EWG combination
This Work: Unified Catalytic Hydroarylation of non-DA cyclopropanes
H
O
O
O
Ar
H
H+ (cat.)
Ar
R
HFIP
R
R
Ar
Ar
H
H+ (cat.)
’Ar
H+
Ar‘
Ar’
HFIP
Scheme 1. Typical hydroarylation reactivity of cyclopropanes under Lewis acid catalysis
using donor-acceptor substrates. This work: Unified, HFIP-assisted, Brønsted acid-
catalyzed cyclopropane hydroarylation.
ring-opening
hydroarylation
of
mono-substituted
cyclopropanes has yet to be reported. Generally speaking, the
reactivity of monosubstituted cyclopropanes is much less
developed than for donor-acceptor cyclopropanes. Existing
ring-opening reactions include oxidative addition into C–C
intermediate, whereas cyclopropanes bearing a carbonyl
group lead to linear products and react via a homo-conjugate
addition pathway.
bonds
with
transition
metals,6,7,8
oxidative
1,3-
difunctionalization,9 frustrated Lewis pairs,10,11 or addition of
strong nucleophiles12,13,14 and mineral acids.15 One-pot
iodination/alkylation procedures are also known.16 Our
laboratory has begun to exploit the catalytically active
aggregates formed between Brønsted acids and solvents such
as hexafluoroisopropanol (HFIP) to enable challenging
transformations17,18 Herein, we report Brønsted acid catalyzed
arylative ring-opening of mono-substituted cyclopropanes in
HFIP (Scheme 1, This Work). Mechanistic experiments and DFT
calculations indicate that, depending on cyclopropane
substitution, two differing mechanistic pathways appear to be
operative. Cyclopropanes bearing an aryl group furnish
branched products and proceed through a carbocation
Results and discussion
Synthetic Studies
Initial investigations began with the optimization of the
reaction between commercial cyclopropyl phenyl ketone 1a
and 1,3,5-trimethoxybenzene. A screen of temperatures, acids,
and solvents rapidly revealed that the combination of triflic
acid (TfOH) catalyst in HFIP promoted smooth reactivity to the
desired ring-opened adduct in near quantitative conversion
and 67% isolated yield (Scheme 2, 2a). Application of these
optimized reaction conditions to a series of ketone-bearing
cyclopropanes19 gave access to a range of γ-arylated ketone
products in good to excellent yields. The aryl ketone was
replaced with a methyl ketone with almost no impact on
reactivity (2b), and a series of cyclopropyl aryl ketones bearing
a variety of substituents (2d-j) was arylatively ring-opened in
67-98% yield. In this series, variation of the nucleophile
revealed a range of electron-rich arenes was well tolerated by
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the reaction system (entries 2c-e and 2j), provided that a 1,3- Given the polarity reversal of such substrates compared to
View Article Online
DOI: 10.1039/C8SC02126K
methoxy motif was present in all cases. Nucleophiles lacking their carbonyl-bearing counterparts, opposing reactivity to
this 1,3-pattern, even 1,2,3- and 1,2,4-trimethoxybenzene, yield the branched ring-opening product was expected.
were found to be ineffective in this reaction, as were 1,4- Indeed, reaction of cyclopropylbenzene with 1,2,4-
dimethoxybenzene, indole derivatives and cyclopropanes trimethoxybenzene yielded the desired, branched product in
bearing nitrile groups.20 The optimal reaction conditions also 79% yield (Scheme 4, 3a). A survey of the reaction scope with
proved applicable to the arylative ring-opening reaction of cyclopropylbenzene revealed a wider range of nucleophiles
cyclopropanes bearing two ester groups (Scheme 3, entries 2k- was tolerated in this reaction system (entries 3b-e,k,l),
n
), with almost no impact on the reaction efficiency. However, including less electron-rich arenes such as anisole (3e).
a substrate bearing a single ester group proved recalcitrant, Additionally, it was found that almost all of these reactions
providing only poor yields of the γ-arylation product (2o). With proceeded efficiently at room temperature. Variation of the
conditions established for the preparation of linear, γ-arylated aryl moiety of the cyclopropane proved unproblematic with
carbonyl derivatives, we next elected to probe simple aryl- electron-rich (3f and 3g), electron-deficient (3h and i) and
cyclopropanes as reaction partners in this catalytic protocol. halogenated ring systems (3j) all well tolerated. The catalytic
To the best of our knowledge, such substrates have yet to be reaction system was also successfully extended to the
engaged in catalytic ring-opening reactions with nucleophiles activation of benzylic cyclopropanes, in particular those
other than thiols21 and a single example of a Friedel-Crafts bearing electron-deficient aryl rings (Scheme 5). In reaction
reaction.22
with mesitylene, both pentafluorophenyl- and 4-nitrophenyl
derivatives delivered methyl-substituted bis-aryls 3m and 3n
O
O
TfOH (10 mol%)
HFIP, 80 ºC, 16 h
Ar
H
Ar
R
O
TfOH (10 mol%)
R
Ar
Ar1
1j-m
Ar
H
Me
1a-f
2a-2j
HFIP, r.t., 16 h
Ar1
3a-l
MeO
OMe
MeO
OMe
MeO
OMe
O
O
OMe
Me
OMe
MeO
MeO
F
HO
MeO
Me
Ph
Ph
OMe
2b, 76% yield
OMe
2a, 67% yield
2c, 87% yieldb
Me
OMe Ph
Ph
Ph
OMe Ph
MeO
OMe
MeO
OMe
MeO
OMe
3a, 79% yieldb,c
3b, 68% yield
3c, 70% yield
3d, 83% yieldc,d
O
O
O
PMP
Ph
Ph
Me
OMe
OMe
2f, 61% yield
MeO
MeO
Cl
F
HO
MeO
2d, 82% yieldb
2e, 70% yieldb
Me
MeO
OMe
MeO
OMe
OMe PNP
Ph
O
O
PMP
PMP
3e, 93% yieldc
3f, 50% yield
3g, 49% yieldd
3h, 32% yieldb,d
OMe
Cl
X
Cl
Me
2j, 74% yieldb
Me
OMe
2g, X = F, 98% yield
2h, X= Cl, 91% yield
2i, X = Br, 69% yield
HO
HO
Me
MeO
Me
Scheme 2. TfOH-catalyzed, arylative ring-opening reactions of keto-bearing
cyclopropanes. aYields of isolated products after column chromatography over silica.
bCombined yield of regioisomeric products – see SI for further details.
Ph
PNP
3i, 60% yieldb
Ph
3k, 94% yieldd
3l, 94% yieldd
Br
3j, 97% yielde
CO2R
TfOH (10 mol%)
Ar
CO2R
CO2R
Ar
H
CO2R
1g-i
Scheme
4.
TfOH-catalyzed,
arylative
ring-opening
reactions
of
HFIP, 100 ºC, 16 h
arylcyclopropanes.aYields of isolated products after column chromatography
over silica. bReaction heated at 80 ºC. cNMR yield. dCombined yield of
regioisomeric products – see SI for further details. e1.1 equiv. of nucleophile was
used. PMP = 4-methoxyphenyl-. PNP = 4-nitrophenyl-.
2k-o
MeO
OMe
MeO
CO2Me
OMe
CO2Et
CO2Et
OMe
CO2Me
TfOH (10 mol%)
OMe
Mes
Mes
H
EWG
2k, 98% yield
EWG
2l, 71% yield
HFIP, 100 ºC, 24 h
Me
3m-n
MeO
OMe
MeO
OMe
MeO
OMe
F
CO2Me
CO2Me
CO2Me
CO2Me
Me
Me
NO2
Me
Me
F
F
F
CO2Me
2m, 77% yieldb
Cl
2n, 56% yieldb
OMe
2o, 15% yieldc
Me
Me
Me
Me
F
Scheme 3. TfOH-catalyzed, arylative ring-opening reactions of ester-bearing
cyclopropanes.a Yields of isolated products after column chromatography over silica.
bCombined yield of regioisomeric products – see SI for further details. cReaction heated
at 100 ºC in 1,2-dichloroethane.
3n, 89% yielda
3m, 90% yielda
Scheme
5.
TfOH-catalyzed
arylative
ring-opening
of
benzylic
cyclopropanes.aYields of isolated products after column chromatography over
silica. Mes = mesitylene.
2 | J. Name., 2012, 00, 1-3
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respectively, presumably via Brønsted acid-mediated ring
opening, followed by a 1,2-hydride shift to give the least
inductively destabilized carbocation prior to nucleophilic
capture by mesitylene.23
View Article Online
DOI: 10.1039/C8SC02126K
Mechanistic & Computational Studies
In situ 1H NMR titration studies of various reaction
components in HFIP with TfOH were carried out in order to
better rationalize the observed reactivity trends. Addition of
10 mol% TfOH to cyclopropylbenzene in HFIP in the absence of
any nucleophile gave a highly exothermic reaction and an
intense orange colour, with 1H NMR analysis suggesting
decomposition of starting material. This is in accord with prior
literature on the reaction of similar cyclopropanes with
mineral acids, in which a direct protonation yields an
intermediate carbocation followed by collapse of the resulting
ion pair. These observations, in combination with the wide
nucleophile scope tolerated by such substrates, suggest that
aryl cyclopropanes ring-open in the presence of TfOH and
react via an SN1-type mechanistic pathway (Scheme 6). In
ppm
7
6
5
4
3
2
Figure 1. 1H NMR titration of 1,3,5-TMB and TfOH in HFIP leading to the observation of
a dearomatized diene intermediate.
OMe
1
1,3,5-TMB
contrast, initial in situ H NMR experiments with cyclopropyl
H
H
O
H+
H
Ar
O
O
R
H
Ar
ketones suggest no spontaneous reactivity with TfOH in the
absence of nucleophile. Rather, addition of TfOH to a 1:1
mixture of cyclopropyl phenyl ketone and 1,3,5-
R
HFIP
MeO
OMe
R
4
Scheme 7: A plausible mechanistic scenario: Brønsted acid catalyzed homo-conjugate
addition.
trimethoxybenzene revealed
a complete preference for
protonation of the latter. Titration of a solution of the 1,3,5-
trimethoxybenzene (1,3,5-TMB) nucleophile in HFIP with TfOH
revealed that 1,3,5-TMB is rapidly and completely protonated
to yield a dearomatized cationic diene (Figure 1).24 At room
temperature, a 1:1 mixture of cyclopropyl phenyl ketone and
1,3,5-TMB shows complete protonation of the latter upon
titration of TfOH.25 While an intriguing observation, thus far it
has not been possible to establish whether this protonated
nucleophile plays a more intimate role than simply being a
‘resting state’ for the catalyst. Additionally, this dearomatizing
protonation is not observed in other solvents, suggesting that
HFIP plays a more intimate role in the reaction beyond that of
a bulk solvent.18d Thus, a tentative mechanistic scenario can be
proposed where TfOH in HFIP initially enables protonation of
most cyclopropyl ketones, allowing it to be protonated by
strong acids like TfOH. The protonated cyclopropyl ketone is
activated for reaction with the arene, due to its partial enol
character. This protonated cyclopropyl is then intercepted by
the arene to form an arenium intermediate, which is the rate-
limiting step. Deprotonation of the arenium intermediate
yields an enol, which then tautomerizes to the ketone product.
The calculated free energy profiles are generally consistent
with the observed reactivity. Cyclopropyl methyl ester 1i
(green line) did not react with 1,3,5-trimethoxybenzene, which
is consistent with the calculations that show the barrier to this
reaction is 9.7 kcal/mol higher than for the cyclopropyl
dimethyl ester 1g (blue line). The calculated barrier for
cyclopropyl dimethyl ester addition is only 1.2 kcal/mol higher
than for the cyclopropyl methyl ketone 1b (black line),
consistent with the high yields for these reactions. Likewise,
the calculated activation energies for addition of 1,2- 1,2,3-
and 1,2,4- methoxy-substituted arenes are significantly higher
than for the reaction with 1,3,5-trimethoxybenzene.25
1,3,5-TMB (Scheme 7). Protonated-TMB
4 can subsequently
act as a reversible proton-reservoir26 to promote a homo-
conjugate addition typical of donor-acceptor cyclopropanes.
To evaluate this hypothesis, this reaction system was
probed via density functional theory calculations (ωB97X-
D/def2-TZVP). A plausible mechanism was identified for the
proposed Brønsted-acid-catalyzed homo-conjugate (Figure 2).
The ketone oxygen was predicted to be moderately basic for
To test the findings of the DFT-investigations
experimentally,
a
series of reactions between 1,3,5-
trimethoxybenzene and various cyclopropyl aryl ketones was
performed and monitored by 1H NMR spectroscopy over time.
In an initial survey of cyclopropyl methyl- 1b, cyclopropyl
phenyl- 1a, and cyclopropyl 4-methoxyphenyl- 1c ketones,
relative rates in agreement with the computed transition state
energies were observed with cyclopropyl methyl ketone
exhibiting a significantly faster rate of arylation (Figure 3). A
a) Mechanistic Proposal for aryl-cyclopropanes
■ SN1-type cyclopropane ring-opening.
■ Acid-induced decomposition in the absence of nucleophile.
■ Wide nucleophile scope.
H+
Ar
H
Ar
R
R
H+
R
HFIP
H
R
Scheme 6: Proposed SN1-type nucleophilic ring opening of arylcyclopropanes.
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DOI: 10.1039/C8SC02126K
R
OH
OMe
O
O
CO2Me
CO2Me
MeO
Me
OMe
OMe
R
OH
43.1
R
OH
33.4
OMe
H
32.2
MeO
OMe
transition
H
state
OMe
O
R
MeO
OMe
10.2 10.7
R
O
O
R
4.4
protonated
carbonyl
OMe
arenium
intermediate
enol
intermediate
reactants
MeO
OMe
products
Figure 2. DFT-calculated reaction profiles for the addition of cyclopropyl ketones or esters to arenes. Energy values in kcal/mol.
Figure 3: Comparison of relative reaction rates for cyclopropyl phenyl ketone 1a (black
squares), cyclopropyl methyl ketone 1b (red circles), and cyclopropyl 4-methoxyphenyl
Figure 4: Hammett Plot of log(kX/kH) vs sigma value for the depicted reaction.
Initial rates were determined by plotting [Product] vs time as determined by 1H
NMR spectroscopy.
ketone 1c (blue triangles) in reaction with 1,3,5-TMB. Reactions were monitored by 1
H
NMR spectroscopy at 65 °C and [Product] is plotted vs time (min).
further comparison of the initial reaction rates of para-
substituted aryl cyclopropanes (4-Me, 4-MeO, 4-F and 4-Cl),
relative to that of the reaction of the parent cyclopropyl
phenyl ketone, allowed a Hammett plot to be constructed for
this reaction by plotting relative reaction rates vs Hammett
substituent parameter (sigma) (Figure 4). Examination of the
resulting plot reveals a strong linear relationship for most data,
with a negative slope; an observation in agreement with the
generation of positive charge on the substrate in the transition
state. The magnitude of this slope is also strongly suggestive of
an SN2-like mechanism, i.e. homo-conjugate addition rather
than a discrete carbocationic intermediate. Whilst most
inductively-stabilising substituents follow the expected trend
and fall nicely on the observed line-of-best-fit, the data-point
obtained for the reaction of the 4-methoxyphenyl
cyclopropane ketone is a notable outlier. This observation can
be rationalized from the computational data, which predicts
the protonated form of this ketone to be exceptionally stable,
so its rate of reaction is slowest if the activation energies are
calculated relative to a protonated-ketone resting state. Taken
together, this combined experimental and computational
insight provide strong support for the proposed homo-
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conjugate addition mechanism, whereby initial HFIP-assisted (Application 418505-2012). Computational resources were
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DOI: 10.1039/C8SC02126K
protonation of the cyclopropyl carbonyl group induces provided by Compute Canada (RAPI: djk-615-ab). F.S. thanks
nucleophilic ring-opening via
a homo-conjugate addition Dr. Liqin Chen for a graduate scholarship.
pathway, leading to the enol form of the observed linear
product (Scheme 8).
Notes and references
OMe
OMe
1
H. N. C. Wong, M.-Y. Hon, C. W. Tse, Y-C. Yip, J. Tanko, T.
Hudlicky Chem. Rev. 1989, 89, 165.
H
H
H
2
For comprehensive overviews of the broad chemistry of
donor-acceptor cyclopropanes, see: a) H-U. Reissig, R.
Zimmer Chem. Rev. 2003, 103, 1151. b) M. Yu, B. L.
Pagenkopf Tetrahedron, 2005, 61, 321. c) T. F. Schneider, J.
Kaschel, D. B. Werz Angew. Chem. Int. Ed. 2014, 53, 5504.
For examples of catalytic arylative ring-opening of donor-
acceptor cyclopropanes, see: a) S. J. Gharpure, M. K. Shukla,
U. Vijayasree Org. Lett. 2009, 11, 5466. b) S. J. Gharpure, U.
Vijayasree, S. Raja Bhushan Reddy Org. Biomol. Chem. 2012,
10, 1735. c) X. Jiang, Z. Lim, Y.-Y. Yeung Tetrahedron Lett.
2013, 54, 1798. d) R. Talukdar, A. Saha, D. P. Tiwari, M. K.
Ghorai Tetrahedron, 2016, 72, 613. e) T. N. Nguyen, T. S.
Nguyen, J. A. May Org. Lett. 2016, 18, 3786. f) T. Kaicharla, T.
Roy, M. Thangaraj, R. G. Gonnade, A. T. Biju Angew. Chem.
Int. Ed. 2016, 55, 10061.
HFIP
MeO
OMe
MeO
OMe
4
‘proton
resting state’
H
3
O
R
HFIP-assisted
protonation
O
R
MeO
MeO
HFIP
HFIP
H
HFIP
OMe
O
R
homo-conjugate addition
R
O
H
O
4
5
P. Harrington, M. A. Kerr Tetrahedron Lett. 1997, 38, 5949.
R
MeO
MeO
An
annulative
cyclopropane
arylation
using
H
superstoichiometric TfOH has been reported: G.-Q. Chen, X.-
Y. Tang, M. Shi Chem. Commun. 2012, 48, 2340.
OMe
MeO
OMe
rearomatization
&
enol/keto tautomerization
6
7
8
9
For reviews, see: a) L. Souillart, N. Cramer Chem. Rev. 2015,
115, 9410. b) G. Fumagalli, S. Stanton, J. F. Bower Chem. Rev.
2017, 17, 9404. For a leading reference, see: b) S. C. Bart, P.
J. Chirik J. Am. Chem. Soc. 2003, 125, 886.
OMe
Scheme 8: A proposed homo-conjugate addition mechanistic pathway consistent
with combined experimental and computational data.
a) D. M. Roundhill, D. N. Lawson, G. Wilkinson, J. Chem. Soc.
A 1968, 845. b) Y. Koga, K. Narasaka Chem. Lett. 1999, 28
705. c) M. H. Shaw, J. F. Bower, Chem. Commun., 2016, 52
10817.
,
,
Conclusions
a) L. Liu, J. Montgomery J. Am. Chem. Soc. 2006, 128, 5348.
In conclusion, a general catalytic system for the arylative ring
opening of mono-substituted cyclopropanes has been
b) L. Liu, J. Montgomery Org. Lett. 2007,
9, 3885. c) T.
Tamaki, M. Ohashi, S. Ogoshi Angew. Chem. Int. Ed. 2011, 50
,
described.
Triflic
acid
in
combination
with
12607.
For
a
recent, transition-metal free oxidative 1,3-
hexafluoroisopropanol provides a superior Brønsted acid
catalyst system, engaging weakly-polarized substrates in
Friedel-Crafts-type reactivity. The regioselectivity and
operative mechanism varies depending on the cyclopropane
substitution, with carbonyl-bearing cyclopropanes reacting via
a homo-conjugate addition pathway. Computational and
mechanistic investigations are congruent with these findings.
difunctionalization of cyclopropanes, see: S. M. Banik, K. M.
Mennie, E. N. Jacobsen J. Am. Chem. Soc. 2017, 139, 9152.
10 J. G. Morton, M. A. Dureen, D. W. Stephan Chem. Comm.
2010, 46, 8947.
11 Z-Y. Zhang, Z-Y. Liu, R.-T. Guo, Y-Q. Zhao, X. Li, X-C. Wang
Angew. Chem. Int. Ed. 2017, 56, 4028.
12 For a short review, see: S. Danishefsky Acc. Chem. Res. 1978,
12, 66.
13 W. A. Bone, W. H. Perkin J. Chem. Soc. Trans. 1895, 67, 108.
14 a) W. E. Truce, L. B. Lindy J. Org. Chem. 1961, 26, 1463. b) A.
Conflicts of interest
There are no conflicts to declare.
B. Smith, R. B. Scarborough Jr Tetrahedron Lett. 1978, 19
1649. c) R. K. Dieter, S. Pounds J. Org. Chem. 1982, 47, 3174.
,
15 For HX-mediated transformations, see: a) W. H. Perkin, T. R.
Marshall, J. Chem. Soc. Trans 1891, 59, 853 b) J. B. Lambert,
J. J. Napoli, K. K. Johnson, K. N. Taba, B. S. Packard J. Org.
Chem. 1985, 50, 1291. c) W. Xu, W. R. Dolbier Jr, J. Salazar, J.
Org. Chem. 2008, 73, 3535. Additionally, an example of
intramolecular bromo-cyclization has also been reported: d)
C. Roesner, U. Hennecke Org. Lett. 2015, 17, 3226.
16 A stoichiometric CeCl3•7H2O/LiI promoted reaction between
indoles and cyclopropyl ketones has also been reported: J. S.
Yadav, B. V. S. Reddy, D. Chandrakanth, G. Satheesh
Tetrahedron Lett. 2007, 48, 8040.
Acknowledgements
This project has received funding from the European Research
Council (ERC) under the European Union's Horizon 2020
research and innovation programme (grant agreement n°
639170) and by grants from LabEx “Chemistry of Complex
Systems”. V.D.V. thanks the French government for an MRT
fellowship. We thank Dr. Helmut Muenster of MasCom for his
assistance with HRMS analysis. F.S. and C.N.R. thank NSERC of
Canada for funding through the Discovery Grant program
17 a) M. Dryzhakov, M. Hellal, E. Wolf, F. C. Falk, J. Moran J. Am.
Chem. Soc. 2015, 137, 9555 b) M. Dryzhakov, J. Moran ACS
Catalysis 2016, 6, 3670. c) M. Dryzhakov, E. Richmond, G. Li,
J. Moran J. Fluor. Chem. 2017, 193, 45. d) V. D. Vukovic, E.
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Richmond, E. Wolf, J. Moran Angew. Chem. Int. Ed. 2017, 56
Journal Name
,
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3085. e) E. Richmond, V. Vuković, J. Moran Org. Lett. 2018,
20, 574.
DOI: 10.1039/C8SC02126K
18 For examples of other HFIP-enabled strong Brønsted acid
catalyzed reactions, see: a) A. Saito, M. Takayama, A.
Yamazaki, J. Numaguchi, Y. Hanzama, Tetrahedron 2007, 63
,
4039 b) H. F. Motiwala, Charaschanya, V. W. Day, J. Aubé, J.
Org. Chem. 2016, 81, 1593 c) X. Zeng, S. Liu, B. Xu, Org. Lett.
2016, 18, 4770; d) W. Liu, H. Wang, C.-J. Li, Org. Lett. 2016,
18, 2184; e) T. Kamitanaka, K. Morimoto, K. Tsuboshima, D.
Koseki, H. Takamuro, T. Dohi, Y. Kita, Angew. Chem. Int. Ed.
2016, 55, 15535. For a more generał overview of HFIP, see: f)
O. Holloczki, A. Berkessel, J. Mars, M. Mezger, A. Wiebe, S. R.
Waldvogel, B. Kirchner ACS Catal. 2017, 7, 1846.
19 See supporting information for structural details of all
cyclopropane starting materials.
20 For further details of ineffective substrate combinations, see
the supporting information file.
21 Y. S. Shabarov, L. G. Saginova, S. V. Veselovskaya, Zh. Org.
Khim+, 1986, 22, 768.
22 A Friedel-Crafts product was also isolated in 12% yield as a
side product in: T. Ohwada, M. Kasuga, K. Shudo J. Org.
Chem. 1990, 55, 2717.
23 In support of this mechanistic hypothesis, benzylic substrates
bearing electron-rich aryl rings were found to give mixtures
of regioisomeric products. Further studies into the
nucleophilic ring-opening of benzylic cyclopropanes are
ongoing.
24 Such behaviour has previously been observed with 1,3,5-
TMB using superacids such as HF-SbF5 as solvent, see: a) G.
A. Olah, Y. K. Mo J. Am. Chem. Soc. 1972, 94, 5341. It has also
been observed in HFIP using laser flash photolysis, see: b) S.
Steenken, R. A. McClelland J. Am. Chem. Soc. 1990, 112
,
9648. c) N. Mathivanan, F. Cozens, R. A. McClelland, S.
Steenken J. Am. Chem. Soc. 1992, 114, 2198.
25 See SI for further information and NMR spectra of these
competitive titration studies. Additionally, 13C and 1H NMR
titration studies of cyclopropyl methyl ketone and TfOH in
HFIP in the absence of nucleophile revealed no spontaneous
cyclopropane opening, but a strong downfield shift of both
the keto-carbonyl and methyl 13C signals was observed.
26 D. Hoefler, M. van Gemmeren, P. Wedemann, K. Kaupmees,
I. Leito, M. Leutzsch, J. B. Lingnau, B. List Angew. Chem. Int.
Ed. 2017, 55, 1411.
6 | J. Name., 2012, 00, 1-3
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