Nucleophilic Opening of Donor-Acceptor Cyclopropanes with Indoles via Hydrogen Bond Activation with 1,1,1,3,3,3-Hexafluoroisopropanol

Article abstract of DOI:10.1021/acs.joc.8b00894

The treatment of donor-acceptor cyclopropanes with the a strong hydrogen bond donor, HFIP, activated the cyclopropanes (via presumed hydrogen bonding) toward homo-Michael additions with indoles as the nucleophiles. This reaction proceeded without the need for high pressure or catalysis.

Full text of DOI:10.1021/acs.joc.8b00894

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Note
Nucleophilic Opening of Donor-Acceptor Cyclopropanes With Indoles
via Hydrogen Bond Activation with 1,1,1,3,3,3-Hexafluoroisopropanol
Lauren C. Irwin, Carling R. Renwick, and Michael Andre Kerr
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00894 • Publication Date (Web): 14 May 2018
Downloaded from http://pubs.acs.org on May 14, 2018
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Nucleophilic Opening of DonorꢀAcceptor Cyclopropanes With Indoles via Hydrogen Bond
Activation with 1,1,1,3,3,3ꢀHexafluoroisopropanol
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Lauren C. Irwin, Carling R Renwick, and Michael A. Kerr*
Department of Chemistry, The University of Western Ontario, London, Ontario, Canada, N6A 5B7
*makerr@uwo.ca
RECEIVED DATE (will be automatically inserted after manuscript is accepted).
Treatment of donorꢀacceptor cyclopropanes with the strong hydrogen bond donor, HFIP, activated the cyclopropanes (via
presumed hydrogen bonding) towards homoꢀMichael additions with indoles as the nucleophiles. This reaction proceeds
without the need for highꢀpressure or catalysis.
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The field of donorꢀacceptor cyclopropane chemistry, while well established, has seen a resurgence of activity in recent years as
new and innovative use for these compounds are reported.1 Their use as homo Michaelꢀacceptors makes them important for the
functionalization of a variety of nucleophiles2 while their ability to act as dipolarophiles has made them useful for the synthesis of
heterocycles3 and carbocycles.4
Our interest in these species dates back over 20 years ago when we reported that indoles could nucleophilically open
cyclopropanes under the influence of a lanthanide triflate (Figure 1).5 This was the first example of such a reaction and since that
time numerous groups have made important developments and improvements. This often involved changing the catalyst, the donor
group, or the acceptor group. Our interest in this particular reaction resurfaced in 2011, when we reported that, what we presume to
be an internal hydrogen bond, allowed cyclopropane hemimalonates to react with indoles under catalystꢀfree conditions at high
pressures.6 This sparked our interest in hydrogen bonding as a mode of activation for donor acceptor cyclopropanes. Herein we
report the results of a study in which we show that various donor acceptor cyclopropanes react smoothly with indoles under catalyst
free conditions in a medium where 1,1,1,3,3,3ꢀhexafluoroisopropanol (HFIP) is either the solvent or coꢀsolvent. At this point, it is
important to note that during the preparation of this manuscript an elegant report by the Moran group appeared which delineates
similar chemistry.7 The work herein complements that research.
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Figure 1. Current and related research from our group.
Our research commenced with the use of cyclopropane hemimalonates since they had shown promise in the milieu of hydrogen
bonding activation. In the initial experiment (Table 1), cyclopropane 2 was treated with 2 equivalents of Nꢀmethyl indole 1 in pure
HFIP at 60oC and produced the desired adduct 3 in 46% yield. In a control experiment, acetonitrile as solvent led to no product
formation. The suspected need for a hydrogen bonding solvent caused us to examine acetic acid, phenol, and trifluoroethanol as
solvents (entries 3,4,and 5). Phenol was chosen since its pKa is similar to HFIP. It is surprising to us that trifluoroethanol produced
no product. Interestingly, isopropanol alone (entry 8) yielded some product. Optimized conditions were realized with a 1:1
mixture of HFIP and isopropanol as the reaction medium and a 2ꢀfold excess of the indole (entry 12).
Table 1. Optimization of reaction conditions for reaction of Nꢀmethyl indole 1 with a cyclopropane hemimalonate 2.
Entry
1 (equiv)
2 (equiv) HFIP:iPrOH Temp
(° C)
Yield 3 (%)
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2
3
4
5
6
7
8
2.0
2.0
2.0
2.0
2.0
1.1
1.1
2.0
2.0
2.0
2.0
2.0
3.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
100:0
MeCN
AcOH
PhOH
TFE
100:0
100:0
iPrOH
50:50
20:80
50:50
50:50
50:50
60
80
110
100
70
60
25
40
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65
65
65
65
46
0
0
0
0
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19
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IC*
67a
76b
70b
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a Sealed tube b Changed purification to aqueous removal of excess indole * Incomplete conversion
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With optimal conditions in hand we turned our attention to a study of substrate performance. Chart 1 shows a series of products
prepared. Several things are worthy of note. While Nꢀmethyl indole added to cyclopropane 5 in 76% yield (6c), indole itself
behaved more poorly, producing the adduct 6d in 31% yield. Substitution at the 2ꢀposition of the indole was well tolerated; in fact,
1,2ꢀdimethylindole was the best nucleophile studied (6a). Substitution on the benzenoid portion of the indole did not have a
significant effect (adducts 6e, 6f) except in the case of 5ꢀnitroindole which failed to form adduct 6i inert under these conditions. As
expected NꢀBoc indole did not react except to undergo Boc removal.8 Finally, a strong electron withdrawing group on the phenyl
ring of the cyclopropane was tolerated, resulting in a 60% yield of 6h.
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Chart 1: Substrate scope for the reaction of indoles with cyclopropane hemimalonates.
In order to compare the hemimalonates with the parent diesters, cyclopropane 8 was treated with indoles 7 under a variety of
conditions (Chart 2). Initially, under the mild conditions used for the hemimalonates, little or no reaction was observed. However,
o
when Nꢀmethyl indole was treated with cyclopropane 8 at 80 C for a prolonged period of time, a 35% yield of adduct 9c was
realized. 2ꢀSubstitution, as expected, enhanced the nucleophilicity and improved yields were noted with the 2ꢀmethylindole and 2ꢀ
phenylindole (adducts 9a and 9b respectively). When the cyclopropanes bore phenyl groups with electron withdrawing moieties,
the expected reduction in yields was observed.
Chart 2: Substrate scope for the reaction of indoles with cyclopropane diesters.
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With some surprising success employing cyclopropanediesters, we turned our attention to cyclopropanes bearing a geminal
bisꢀtrifluoroethyl ester moiety. We, and others, have noted the enhanced reactivity of such cyclopropanes.9 To our delight,
excellent yields were observed in most cases. Chart 3 shows the results. Nꢀmethyl indole reacted with cyclopropane 11a to
produce adduct 12a in 85% yield. In this study we again noted that indole itself resulted in poor yields of adduct 12i. In contrast to
the hemimalonates, 5ꢀnitroindole produced adduct 12e in 47% yield. The excellent yields for the fluoroethylesterꢀbearing
cyclopropanes is certainly a result of the enhanced electron withdrawing nature, however an additional effect could be the
interaction of HFIP with the CꢀF bonds of the cyclopropane. This has been noted by Paquin.10
Chart 3: Substrate scope for the reaction of indoles with cyclopropane fluoroesters.
The essential role of HFIP as a coꢀsolvent is certainly centered around its excellent ability to act as a hydrogen bond donor. The
way in which it does so in this study is somewhat unclear, however several possible modes of activation are shown in Figure 2. In
the case of the diesters (I), hydrogen bonding to the carbonyl oxygen(s) should provide activation toward nucleophilic attack by the
indole. With the cyclopropyl hemimalonate the situation may be more complex (see II). An internal hydrogen bond may also be in
play in addition to the participation by HFIP. While the fluoroesters are expected to be electron withdrawing, a fluorine hydrogen
bond (as noted by Paquin10)would make them even more so (see III). In addition to enhancing the electron withdrawing nature of
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the ester moieties, hydrogen bonding may serve to stereoelectronically align the carbonyls to accept the impending negative charge
upon ring opening.
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Figure 2. Possible hydrogen bonding motifs for donorꢀacceptor cyclopropanes in HFIP.
In conclusion, we have reported a simple and catalyst free method for the activation of donorꢀacceptor cyclopropanes with
hexafluoroisopropanol, and the subsequent addition of indoles. Both fluoroesters 11 and hemiꢀmalonates 8 were found to be more
reactive under these conditions with fluoroesters providing excellent yields of adducts. Future work will examine other ringꢀ
opening and annulation reactions under similar reaction conditions.
Experimental Section
General Information. Reaction flasks were ovenꢀdried at 110 °C and cooled in a desiccator prior to use. All cyclopropane
opening reactions were conducted in sealed tubes that had been flushed with argon before the addition of reagents unless
otherwise indicated. The tubes were sealed with a Teflon stopper and capped with an aluminum crimping cap. All chemicals
were of reagent quality and used as obtained from commercial sources. HFIP was purchased from Oakwood Chemical and
dried with 3Å molecular sieves. Isopropanol was purchased as distilled in glass from Caledon Scientific and stored over 3Å
molecular sieves. High resolution mass spectra (HRMS) were obtained on a Thermo Scientific DFS mass spectrometer using
electron impact ionization. Dichloromethane (DCM), acetonitrile (MeCN) and tetrahydrofuran (THF) were dried and
deoxygenated by passing the nitrogen purged solvents through activated alumina columns. All other reagents and solvents
were used as purchased from Aldrich, Alfa Aesar (VWR), or Caledon. Reaction progress was followed by thin layer
chromatography (TLC) (Merck, TLC Silica gel 60 F254) visualizing with UV light, and the plates were developed using
acidic pꢀanisaldehyde. Column chromatography was performed using silica gel purchased from Silicycle Chemical Division
Inc. (230ꢀ400 mesh). All columns were performed using Still’s procedure for flash chromatography.11 IR spectra were
acquired using a PerkinElmer Spectrum Two FTꢀIR. Melting points were determined using a Gallenkamp melting point
apparatus and are uncorrected. NMR experiments were performed on either a Bruker AvIII 400 or Inova 600 instrument and
samples were obtained in CDCl3 (referenced to 7.25 ppm for 1H and 77.0 ppm for 13C). Coupling constants (J) are in Hz. The
multiplicities of the signals are described using the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, dd
= doublet of doublets, dt = doublet of triplets, dq = doublet of quartets, m = multiplet, br = broad.
General Experimental Procedure for the Synthesis of Indole Starting Materials
Commercially available indole starting materials were used as purchased. When not available the substrates were obtained by
Nꢀmethylation or alkylation of the parent indole following literature procedures and then confirmed by comparison to
reported characterization data for these compounds. Methylated/alkylated indoles were synthesized following literature
procedures 12,13,14 using the following conditions: Desired indole (1 equiv.) was dissolved in dry THF or DMF in an argon
flushed flask to give a 0.3 M solution. NaH (60% dispersed in mineral oil, 1.5 eq) was added portion wise at 0 °C and then
the reaction septum was returned. The flask was evacuated and placed under argon once more. The reaction was warmed to
room temperature and stirred for 1.5 h. At which point, the reaction was cooled again to 0 °C and MeI (1.3 equiv.) or BnBr
(1.1 eq) was added dropwise via syringe. The reactions were allowed to stir at room temperature until TLC analysis
confirmed consumption of starting materials, or until 24 h had passed. Water was added to quench the reaction, and then
extracted 3x with Et2O. The organic layers were combined and washed 1x with brine, and then dried using MgSO4. Upon
filtering and concentrating, the crude mixture was purified via flash column chromatography (EtOAc:Hex) and pure product
was collected.
Synthesis of Cyclopropane Starting Materials
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All diester and hemimalonate cyclopropanes were synthesized via literature methods and confirmed by comparison to the
reported characterization data: 5aꢀ5b6, 8aꢀd 12&13, 11aꢀ11b9d
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General Experimental Procedure: Nucleophilic Opening of Hemimalonate Cyclopropanes (6aꢀh) (GP1)
To an argon flushed sealed tube was added cyclopropane (1 equiv.), indole substrate (2 equiv.) and 50:50 iꢀPrOH:HFIP for a
concentration of 0.2 M. The tube was sealed and submerged into an oil bath at 65ꢀ70°C and left to react for 12ꢀ24 h. Upon
confirmation of starting material consumption via TLC, the reactions were poured into a round bottom flask, rinsed with
DCM and then concentrated in vacuo. The crude mixture was subjected to flash column chromatography using appropriate
eluent system of either AcOH:MeOH:DCM or AcOH:EtOAc:Hex. In some cases (indicated below), instead of a column, the
crude material was taken up in 2M NaOH, extracted with Et2O or DCM 3x to remove excess indole. The collected aqueous
fraction was then acidified with concentrated HCl (very slowly, with cooling if needed) to a pH of 1. The resulting acidic
aqueous layer was then extracted with 3x EtOAc, organic fractions combined, washed with brine, dried with MgSO4, filtered
and concentrated in vacuo to yield purified product.
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(6a) 4-(1,2-dimethyl-1H-indol-3-yl)-2-(methoxycarbonyl)-4-phenylbutanoic acid Following GP1, CP 5a (0.05 g, 0.23
mmol), 1,2ꢀdimethylindole (0.066 g, 0.45 mmol) in 1.2 mL of HFIP:iPrOH was reacted for 20 h. The reaction was
concentrated in vacuo and then taken up in 1M NaOH and placed into a separatory funnel. Extractions using DCM 3x and
monitoring by TLC showed that all indole had been removed from the aqueous phase. The basic aqueous layer was then
carefully acidified with concentrated HCl to pH =1 and extracted with DCM 3x. The organic layers were washed with brine
1x and then dried with MgSO4. Upon filtering and concentrating in vacuo the pure product 6a was isolated as a white solid
(0.069 g, 83% yield). Rf = 0.26 30% EtOAc:1% AcOH: 69% Hex. Characterization data for this compound matched
literature reports.6 1H NMR (400 MHz, Chloroformꢀd) δ mixture of diastereomers = 7.46 (t, J = 7.7 Hz, 1H), 7.34 (d, J =
7.6 Hz, 2H), 7.23ꢀ7.21 (m, 3H), 7.16 – 7.07 (m, 2H), 7.01 – 6.95 (m, 1H), 4.36 – 4.26 (m, 1H), 3.65 3.62 and 3.56 (s, 6 H
total), 3.36 – 3.29 (m, 1H), 2.97 – 2.86 (m, 2H), 2.33 and 2.32 (s, 3H total)
(6b) 2-(methoxycarbonyl)-4-(1-methyl-2-phenyl-1H-indol-3-yl)-4-phenylbutanoic acid Following GP1, hemimalonate CP
5a (0.05 g, 0.23 mmol), 2ꢀphenylꢀ1ꢀmethylindole (0.10 g, 0.48 mmol) in 1.2 mL of HFIP:iPrOH was reacted for 16 h. The
reaction was concentrated in vacuo and purified directly via flash column chromatography. The pure product was isolated as
a white solid (0.072 g, 70%). MP = 165ꢀ169 °C Rf = 0.37 40% EtOAc: 1% AcOH: 59% Hex. 1H NMR (599 MHz, CDCl3)
mixture of diastereomers δ = 7.63 (t, J = 8.2 Hz, 1H), 7.45 – 7.26 (m, 8H), 7.20 – 7.05 (m, 5H), 4.13 (m, 1H), 3.56 and 3.55
(s, 3H), 3.46 (s, 3H), 3.29 – 3.21 (m, 1H), 2.92 – 2.71 (m, 2H) 13C NMR mixture of diastereomers (101 MHz, CDCl3) δ
175.21, 174.89, 171.58, 169.47, 169.43, 144.59, 144.50, 139.73, 139.72, 137.73, 137.67, 134.16, 131.59, 131.55, 130.95,
130.91, 129.19, 128.52, 128.49, 128.45, 128.42, 128.02, 127.78, 127.74, 126.38, 126.34, 126.15, 121.84, 121.75, 120.72,
120.69, 119.70, 119.62, 112.64, 112.42, 109.76, 109.70, 77.48, 77.36, 77.16, 76.84, 52.62, 52.50, 52.47, 50.50, 50.29, 40.36,
40.30, 39.92, 34.18, 33.90, 31.01, 30.95, 21.19. IR (cmꢀ1) 2954, 1743, 1694, 1468, 1433, 1290, 1146, 744, 699 HRMS (EI)
m/z: [M+] Calcd for C27H25NO4 427.1784; Found 427.1775
(6c) 2-(methoxycarbonyl)-4-(1-methyl-1H-indol-3-yl)-4-phenylbutanoic acid Following GP1, hemimalonate CP 5a (0.10 g,
0.46 mmol), 1ꢀmethylindole (0.126 g, 0.92 mmol) in 2.4 mL of HFIP:iPrOH was reacted for 20 h. The reaction was
concentrated in vacuo and taken up in 1M NaOH and followed GP2 extraction work up. The pure product was isolated as an
offꢀwhite solid (0.12 g, 76 % yield) Rf = 0.47 1% AcOH:1% MeOH: 98% DCM. Characterization data for this compound
matched literature reports.6 1H NMR (400 MHz, Chloroformꢀd) mixture of diastereomers δ = 9.91 (br.s, 1H), 7.45 (m, 1H),
7.36 – 7.26 (m, 4H), 7.22 – 7.15 (m, 3H), 7.02 (m, 1H), 6.90 and 6.88 (s, 1H total), 4.26 (m, , 1H), 3.74 and 3.68 (s, 6H
total), 3.44 (m,1H), 2.85m, 1H), 2.71 – 2.58 (m, 1H)
(6d) 4-(1H-indol-3-yl)-2-(methoxycarbonyl)-4-phenylbutanoic acid Following GP1, hemimalonate CP 5a (0.05 g, 0.23
mmol), indole (0.054 g, 0.46 mmol) in 1.2 mL HFIP:iPrOH was reacted for 20 h. The crude mixture was concentrated in
vacuo and purified by flash column chromatography. Rf = 0.32 1% AcOH:1% MeOH: 98% DCM. The product was isolated
as a yellow oil (0.024 g, 31%). Even after multiple purification attempts characterization data was unclean but had matching
results to reported literature.6
(6e) 4-(5-bromo-1-methyl-1H-indol-3-yl)-2-(methoxycarbonyl)-4-phenylbutanoic acid Following GP1, hemimalonate CP
5a (0.075g, 0.34 mmol), 5ꢀbromoꢀ1ꢀmethylindole (0.14 g, 0.68 mmol) in 1.7 mL HFIP:iPrOH were heated for 30 h. The
crude mixture was subjected to the extraction method of purification as described in GP1. The resultant solid from the
extractions was further purified by recrystallization in pentane/DCM to yield pure product as a pale yellow solid (0.10 g,
72%). Rf = 0.5 1% AcOH: 1% MeOH: 98% DCM. Characterization data for this compound matched literature results.6 1H
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NMR (400 MHz, Chloroformꢀd) mixture of diastereomers δ = 7.54 (m, 1H), 7.31 – 7.27 (m, 4H), 7.25 – 7.18 (m, 2H), 7.13
and 7.11 (s, 1H total), 6.92 and 6.89 (s, 1H total), 4.21ꢀ4.12 (m, 1H), 3.76 and 3.73 and 3.72 and 3.69 (s, 6H total), 3.44 –
3.37 (m, 1H), 2.85 – 2.71 (m, 1H), 2.68 – 2.54 (m, 1H)
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(6f) 4-(5-methoxy-1-methyl-1H-indol-3-yl)-2-(methoxycarbonyl)-4-phenylbutanoic acid Following GP1, hemimalonate CP
5a (0.05 g, 0.23 mmol), 5ꢀmethoxyꢀ1ꢀmethylindole (0.074 g, 0.46 mmol) in 1.2 mL of HFIP:iPrOH was reacted for 16 h. The
reaction was concentrated in vacuo and purified directly via flash column chromatography. The pure product was isolated as
1
a white foam (0.056 g, 64%) Rf = 0.27 40% EtOAc: 1% AcOH: 59% Hex. H NMR (400 MHz, CDCl3) mixture of
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diastereomers δ = 7.34 – 7.26 (m, 4H), 7.19 (t, J = 7.0 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 6.88 (m, 1H), 6.86 – 6.79 (m, 2H),
4.19 (m, 1H), 3.76 and 3.67 (s, 3H total), 3.74 and 3.73 (3H total), 3.70 (s, 3H), 3.43 (m, 1H), 2.83 (m, 1H), 2.67 – 2.55 (m,
1H) 13C NMR (101 MHz, CDCl3) mixture of diastereomers δ = 174.7, 169.9, 153.8, 143.4, 132.8, 128.7, 128.5, 128.1,
126.9, 126.7, 116.6, 112.0, 110.1, 101.6, 101.5, 56.0, 52.8, 50.0, 40.8, 35.1 33.0. IR (cmꢀ1) 2949, 1732, 1490, 1451, 1212,
1035, 792, 700, 587 HRMS (EI) m/z: [M+] Calcd for C22H23NO5 381.1576; Found 381.1574
(6g) 4-(1-benzyl-1H-indol-3-yl)-2-(methoxycarbonyl)-4-phenylbutanoic acid Following GP1, hemimalonate CP 5a (0.05 g,
0.23 mmol), 1ꢀbenzylindole (0.095 g, 0.46 mmol) in 1.2 mL of HFIP:iPrOH was reacted for 16 h. The reaction was
concentrated in vacuo and purified directly via flash column chromatography. The pure product was isolated as a white solid
(0.062 g, 63%) Rf = 0.31 30% EtOAc: 1% AcOH: 69% Hex. Characterization data for this compound matched literature
reports.6 1H NMR (400 MHz, Chloroformꢀd) mixture of diastereomers δ = 7.45 (m, 2H), 7.36 – 7.25 (m, 7H), 7.23 – 7.15
(m, 3H), 7.15 – 7.06 (m, 3H), 7.04 – 6.96 (m, 2H), 5.28 (m, 1H), 4.28 (m, 1H), 3.73 and 3.66 (s, 3H total), 3.44 – 3.39 (m,
1H), 2.91 – 2.78 (m, 1H), 2.70 – 2.57 (m, 1H)
(6h) 2-(methoxycarbonyl)-4-(1-methyl-1H-indol-3-yl)-4-(4-nitrophenyl)butanoic acid Following GP1, hemimalonate CP
5b (0.05 g, 0.19 mmol), 1ꢀmethylindole (0.05 g, 0.38 mmol) in 0.65 mL of HFIP:iPrOH was reacted for 24 h. The reaction
was concentrated in vacuo and purified directly via flash column chromatography. The pure product was isolated as a yellow
foam (0.044 g, 64%) Note: Compound 6h is light sensitive and decomposed upon 13C NMR data acquisition as evidenced by
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a color change. Rf = 0.28 40% EtOAc: 1% AcOH:1% MeOH: 58% Hex. H NMR (599 MHz, Chloroformꢀd) mixture of
diastereomers δ 8.07 (d, J = 8.7 Hz, 1H), 8.02 (d, J = 8.7 Hz, 2H), 7.37 (m, 3H), 7.30 (d, J = 8.8 Hz, 1H), 7.10 (t, J = 7.6 Hz,
1H), 6.95 – 6.88 (m, 1H), 6.86 (m, 1H), 4.27 (t, J = 7.7 Hz, 1H), 3.67 (apparent d, J = 3.2 Hz, 1.5H), 3.25 (s, 1.3H), 3.63 and
3.61 (s, 3H), 3.32 (t, J = 8.7 Hz, 1H), 2.81 – 2.64 (m, 1H), 2.55 (m, 1H) 13C NMR (101 MHz, CDCl3) mixture of
diastereomers δ 177.61, 174.75, 171.42, 169.44, 151.62, 146.81, 141.78, 137.52, 130.12, 128.87, 128.46, 126.86, 126.40,
123.98, 123.63, 122.32, 119.47, 119.17, 115.00, 109.63, 52.95, 49.80, 40.54, 37.36, 34.59, 32.98, 21.47, 20.84.
IR (cmꢀ1) 2953, 1733, 1706, 1598, 1514, 1344, 1287, 1152, 855, 737 HRMS (EI) m/z: [M+] Calcd for C21H20N2O6 396.
1321; Found 396.1325
General Experimental Procedure: Nucleophilic Opening of Bisꢀdimethylester Cyclopropanes (9aꢀf) (GP2)
To an argon flushed sealed tube was added cyclopropane (1 equiv.), indole substrate (3 equiv.) and HFIP for a concentration
of 0.3 M. The tube was sealed off and submerged into an oil bath at 80 °C and left to react for 12ꢀ24 h. Upon confirmation of
starting material consumption via TLC, the reaction was poured into a round bottom flask, rinsed with DCM and then
concentrated down in vacuo. The crude material was directly subjected to flash column chromatography using appropriate
eluent system of EtOAc:Hex to isolate purified material.
(9a) dimethyl 2-(2-(1,2-dimethyl-1H-indol-3-yl)-2-phenylethyl)malonate Following GP2, CP 8a (0.05 g, 0.21 mmol) and
1,2ꢀdimethylindole (0.093g, 0.64 mmol) in HFIP (0.7 mL) were subjected to heat for 29 h. The crude material was purified
via flash column chromatography 20%EtOAc:80%Hex to collect a white solid (0.073 g, 91%). MP = 81ꢀ83 °C Rf = 0.24
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(20%EtOAc:80%Hex) H NMR (599 MHz, Chloroformꢀd) δ = 7.46 (d, J = 8.0 Hz, 1H), 7.35 – 7.33 (m, 2H), 7.25 – 7.20
(m, 3H), 7.16 – 7.10 (m, 2H), 7.00 – 6.96 (m, 1H), 4.28 (t, J = 8.3 Hz, 1H), 3.72 (s, 3H), 3.65 (s, 3H), 3.53 (s, 3H), 3.30 (dd,
J = 8.0, 6.8 Hz, 1H), 2.89 (m, 2H), 2.32 (s, 3H). 13C NMR (101 MHz, CDCl3) δ = 170.1, 170.0, 144.3, 137.1, 134.3, 128.4,
127.7, 126.7, 126.1, 120.6, 119.6, 119.0, 111.2, 108.8, 52.6, 52.5, 50.6, 39.7, 33.5, 29.7, 10.7. IR (cmꢀ1) 2950, 1748, 1724,
1472, 1431, 1249, 1229, 1147,1033, 999 HRMS (EI) m/z: [M+] Calcd for C23H25NO4, 379.1784; Found 379.1786
(9b) dimethyl 2-(2-(1-methyl-2-phenyl-1H-indol-3-yl)-2-phenylethyl)malonate Following GP2, CP 8a (0.037 g, 0.16 mmol)
and 2ꢀphenylꢀ1ꢀmethylindole (0.036g, 0.17 mmol, 1.1 equiv) in HFIP (0.5 mL) were subjected to heat for 24 h. The crude
material was purified via flash column chromatography 20%EtOAc:80%Hex to collect a white solid (0.044 g, 62%). MP=
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119ꢀ120 °C Rf = 0.32 (20%EtOAc:80%Hex). 1H NMR (400 MHz, Chloroformꢀd) δ = 7.67 (d, J = 8.0 Hz, 1H), 7.49 – 7.43
(m, 3H), 7.37 (t, J = 7.9 Hz, 3H), 7.33 – 7.29 (m, 2H), 7.26 (m, 3H), 7.21 – 7.15 (m, 1H), 7.12 (ddd, J = 8.0, 7.1, 1.0 Hz, 1H),
4.08 (dd, J = 10.7, 5.8 Hz, 1H), 3.56 (s, 3H), 3.48 (s, 3H), 3.45 (s, 3H), 3.24 (dd, J = 9.2, 5.5 Hz, 1H), 2.91 – 2.72 (m, 2H).
13C NMR (101 MHz, CDCl3) δ = 169.9, 169.8, 144.7, 139.6, 137.7, 131.7, 131.0, 128.4, 127.8, 126.4, 126.1, 121.8, 120.8,
119.6, 112.8, 109.7, 52.4, 50.6, 40.5, 34.2, 31.0. IR (cmꢀ1) 3026, 2953, 1731, 1467, 1435, 1215, 1153, 701 HRMS (EI) m/z:
[M+] Calcd for C28H27NO4 441.1940; Found 441.1948
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(9c) dimethyl 2-(2-(1-methyl-1H-indol-3-yl)-2-phenylethyl)malonate Following GP2, CP 8a (0.05 g, 0.21 mmol) and 1ꢀ
methylindole (0.083g, 0.63 mmol) in HFIP (0.7 mL) were subjected to heat for 48 h. The crude material was purified via
flash column chromatography 20%EtOAc:80%Hex to collect a clear oil (0.026 g, 35%). Rf = 0.24 (20%EtOAc:80%Hex).
Characterization data matched literature reports.15 1H NMR (599 MHz, Chloroformꢀd) δ = 7.45 (dt, J = 7.8, 0.9 Hz, 1H),
7.34 – 7.25 (m, 5H), 7.19 (m, 2H), 7.02 (ddd, J = 7.9, 7.0, 1.0 Hz, 1H), 6.88 (s, 1H), 4.22 (t, J = 7.9 Hz, 1H), 3.74 (s, 3H),
3.73 (s, 3H), 3.67 (s, 3H), 3.41 (dd, J = 8.0, 6.6 Hz, 1H), 2.83 (ddd, J = 13.6, 8.0, 7.0 Hz, 1H), 2.62 (ddd, J = 13.6, 8.8, 6.7
Hz, 1H) 13C NMR (101 MHz, CDCl3) δ = 170.0, 143.6, 137.4, 128.7, 128.1, 127.3, 126.6, 126.2, 121.8, 119.6, 119.0, 117.3,
109.3, 52.7, 52.6, 50.2, 40.7, 35.1, 32.8. IR(cmꢀ1) 2952, 1754, 1488, 1282, 1159, 974
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(9d) dimethyl 2-(2-(1,2-dimethyl-1H-indol-3-yl)-2-(4-nitrophenyl)ethyl)malonate Following GP2, CP 8b (0.022 g, 0.08
mmol) and 1,2ꢀdimethylindole (0.034g, 0.24 mmol) in HFIP (0.3 mL) were subjected to heat for 25 h. The crude material
was purified via flash column chromatography 30%EtOAc:70%Hex to collect a yellow oil (0.07 g, 19%). Rf = 0.2
(30%EtOAc:70%Hex). 1H NMR (400 MHz, Chloroformꢀd) δ = 8.09 (d, J = 8.8 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.34 (d, J
= 8.0 Hz, 1H), 7.28 (t, J = 4.4 Hz, 1H), 7.14 (t, J = 8.1 Hz, 1H), 7.02 – 6.97 (m, 1H), 4.37 (t, J = 8.1 Hz, 1H), 3.73 (s, 3H),
3.67 (s, 3H), 3.54 (s, 3H), 3.27 (dd, J = 8.1, 6.7 Hz, 1H), 2.88 (dd, J = 9.0, 6.7 Hz, 1H), 2.32 (s, 3H) 13C NMR (101 MHz,
CDCl3) δ = 169.9, 169.6, 152.1, 146.4, 137.2, 134.7, 128.5, 126.2, 123.7, 121.1, 119.5, 119.0, 109.6, 109.1, 52.7, 52.6, 50.2,
39.6, 33.0, 29.8, 10.7. IR (cmꢀ1) 2952, 1732, 1596, 1516, 1471, 1434, 1344, 1251, 1230, 853 HRMS (EI) m/z: [M+] Calcd
for C23H24N2O6 424.1634; Found 424.1631
(9e) dimethyl 2-(2-(4-bromophenyl)-2-(1,2-dimethyl-1H-indol-3-yl)ethyl)malonate Following GP2, CP 8c (0.050 g, 0.16
mmol) and 1,2ꢀdimethylindole (0.070g, 0.48 mmol) in HFIP (0.55 mL) were subjected to heat for 24 h. The crude material
was purified via flash column chromatography 20%EtOAc:80%Hex to collect a viscous yellow oil (0.039 g, 54%). Rf = 0.26
(20%EtOAc:80%Hex). 1H NMR (400 MHz, Chloroformꢀd) δ = 7.43 (d, J = 7.9 Hz, 2H), 7.40 – 7.35 (m, 2H), 7.31 – 7.26
(m, 2H), 7.23 (s, 1H), 7.20 – 7.12 (m, 1H), 7.02 (m, 1H), 4.26 (t, J = 8.1 Hz, 1H), 3.76 (s, 3H), 3.69 (s, 3H), 3.57 (s, 3H),
3.30 (t, J = 7.9 Hz, 1H), 2.88 (m, 2H), 2.34 (s, 3H). 13C NMR (101 MHz, CDCl3) δ = 170.0, 169.8, 143.4, 137.1, 134.4,
131.4, 129.5, 126.4, 120.8, 119.9, 119.3, 119.2, 110.5, 108.9, 52.6, 52.5, 50.4, 39.1, 33.3, 29.8, 10.6. IR (cmꢀ1) 2947, 1730,
1433, 1368, 1222, 1150, 735, 691 HRMS (EI) m/z: [M+] Calcd for C23H24BrNO4 457.0889; Found 457.0889
(9f) dimethyl 2-(2-(4-chlorophenyl)-2-(1,2-dimethyl-1H-indol-3-yl)ethyl)malonate Following GP2, CP 8d (0.050 g, 0.19
mmol) and 1,2ꢀdimethylindole (0.081g, 0.59 mmol) in HFIP (0.6 mL) were subjected to heat for 48 h. The crude material
was purified via flash column chromatography 20%EtOAc:80%Hex to collect a clear oil (0.051 g, 66%). Rf = 0.23
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(20%EtOAc:80%Hex). H NMR (400 MHz, Chloroformꢀd) δ 7.44 (d, J = 7.9 Hz, 1H), 7.34 – 7.27 (m, 3H), 7.26 – 7.22
(m, 2H), 7.20 – 7.14 (m, 1H), 7.04 (t, J = 8.0 Hz, 1H), 4.29 (t, J = 8.1 Hz, 1H), 3.77 (s,3H), 3.70 (s, 3H), 3.58 (s, 3H), 3.31
(dd, J = 7.9, 6.9 Hz, 1H), 2.89 (m, 2H), 2.35 (s, 3H) 13C NMR (101 MHz, CDCl3) δ = 170.0, 169.8, 142.8, 137.1, 134.4,
131.8, 129.1, 128.4, 126.4, 120.8, 119.3, 119.2, 110.6, 108.9, 52.6, 52.5, 50.4, 39.1, 33.3, 29.7, 10.6. IR (cmꢀ1) 2951, 1731,
1490, 1471, 1434, 1250, 1151, 1013 HRMS (EI) m/z: [M+] Calcd for C23H24ClNO4 413.1394; Found 413.1393
General Experimental Procedure: Nucleophilic Opening of Bisꢀtrifluoroethylester Cyclopropanes (12aꢀi) (GP3)
To an argon flushed sealed tube was added cyclopropane (1 equiv.), indole substrate (3 equiv.) and HFIP for a concentration
of 0.3 M. The tube was sealed off and submerged into an oil bath at 80 °C and left to react for 8ꢀ24 h. Upon confirmation of
starting material consumption via TLC, the reaction was poured into a round bottom flask, rinsed with DCM and then
concentrated down in vacuo. The crude material was directly subjected to flash column chromatography using appropriate
eluent system of EtOAc:Hex to isolate purified material.
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(12a) bis(2,2,2-trifluoroethyl) 2-(2-(1-methyl-1H-indol-3-yl)-2-phenylethyl)malonate Following GP3, CP 11a (0.05 g, 0.13
mmol) and 1ꢀmethylindole (0.053g, 0.41 mmol) in HFIP (0.5 mL) were subjected to heat for 24 h. The crude material was
purified via flash column chromatography 12%EtOAc:88% Hexanes to collect a clear oil (0.057 g, 85%). Rf = 0.38 12%
EtOAc:88% Hexanes. 1H NMR (400 MHz, CDCl3) δ = 7.47 (d, J = 8.0 Hz, 1H), 7.35 – 7.27 (m, 5H), 7.24 – 7.18 (m, 2H),
7.09 – 7.01 (m, 1H), 6.88 (s, 1H), 4.57 – 4.38 (m, 4H), 4.26 (t, J = 8.0 Hz, 1H), 3.75 (s, 3H), 3.60 (t, J = 7.2 Hz, 1H), 2.96 –
2.85 (m, 1H), 2.76 – 2.65 (m, 1H). 19F NMR (376 MHz, Chloroformꢀd) δ = ꢀ73.74 (t, J = 7.3 Hz, 3F) ꢀ73.75 (t, J = 7.6 Hz,
3F). 13C NMR (101 MHz, CDCl3) δ = 167.3, 143.0, 137.5, 128.8, 128.0, 127.1, 126.9, 126.4, 122.7 (q, 1JCꢀF= 277 Hz),
122.7 (q, 1JCꢀF= 277 Hz), 122.0, 119.6, 119.2, 116.5, 109.4, 61.16 (q, 2JC-F = 37 Hz), 49.7, 40.7, 34.8, 32.9. IR (cmꢀ1) 3028,
1754, 1410, 1281, 1216, 1164, 1136, 977, 703 HRMS (EI) m/z: [M+] Calcd for C24H21F6NO4 501.1375; Found 501.1372
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(12b) bis(2,2,2-trifluoroethyl) 2-(2-(1-benzyl-1H-indol-3-yl)-2-phenylethyl)malonate Following GP3, CP 11a (0.05 g, 0.13
mmol) and 1ꢀbenzylindole (0.084g, 0.41 mmol) in HFIP (0.5 mL) were subjected to heat for 8 h. The crude material was
purified via flash column chromatography 10%EtOAc:90%Hex to collect a clear oil (0.070 g, 90%). Rf = 0.23
(10%EtOAc:90%Hex). 1H NMR (400 MHz, Chloroformꢀd) δ 7.47 (d, J = 7.9 Hz, 1H), 7.35 – 7.25 (m, 7H), 7.22 (dt, J =
8.6, 2.8 Hz, 2H), 7.18 – 7.09 (m, 3H), 7.04 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 6.99 (s, 1H), 5.29 (s, 2H), 4.57 – 4.38 (m, 4H),
4.28 (t, J = 8.0 Hz, 1H), 3.62 – 3.55 (m, 1H), 2.91 (dt, J = 14.1, 7.5 Hz, 1H), 2.71 (ddd, J = 13.9, 8.8, 6.8 Hz, 1H). 19F NMR
(376 MHz, Chloroformꢀd) δ = ꢀ73.72 (t, J = 8.1 Hz, 3F), ꢀ73.75 (t, J= 8.4 Hz, 3F). 13C NMR (101 MHz, CDCl3) δ = 167.3,
167.2, 142.8, 137.5, 137.0, 128.8, 128.7, 127.9, 127.7, 127.3, 126.8, 126.7, 125.6, 122.6 (q, 1JCꢀF = 278 Hz), 122.5 (q, 1JCꢀF
=
277 Hz), 122.2, 119.6, 119.4, 117.2, 109.9, 61.04 (q, 2JCꢀF = 37 Hz), 50.1, 49.5, 40.7, 34.7. IR (cmꢀ1) 3030, 1753, 1453, 1280,
1216, 1165, 977, 908 HRMS (EI) m/z: [M+] Calcd for C30H25F6NO4 577.1688; Found 577.1688
(12c) bis(2,2,2-trifluoroethyl) 2-(2-(1,2-dimethyl-1H-indol-3-yl)-2-phenylethyl)malonate Following GP3, CP 11 (0.05 g,
0.13 mmol) and 1,2ꢀdimethylindole (0.059g, 0.41 mmol) in HFIP (0.5 mL) were subjected to heat for 18 h. The crude
material was purified via flash column chromatography 12.5%EtOAc:87.5%Hex to collect a clear oil (0.050 g, 72%). Rf =
0.47 20%EtOAc:80% Hexanes. 1H NMR (400 MHz, Chloroformꢀd) δ = 7.50 (d, J = 8.0 Hz, 1H), 7.36 – 7.32 (m, 2H), 7.30
– 7.22 (m, 3H), 7.20 – 7.11 (m, 2H), 7.02 (ddd, J = 8.0, 7.1, 1.0 Hz, 1H), 4.50 (m, 2H (two overlapping dq unresolved)), 4.35
– 4.12 (m, 1H), 3.66 (s, 3H), 3.51 (dd, J = 9.3, 5.2 Hz, 1H), 3.07 – 2.87 (m, 2H), 2.32 (s, 3H). 19F NMR (376 MHz,
Chloroformꢀd) δ = ꢀ73.71 (dt, J = 8.3, 4.2 Hz, 3F), ꢀ73.87 (dt, J = 8.3, 0.9 Hz, 3F). 13C NMR (101 MHz, Chloroformꢀd) δ
= 167.3, 143.9, 137.1, 134.7, 128.5, 127.6, 126.5, 126.3, 122.7 (q, 1JCꢀF= 277 Hz), 122.6 (q, 1JCꢀF= 278 Hz), 120.8, 119.4,
119.3, 110.3, 109.0, 61.1 (q, 2JCꢀF = 36 Hz), 60.9 (q, 2JCꢀF = 37 Hz), 50.0, 39.9, 33.4, 29.8, 10.5 IR (cmꢀ1) 2941, 1753, 1409,
1280, 1162, 976, 700, 561 HRMS (EI) m/z: [M+] Calcd for C25H23F6NO4 515.1531; Found 515.1525
(12d) bis(2,2,2-trifluoroethyl) 2-(2-(1-methyl-2-phenyl-1H-indol-3-yl)-2-phenylethyl)malonate Following GP3, CP 11a
(0.050 g, 0.13 mmol) and 2ꢀphenylꢀ1ꢀmethylindole (0.084g, 0.41 mmol) in HFIP (0.5 mL) were subjected to heat for 4 h. The
crude material was purified via flash column chromatography 10%EtOAc:90%Hex to collect a clear oil (0.071 g, 91%). Rf =
0.32 (15%EtOAc:85%Hex). 1H NMR (599 MHz, Chloroformꢀd) δ = 7.62 (d, J = 8.0 Hz, 1H), 7.42 (m, 3H), 7.36 (d, J = 8.2
Hz, 1H), 7.32 (d, J = 7.5 Hz, 2H), 7.27 – 7.22 (m, 5H), 7.17 (t, J = 7.3 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 4.30 (dq, J = 12.6,
8.4 Hz, 1H), 4.19 (dq, J = 12.5, 8.3 Hz, 1H), 4.15 – 4.08 (m, 2H), 4.00 (dq, J = 12.6, 8.3 Hz, 1H), 3.56 (s, 3H), 3.39 (dd, J =
8.9, 5.4 Hz, 1H), 2.94 (ddd, J = 13.9, 11.5, 5.4 Hz, 1H), 2.80 (ddd, J = 14.1, 8.9, 5.4 Hz, 1H). 19F NMR (376 MHz,
Chloroformꢀd) δ ꢀ73.74 (t, J = 8.3 Hz, 3F), ꢀ73.88 (t, J = 8.9 Hz, 3F). 13C NMR (151 MHz, cdcl3) δ 167.0, 166.8, 144.1,
139.7, 137.6, 131.4, 130.8, 128.5, 128.4, 128.4, 127.6, 126.2, 126.1, 122.51 (q, 1JCꢀF = 277 Hz), 122.4 (q, 1JCꢀF = 277 Hz)
121.8, 120.5, 119.7, 111.8, 109.7, 60.9 (q, 2JCꢀF = 36 Hz, ), 60.7 (q, 2JCꢀF = 38 Hz), 49.9, 40.4, 33.9, 30.9. IR (cmꢀ1) 3091,
2940, 1774, 1756, 1279, 1240, 1165, 1138, 970, 742, 699, 648 HRMS (EI) m/z: [M+] Calcd for C30H25F6NO4 577.1688;
Found 577. 1693
(12e) bis(2,2,2-trifluoroethyl) 2-(2-(1-methyl-5-nitro-1H-indol-3-yl)-2-phenylethyl)malonate Following GP3, CP 11a (0.05
g, 0.13 mmol) and 5ꢀnitroꢀ1ꢀmethylindole (0.071g, 0.41 mmol) in HFIP (0.5 mL) were subjected to heat for 20 h. The crude
material was purified via flash column chromatography 40%EtOAc:60%Hex to collect a yellow solid (0.035 g, 47%). MP =
78ꢀ81 °C Rf = 0.28 40%EtOAc:60% Hexanes. 1H NMR (400 MHz, Chloroformꢀd) δ = 8.36 (d, J = 2.1 Hz, 1H), 8.09 (dd, J
= 9.1, 2.2 Hz, 1H), 7.37 – 7.26 (m, 6H), 7.06 (s, 1H), 4.65 – 4.40 (m, 4H), 4.26 (dd, J = 9.0, 6.9 Hz, 1H), 3.81 (s, 3H), 3.54
(dd, J = 7.9, 6.6 Hz, 1H), 2.84 (m, 1H), 2.70 (ddd, J = 14.0, 9.2, 6.6 Hz, 1H). 19F NMR (376 MHz, Chloroformꢀd) δ = ꢀ
73.69 – ꢀ73.87 (m, 6F). 13C NMR (101 MHz, CDCl3) δ = 167.1, 141.9, 141.5, 140.1, 129.2, 129.1, 127.9, 127.5, 126.4,
122.7 (q, 1JCꢀF=277.5 Hz), 122.6 (q, 1JCꢀF= 277.3 Hz) 120.0, 117.9, 116.8, 109.4, 61.30 (q, 2JCꢀF = 37.2 Hz), 49.4, 40.4, 34.7,
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Found 546.1226
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(12f) bis(2,2,2-trifluoroethyl) 2-(2-(5-methoxy-1-methyl-1H-indol-3-yl)-2-phenylethyl)malonate Following GP3, CP 11a
(0.05 g, 0.13 mmol) and 5ꢀmethoxyꢀ1ꢀmethylindole (0.065g, 0.41 mmol) in HFIP (0.5 mL) were subjected to heat for 18 h.
The crude material was purified via flash column chromatography 12.5%EtOAc:87.5%Hex to collect a clear oil (0.0632 g,
89%). Rf = 0.34 20%EtOAc:80% Hexanes. 1H NMR (400 MHz, Chloroformꢀd) δ = 7.33 – 7.29 (m, 4H), 7.22 (ddd, J = 8.6,
4.8, 3.3 Hz, 1H), 7.16 (d, J = 9.1 Hz, 1H), 6.90 – 6.82 (m, 3H), 4.58 – 4.40 (m, 4H), 4.19 (t, J = 8.0 Hz, 1H), 3.77 (s, 3H),
3.72 (s, 3H), 3.59 (t, J = 7.2 Hz, 1H), 2.88 (dt, J = 14.1, 7.5 Hz, 1H), 2.68 (ddd, J = 14.0, 8.7, 6.8 Hz, 1H) 19F NMR (376
MHz, Chloroformꢀd) δ = ꢀ73.73 (t, J = 8.7 Hz, 3F), ꢀ73.76 (t, J= 8.6 Hz, 3F). 13C NMR (101 MHz, CDCl3) δ = 167.4,
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167.3, 153.9, 143.0, 132.9, 128.8, 128.0, 127.4, 126.9, 122.7 (q, 1JCꢀF= 277 Hz), 116.0, 112.1, 110.2, 101.5, 61.15 (q, 2JCꢀF
=
37 Hz), 55.9, 49.6, 40.7, 34.7, 33.0. IR (cmꢀ1) 2945, 1753, 1623, 1491, 1280, 1162, 1136, 1058, 701 HRMS (EI) m/z: [M+]
Calcd for C25H23F6NO5 531.1481; Found 531.1483
(12g) bis(2,2,2-trifluoroethyl) 2-(2-(5-bromo-1-methyl-1H-indol-3-yl)-2-phenylethyl)malonate Following GP3, CP 11a
(0.05 g, 0.13 mmol) and 5ꢀbromoꢀ1ꢀmethylindole (0.085g, 0.41 mmol) in HFIP (0.5 mL) were subjected to heat for 16 h. The
crude material was purified via flash column chromatography 15%EtOAc:85%Hex to collect a paleꢀyellow oil (0.062 g,
79%). Rf = 0.40 15% EtOAc:85% Hexanes. 1H NMR (400 MHz, Chloroformꢀd) δ = 7.45 (d, J = 8.0 Hz, 1H), 7.33 – 7.26
(m, 4H), 7.23 – 7.17 (m, 2H), 7.03 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 6.87 (s, 1H), 4.56 – 4.37 (m, 4H), 4.24 (t, J = 8.0 Hz, 1H),
3.75 (s, 3H), 3.58 (t, J = 7.2 Hz, 1H), 2.88 (dt, J = 14.1, 7.5 Hz, 1H), 2.69 (ddd, J = 14.0, 8.6, 7.0 Hz, 1H). 19F NMR (376
MHz, Chloroformꢀd) δ = ꢀ73.73 (t, J = 7.6 Hz, 3F), ꢀ73.76 (t, J= 8.2 Hz, 3F). 13C NMR (101 MHz, CDCl3) δ = 167.3,
143.0, 137.5, 128.8, 128.0, 127.1, 126.9, 126.4, 122.7 (q, 1JCꢀF = 277 Hz), 122.6 (q, 1JCꢀF= 277 Hz), 122.0, 119.6, 119.2,
116.5, 109.4, 61.17 (q, 2JCꢀF = 37 Hz), 49.7, 40.7, 34.8, 32.9. IR (cmꢀ1) 2935, 1753, 1411, 1279, 1162, 976, 703, 664 HRMS
(EI) m/z: [M+] Calcd for C24H20BrF6NO4 579.0478; Found 579.0478
(12h) bis(2,2,2-trifluoroethyl) 2-(2-(4-bromophenyl)-2-(1-methyl-1H-indol-3-yl)ethyl)malonate Following GP3, CP 11b
(0.050 g, 0.11 mmol) and 1ꢀmethylindole (0.044g, 0.33 mmol) in HFIP (0.4 mL) were subjected to heat for 24 h. The crude
material was purified via flash column chromatography 15%EtOAc:85%Hex to collect a clear oil (0.061 g, 95%). Rf = 0.35
(15%EtOAc:85%Hex). 1H NMR (400 MHz, Chloroformꢀd) δ = 7.45 – 7.37 (m, 3H), 7.29 (d, J = 8.2 Hz, 1H), 7.24 – 7.15
(m, 3H), 7.08 – 7.01 (m, 1H), 6.88 (s, 1H), 4.61 – 4.36 (m, 4H), 4.21 (t, J = 8.0 Hz, 1H), 3.76 (s, 3H), 3.57 (t, J = 7.2 Hz,
1H), 2.86 (dt, J = 14.0, 7.6 Hz, 1H), 2.66 (ddd, J = 14.0, 8.1, 7.2 Hz, 1H). 19F NMR (376 MHz, Chloroformꢀd) δ = ꢀ73.73
(t, J = 8.2 Hz, 3F), ꢀ73.74 (t, J = 7.5 Hz, 3F) 13C NMR (101 MHz, CDCl3) δ = 167.3, 167.2, 142.2, 137.5, 131.9, 129.7,
126.9, 126.4, 122.7 (q, 1JCꢀF = 277 Hz), 122.2, 120.7, 119.4, 115.7, 109.5, 61.20 (q, 2JCꢀF = 37 Hz), 49.5, 40.1, 34.6, 32.9. IR
(cmꢀ1) 3422, 2945, 1754, 1411, 1279, 1162, 976, 701, 664 HRMS m/z: [M+] Calcd for C24H20BrF6NO4 579.0480; Found
579.0454
(12i) bis(2,2,2-trifluoroethyl) 2-(2-(1H-indol-3-yl)-2-phenylethyl)malonate Following GP3, CP 11a (0.050 g, 0.13 mmol)
and indole (0.047g, 0.41 mmol) in HFIP (0.5 mL) were subjected to heat for 24 h. The crude material was purified via flash
column chromatography 20%EtOAc:80%Hex to collect a clear oil (0.017 g, 25%). Rf = 0.23 (20%EtOAc:80%Hex). 1H
NMR (400 MHz, Chloroformꢀd) δ = 8.02 (s, br, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.37 – 7.27 (m, 5H), 7.24 – 7.13 (m, 2H),
7.08 – 7.00 (m, 2H), 4.59 – 4.38 (m, 4H), 4.26 (t, J = 8.0 Hz, 1H), 3.58 (t, J = 7.2 Hz, 1H), 2.90 (dt, J = 14.0, 7.5 Hz, 1H),
2.70 (ddd, J = 14.0, 8.7, 6.9 Hz, 1H) 19F NMR (376 MHz, Chloroformꢀd) δ = ꢀ73.75 (q, J = 8.9 Hz) 13C NMR (101 MHz,
CDCl3) δ 167.4, 167.3, 142.8, 136.7, 128.8, 128.0, 127.0, 126.7, 122.7 (q, 1JCꢀF = 277 Hz), 122.5, 121.5, 119.8, 119.5, 118.2,
111.3, 61.17 (q, 2JCꢀF = 37 Hz), 49.7, 40.7, 34.7. IR (cmꢀ1) 3422, 1752, 1457, 1413, 1281, 1165, 977 HRMS (EI) m/z: [M+]
Calcd for C23H19F6NO4 487.1218; Found 487.1219
Acknowledgments. We thank the Natural Sciences and Engineering Research Council of Canada for generous funding of this
research. LCI is the recipient of an Ontario Graduate Scholarship. We are grateful to Mr. Doug Hairsine of the Western University
Mass Spectrometry facility for performing MS analyses.
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1 Selected reviews on donorꢀacceptor cyclopropanes see: a) Pagenkopf, B.L.; Vemula, N. Cycloadditions of Donor–Acceptor
Cyclopropanes and Nitriles. Eur. J. Org. Chem 2017, 18, 2561ꢀ2567. b) Gharpure, S.J.; Nanda, L.N. Application of
Oxygen/Nitrogen Substituted DonorꢀAcceptor Cyclopropanes in the Total Synthesis of Natural Products. Tetrahedron Lett.
2017, 58, 711ꢀ720. c) Cavitt, M.A.; Phun, L.H.; France, S. Intramolecular Donor–Acceptor Cyclopropane RingꢀOpening
Cyclizations. Chem. Soc. Rev. 2014, 43, 804ꢀ818. d) Schneider, T.F.; Kaschel, J.; Werz, D. A New Golden Age for Donor–
Acceptor Cyclopropanes. Angew. Chem. Int. Ed. 2014, 53, 5504ꢀ5523 e) Lebold, T.P.; Kerr. M.A. Intramolecular
Annulations of Donor–Acceptor Cyclopropanes. Pure Appl. Chem. 2010, 82, 1797ꢀ1812 f) Ming, Y.; Pagenkopf, B.L. Recent
Advances in DonorꢀAcceptor (DA) Cyclopropanes. Tetrahedron 2005, 61, 321ꢀ347.
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2 a) Budynina, E.M.; Ivanov, K.L.; Sorokin, I.D.; Melnikov, M.Y. Ring Opening of Donor–Acceptor Cyclopropanes with Nꢀ
Nucleophiles. Synthesis 2017, 49, 3035ꢀ3068. b) Wales, S.M.; Walker, M.M.; Johnson, J.S. Asymmetric Synthesis of Indole
HomoꢀMichael Adducts via Dynamic Kinetic Friedel–Crafts Alkylation with Cyclopropanes. Org. Lett. 2013, 15, 2558ꢀ2561.
3 a) Humenny, W.J.; Kyriacou, P.; Sapeta, K.; Karadeolian, A.; Kerr. M.A. Multicomponent Synthesis of Pyrroles from
Cyclopropanes: A OneꢀPot Palladium (0)ꢀCatalyzed Dehydrocarbonylation/Dehydration. Angew. Chem. Int. Ed. 2012, 51,
11088ꢀ11091. b) Xiao, JꢀA.; Li, J.; Xia, PꢀJ.; Zhou, ZꢀF.; Deng, ZꢀX.; Xiang, HꢀY.; Chen, XꢀQ.; Yang, H. Diastereoselective
Intramolecular [3 + 2]ꢀAnnulation of Donor–Acceptor Cyclopropane with ImineꢀAssembling Hexahydropyrrolo[3,2-
c]quinolinone Scaffolds. J. Org. Chem. 2016, 81, 11185ꢀ11194. c) Leduc, A.B.; Lebold, T.P.; Kerr, M.A. Synthesis of
Tetrahydropyrans from Propargyl Alcohols and 1,1ꢀCyclopropanediesters: A OneꢀPot RingꢀOpening/Coniaꢀene Protocol. J.
Org. Chem. 2009, 74, 8414ꢀ8416. d) Carson, C.A.; Kerr, M.A. Heterocycles from Cyclopropanes: Applications in Natural
Product Synthesis. Chem. Soc. Rev. 2009, 38, 3051ꢀ3060. e) Pohlhaus, P.D.; Sanders, S.D.; Parsons, A.T.; Li, W.; Johnson,
J.S. Scope and Mechanism for Lewis AcidꢀCatalyzed Cycloadditions of Aldehydes and Donor−Acceptor Cyclopropanes:
Evidence for a Stereospecific Intimate Ion Pair Pathway. J. Am. Chem. Soc. 2008, 130, 8642ꢀ8650.
4 Huck, G.K.; Emmet, M.R.; Kerr, M.A. Carbocycles from DonorꢀAcceptor Cyclopropanes. Org. Biomol. Chem. 2015, 13,
655ꢀ671.
5 Harrington, P.; Kerr, M.A. The High Pressure Reaction of Cyclopropanes with Indoles Catalyzed by Ytterbium Triflate.
Tetrahedron Lett. 1997, 38, 5949ꢀ5952.
6 Emmett, M.R.; Kerr. M.A. Nuclleophilic Ring Opening of Cyclopropane Hemimalonates Using Internal Brønsted Acid
Activation. Org. Lett. 2011, 13, 4180ꢀ4183.
7 Richmond, E.; Vukovic, V.D.; Moran, J. Nucleophilic Ring Opening of Donor–Acceptor Cyclopropanes Catalyzed by a
Brønsted Acid in Hexafluoroisopropanol. Org. Lett. 2018, 20, 574ꢀ577.
8 Choy, J.; JaimeꢀFigueroa, S.; Jiang, L.; Wagner, P. Novel Practical Deprotection of NꢀBoc Compounds Using Fluorinated
Alcohols. Synth. Commun. 2008, 38, 3840ꢀ3853.
9 a) Preindl, J.; Chakrabarty, S.; Waser, J. Dearomatization of electron poor sixꢀmembered Nꢀheterocycles through [3 + 2]
annulation with aminocyclopropanes. Chem. Sci. 2017, 8, 7112ꢀ7118. b) Wang, ZꢀH.; Zhang, HꢀH.; Wang, DꢀM; Xu, PꢀF.;
Luo, YꢀC. Lewis acid catalyzed diastereoselective [3+4]ꢀannulation of donor–acceptor cyclopropanes with anthranils:
synthesis of tetrahydroꢀ1ꢀbenzazepine derivatives. Chemical Commun. 2017, 53, 8521ꢀ8524. c) Laugeois, M.; Ling, J.;
Ferard, C.; Michelet, V.; RatovelomananaꢀVidal, V.; Vitale, M. R. Palladium(0)ꢀCatalyzed Dearomative [3 + 2]
Cycloaddition of 3ꢀNitroindoles with Vinylcyclopropanes: An Entry to Stereodefined 2,3ꢀFused Cyclopentannulated Indoline
Derivatives. Org. Lett. 2017, 19, 2266ꢀ2269. d) Curiel Tejeda, J. E.; Irwin, L. C.; Kerr, M. A. Annulation Reactions of
Donor–Acceptor Cyclopropanes with (1ꢀAzidovinyl)benzene and 3ꢀPhenylꢀ2Hꢀazirine. Org. Lett. 2016, 18, 4738ꢀ4741 e)
Serrano, E.; de Nanteuil, F.; Waser, J. DiesterꢀSubstituted Aminocyclopropanes: Synthesis and Use in [3+2] Annulation
Reactions. Synlett 2014, 25, 2285ꢀ2288. f) de Nanteuil, F.; Loup, J.; Waser, J. Catalytic Friedel–Crafts Reaction of
Aminocyclopropanes. Org. Lett. 2013, 15, 3738ꢀ3741. .
10 a) Hamel, JꢀD.; Beaudoin, M.; Cloutier, M.; Paquin, JꢀF. HydrogenꢀBondꢀPromoted Friedel–Crafts Reaction of Secondary
Propargylic Fluorides: Preparation of 1ꢀAlkylꢀ1ꢀarylꢀ2ꢀalkynes. Synlett 2017, 28, 2823ꢀ2828 b) Champagne, P. A.;
Benhassine, Y.; Desroches, J.; Paquin, J. F. Friedel–Crafts Reaction of Benzyl Fluorides: Selective Activation of CF Bonds
as Enabled by Hydrogen Bonding Angew. Chem. Int. Ed. 2014, 53, 13835–13839.
11 Still, W.C.; Kahn, M.; Mitra, A. Rapid Chromatographic Technique for Preparative Separations with Moderate Resolution.
J. Org. Chem. 1978, 43, 2923ꢀ2925.
12 Tolnai, G.L.; Ganss, S.; Brand, J.P.; Waser, J. C2ꢀSelective Direct Alkynylation of Indoles. Org. Lett., 2012, 15, 112ꢀ115.
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13 Klare, H.F.T.; Oestreich, M.; Ito, Jꢀi.; Nishiyama, H.; Ohki, Y.; Tatsumi, K. Cooperative Catalytic Activation of Si−H
Bonds by a Polar Ru−S Bond: Regioselective LowꢀTemperature C−H Silylation of Indoles under Neutral Conditions by a
Friedel−Crafts Mechanism. J. Am. Chem. Soc., 2011, 133, 3312–3315.
14 (a) Johansen, M.B.; Kerr, M.A. Direct Functionalization of Indoles: CopperꢀCatalyzed Malonyl Carbenoid Insertions. Org.
Lett. 2010, 12, 4956ꢀ4959. (b) Perreault, C.; Goudreau, S. R.; Zimmer, L. E.; Charette, A. B. Cycloadditions of Aromatic
Azomethine Imines with 1,1ꢀCyclopropane Diesters. Org.Lett. 2008,10, 689.
15 Dulin, C.C.; Murphy, K.L.; Nolin, K.A. Calciumꢀcatalyzed FriedelꢀCrafts Addition of 1ꢀmethylindole to Activated
Cyclopropanes. Tetrahedron Lett. 2014, 55, 5280ꢀ5282.
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