Corey-Chaykovsky Reactions of Nitro Styrenes Enable cis-Configured Trifluoromethyl Cyclopropanes

Article abstract of DOI:10.1021/acs.joc.7b00951

Trifluoromethyl-substituted cyclopropanes are an attractive family of building blocks for the construction of pharmaceutical and agrochemical agents. This work demonstrated the utilization of fluorinated sulfur ylides as versatile reagents for Corey-Chaykovsky cyclopropanation reactions of nitro styrenes. This protocol favored the synthesis of cis-configured trifluoromethyl cyclopropanes for a broad range of substrates with excellent yields and good diastereoselectivities.

Full text of DOI:10.1021/acs.joc.7b00951

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Note
Corey Chaykovsky Reactions of Nitro Styrenes
Enable cis-Configured Trifluoromethyl Cyclopropanes
Katharina J. Hock, Renè Hommelsheim, Lucas Mertens,
Junming Ho, Thanh Vinh Nguyen, and Rene M Koenigs
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00951 • Publication Date (Web): 21 Jun 2017
Downloaded from http://pubs.acs.org on June 22, 2017
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The Journal of Organic Chemistry
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Corey Chaykovsky Reactions of Nitro Styrenes Enable cis-
Configured Trifluoromethyl Cyclopropanes
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Katharina J. Hock,#,§ Renè Hommelsheim,# Lucas Mertens,# Junming Ho,‡,* Thanh V. Nguyen§,*, Rene
M. Koenigs#,§,*
# Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
§ School of Chemistry, University of New South Wales, Sydney, Australia
‡ Institute of High Performance Computing, Agency for Science Technology and Research, Singapore
Supporting Information Placeholder
CF3
OTf
CF3
base
Ph
NO2
S
Ar
Ar
NO2
Ph
24 examples, yields up to 96%
d.r. up to 10:1
no diazo compound required
ABSTRACT: Trifluoromethylꢀsubstituted cyclopropanes are an attractive family of building blocks for the construction of pharꢀ
maceutical and agrochemical agents. This work demonstrated the utilization of fluorinated sulfur ylides as versatile reagents for
CoreyꢀChaykovsky cyclopropanation reactions of nitro styrenes. This protocol favored the synthesis of cisꢀconfigured trifluoromeꢀ
thyl cyclopropanes on a broad range of substrates with excellent yields and good diastereoselectivity.
salts offer attractive and reliable alternatives to trifluoro
Cyclopropanes are a small and fascinating class of building
diazoethane.12 This sulfonium salt was recently demonstrated
blocks and possess unique and highly desirable properties for
organic synthesis.1 Due to their unique structure, they allow
to be a versatile trifluoromethyl carbene source for ironꢀ
catalyzed cyclopropanation reactions of alkenes12b and Coreyꢀ
precise spatial arrangement of functional groups and hence
Chaykovsky cyclopropanation reactions of terminal vinyl
unsurprisingly cyclopropanes find widespread application in
ketones.12a In line with our current research interests in the
pharmaceutical or agrochemical research.1a,2 Of particular
chemistry of diazo compounds8 and electronꢀrich alkenes with
interest are fluorinated cyclopropane moieties where the
ylide character,13 we were intrigued to utilize fluorinated
introduction of one or more fluorine atoms3 can significantly
diphenylsulfonium ylides in the cyclopropanation reaction of
alter the chemical, biological and physiological properties of
the molecules.4 The construction of trifluoromethylꢀsubstituted
nitro styrenes. To our knowledge, there have been only a
limited number of examples in the literature describing
cyclopropanes is important in the design of new bioactive
cyclopropanation reactions of nitro styrene derivatives with
molecules, as they are often considered the fluorinated
bioisostere of the tertꢀbutyl group.5
sulfur ylides; however little was known about their substrate
scope and applicability.14 Herein, we report our development
Recently, there have been numerous innovative developments
in the synthesis of trifluoromethyl cyclopropanes, ranging
from the ringꢀcontraction reaction to the ringꢀclosure of
acyclic precursors or the [2+1] cycloaddition reaction between
alkenes and carbenes.5a,6 Of the latest strategy, trifluoro
diazoethane as CF3ꢀbearing carbene precursor has found its
way into the standard organic synthesis repertoire.7 However,
handling this small and reactive molecule is not favorable and
still poses serious safety hazards even with modern
technological solutions.8 Encouraged by our own experience
in the field,8 we set out to develop a new convenient and
efficient synthetic approach for the trifluoromethylation
reaction of alkenes using sulfur ylides (Scheme 1).
of the first general example of CoreyꢀChaykovsky
cyclopropanation reactions of nitro olefins, which enable
access to a family of synthetically useful trifluoromethylꢀ and
nitrogenꢀsubstituted cyclopropanes with unusual cisꢀ
configurations.
Scheme 1. Synthesis of trifluoromethyl cyclopropanes
Sulfurꢀylides are a wellꢀknown class of reagents and have
been extensively studied over the past years as stoichiometric
reagents9,10 or catalysts.11 Fluorinated sulfurꢀylides, however,
were only introduced recently as reagents for organic
synthesis.5a In particular, trifluoroethyl diphenylsulfonium
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Table 1. Optimization of reaction conditions
donating and withdrawing substituents in the paraꢀposition are
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well tolerated and the desired cisꢀtrifluoromethyl
cyclopropanes were isolated in moderate to excellent yields
and moderate to good diastereomeric excess. Further
investigations concentrated on orthoꢀ and metaꢀ substituted
nitro styrene. While a substantial decrease in reaction yield
was observed for oꢀmethyl or oꢀmethoxy nitro styrenes (Table
2, entry 4j and 4l), the more electronꢀdeficient fluorinated or
nitroꢀsubstituted analogues (Table 2, entry 4k and 4m) reacted
smoothly and the trifluoromethyl cyclopropanes were isolated
in excellent yields. Notably, the mesityl substituted nitro olefin
did not convert to the desired cyclopropane, probably due to
the bulkiness of the 2,4,6ꢀtrisubstituted aromatic system.
Halogens or electronꢀdonating groups are well tolerated in the
meta position; similarly disubstituted nitro styrenes smoothly
converted to the cyclopropanes product.
a
yieldb 3 yieldb 4 & epiꢀ3
9
#
base
solvent
toluene
CHCl3
CHCl3
CHCl3
CHCl3
DMF
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1
TBAT
TBAT
K2CO3
CsF
56%
n.d.
ꢀꢀ
37%
2
3
4
5
6
7
8
43%
7% (n.d.)
2% (n.d.)
No reaction
No reaction
67% (1:1)
60% (1:1)
85% (10:1)
ꢀꢀ
NaH
ꢀꢀ
Further studies concentrated on different carboꢀ and
heterocyclic substituted nitro styrene derivatives. In all cases,
the desired cisꢀconfigured cyclopropanes were obtained in
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
ꢀꢀ
DMAc
THF
n.d.
n.d.
9%
Table 2. Substrate scopea
9c
CHCl3
a
Nitro styrene 1a (0.2 mmol), sulfonium salt (2.0 eq.,
0.4 mmol), base (2.0 eq., 0.4 mmol) and 80 mg molecular sieves
4Å, were suspended in the indicated solvent and stirred at room
temperature for 4 hours. b Yields were reported for isolated prodꢀ
ucts; n.d. = not determined. c 24 hour reaction time.
We started our investigations towards the Corey Chaykovsky
cyclopropanation of nitro styrenes using trifluoroethyl
diphenylsulfonium triflate as the ylide precursor. As the base
plays a key role in the deprotonation of the sulfonium salt, we
first investigated different bases and were delighted to observe
that tetrabutyl ammonium difluoro triphenyl silicate (TBAT)
provided the desired cyclopropane in excellent total yield
(Table 1, entry 1). However, the reaction proceeded only with
little diastereoselectivity and 3 and 4 could be isolated with
56% and 37% yield, respectively. Different solvents were
investigated, and interestingly, a switch from toluene to
chloroform proved highly effective and a 20:1 mixture of
isomer 4 and 3 was obtained, yet with significantly diminished
yield (43%). Interestingly, epiꢀ3 was not formed under these
reaction conditions (Table 1, entry 2).
Further investigations thus concentrated on different bases
using chloroform as solvent. Potassium carbonate, cesium
fluoride and sodium hydride led to sluggish reactions and little
or no product could be isolated.15 We hypothesized that
hydrogen bonding catalysts might be beneficial for the
activation of nitro olefin; however, application of Schreiner’s
catalyst provided no reaction product in the absence of base.15
Surprisingly, cesium carbonate was very effective and the
desired product was obtained after 24 hours of reaction time in
85% yield as a 10:1 mixture of 4 and epiꢀ3 (Table 1, entry 9).
Again, different solvents were investigated, though only in
THF and dimethyl acetamide the desired cyclopropane could
be isolated in acceptable yield, however only as a 1:1 mixture
of 4 and epiꢀ3. In a further test, we probed this transformation
in the absence of base, yet no product was observed.15
a
Nitro styrene 1 (0.2 mmol), sulfonium salt 2 (2.0 eq.,
0.4 mmol), Cs2CO3 (2.0 eq., 0.4 mmol) and 80 mg molecular
sieves 4Å, were suspended in CHCl3 and stirred at room temperaꢀ
ture for 24 hours. Yields were reported for isolated products. D.r.
refers to the ratio of 4 and epiꢀ3 b Yield by NMR spectroscopy.
With the optimal conditions (Table 1, entry 9) in hand, we
subsequently investigated the substrate scope of this
transformation. We investigated
a range of different
substituted nitro styrenes. Different halogens, electron
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good to excellent yields with diastereomeric ratio ranging are provided in Figure S2 in SI). Whilst the 2’ conformer is
1
2
3
4
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from 3:1 to 8:1. Notably, heteroaromatic systems such as
pyridine, Bocꢀprotected indole and thiophene provided the
desired cyclopropanes in 78ꢀ80% isolated yield. The Boc
group proved to be compatible under the reaction conditions
as no cleavage was observed. Aliphatic nitroalkenes were
investigated, though the desired product (Table 2, entry 4x)
was obtained only in significantly reduced yield, as
determined by NMR spectroscopy. It should be noted, that αꢀ
methylꢀnitro styrene did not react under the present reaction
conditions.
the global minimum structure, the subsequent cyclization to
form 3 involves a significantly higher barrier of about 92.9 kJ
molꢀ1 due to poor alignment between the carbanion loneꢀpair
(HOMO) and the CꢀS antibonding σ* molecular orbital
(LUMO). By comparison, formation of the higher energy
intermediate 2 proceeds via a similar addition barrier (~ 58 kJ
molꢀ1), but the subsequent cyclization to form 4 has a
significantly lower barrier (19.5 kJ molꢀ1). As such, cyclization
of 2 (a reactive conformer) is likely to proceed very rapidly. It
is also noted that there may be sufficient time for 2 to
equilibrate into the global minimum 2’ conformer (the CꢀC
rotational barrier from 2 to 2’ is about 10 kJ molꢀ1). Analogous
free energy profiles for reactive conformers resulting in the
formation of epiꢀ4 display significantly higher barriers due to
steric effects (See SI). These results suggest that addition of
sulfur ylide to 1a to form 2 would lead to cyclopropane 4 as
the dominant kinetic product.
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Theoretical calculations (RIMP2/augꢀccꢀpVTZ//M062X/6ꢀ
31+G(d) and SMD implicit solvent model (chloroform))15,16
were carried out to investigate the proposed twoꢀstep
mechanism (Scheme 2), where the sulfur ylide first adds to the
nitro olefin to form a zwitterionic intermediate, followed by
cyclization to form the cyclopropane products. There are two
possible pathways involving Michael addition to either face of
the nitro olefin that will form one of the two diastereomeric
intermediates 2 and isoꢀ2.
Considering next the pathway involving the iso-2 diastereomer
(Scheme 2b). The free energy profiles involving the reactive
conformers iso-2 and iso-2’ that will lead to products 3 and
epiꢀ3 respectively are shown in Figure 2. The latter conformer
is not likely to be formed in the Michael addition step since it
would require the nitro olefin to be in the cisꢀconfiguration.
Most likely, formation of iso-2 takes place first, and can
interconvert with the iso-2’ conformer through rotation of the
–CHꢀNO2 group. Consistent with expectation, the cyclization
barrier of the reactive conformers is
Considering first the pathway involving diastereomer 2 that
leads to the formation of cisꢀconfigured trifluoromethyl
cyclopropane 4 (Scheme 2a). Figure 1 shows the free energy
profiles based on two different conformers (details of
conformer searches and structures of all relevant conformers
Scheme 2. Proposed mechanism of the reaction.
significantly lower compared to the Michael
addition step. The cyclization of iso-2 (to form
3) is approximately 28 kJ molꢀ1, whilst the
corresponding barrier for the iso-2’ (to form
epiꢀ3) is slightly lower around 23.5 kJ molꢀ1.
We have computed the barrier for rotation of –
CHꢀNO2 group iso-2 ꢀ> iso-2’ (39 kJ molꢀ1)
and found that it is higher than the barrier for
cyclization, which suggests that 3 is the
favored product.
Figure 2. Free energy profiles (kJ molꢀ1) or
two competing reactive conformations
involving the isoꢀ2 diastereomer and
formation of 3 and epi-3 (RIMP2/augꢀccꢀpVTZ//M062X/6ꢀ
31+G(d) and SMD implicit solvent model (chloroform)).
Figure 1. Free energy profiles involving reactive (red dashed)
and nonꢀreactive conformations for pathways involving the
diastereomer
2
and formation of
4
(RIMP2/augꢀccꢀ
pVTZ//M062X/6ꢀ31+G(d) and SMD implicit solvent model
(chloroform)).
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To reconcile with the experimental observation that epiꢀ3 is
Synthesis of Diphenyl(2,2,2-Trifluoroethyl) Sulfonium
Trifluoro Methanesulfonate. In a tightly capped vial, 4 mL
diphenyl (5 eq.) sulfide and trifluoro ethane
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2
3
4
5
6
7
8
formed when a strong base (Cs2CO3) is used, we hypothesize
that 3, which is formed first, can readily undergo
epimerization to form the thermodynamic product epiꢀ3 (see
entry 9 in Table 1 and SI page S2 for thermodynamic product
ratios predicted computationally and SI page S9 for the
experimentally oberseved isomerization).
1
g
trifluoromethylsulfonate (1 eq.) was added. The resulting
mixture was heated to 150 °C for 30 h, then slowly cooled to
room temperature. A white solid precipitated during cooling.
The reaction mixture was added 20 mL of diethyl ether and
the resulting mixture was filtered to afford the title compound
The above calculations indicate that 4 is the kinetic product
arising from Michael addition of the sulfur ylide to one face of
the nitro olefin. In support of these calculations, which predict
that the Michael addition step is rateꢀlimiting, simple kinetic
studies have shown that the rateꢀlimiting step is likely to
follow secondꢀorder kinetics.15 Based on the most favorable
pathways for the formation of 4 and 3, we note that the
barriers for the rateꢀlimiting step in each case is around 57.9
kJ molꢀ1 (1a + ylide ꢀ 2) and 61.4 kJ molꢀ1 (1a + ylide ꢀ iso-
2) respectively, because the latter transition state has a
configuration where the CF3 and NO2 groups are slightly
eclipsed. Naively, the difference in these barriers are actually
in accord with the observed 4 : 3 product ratios. These
mechanistic insights will facilitate in-silico screening of more
effective reagents, and further optimization of this synthetic
procedure.
1
as a colorless solid (1.51 g, 84%). H NMR (400 MHz, aceꢀ
toneꢀd6): δ = 8.38 – 8.37 (m, 4H), 7.98 – 7.90 (m, 2H), 7.89 –
7.83 (m, 4H), 5.75 (q, J = 8.8 Hz, 2H); 19F NMR (376 acetoneꢀ
d6): δ = ꢀ61.29 (t, J = 8.8 Hz), ꢀ78.95; MS (CI): m/z (%): 269.
([M+H], 100%), 214.2 ([MꢀOH], 53%), 185.2 ([MꢀNO2],
59%); HRMS (ESI): m/z calc. for [C14H12F3S+] = [MꢀOTf]+:
269.06063, found 269.06003; IR (KBr) = 3066, 299, 2935,
1449, 1339, 1241, 1157, 1093, 1020, 749, 685 cmꢀ1. The
analytical data is in correspondence with the literature.[12a]
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General
Cyclopropanation Reactions. Nitrostyrene (1eq, 0.2 mmol)
was added to diphenyl(2,2,2ꢀtrifluoroethyl)sulfonium
Procedure
for
the
Corey-Chaykovsky
trifluoromethane sulfonate (2 eq), Cs2CO3 (1.5 eq) and 4Å
molecular sieve (80 mg). Then 0.5 mL chloroform is added
under argon atmosphere and the resulting mixture is stirred for
24 h at rt. DCM and silicaꢀgel was added, and the solvent was
evaporated under reduced pressure to run a dry loaded column
to afford the desired product.
In conclusion, we have developed new convenient and
efficient synthetic approach for the sulfonium ylideꢀmediated
trifluoromethylation reactions of nitroalkenes to afford a
family of cisꢀtrifluoromethyl cyclopropanes. These
cyclopropanes are important synthetic building blocks that
possess unique and highly desirable configurational properties
for construction of pharmaceutical and agrochemical agents.
((1R*,2R*,3R*)-2-nitro-3-(trifluoromethyl)cyclopropyl) ben-
zene (4a). Compound 4a was prepared according to general
procedure and was obtained after column chromatography (nꢀ
pentane ꢀ> nꢀpentane: diethyl ether 50:1) as colorless liquid in
85% yield (39 mg, d.r. 10:1). 1H NMR (600 MHz, CDCl3): δ =
7.41 – 7.29 (m, 5H), 4.99 (dd, J = 4.7, 3.7 Hz) AND 4.85 (dd,
J = 9.2, 3.7 Hz, 1H), 3.70 – 3.49 AND 3.46 – 3.33 (m, 1H),
3.28 – 3.19 AND 3.15 – 3.04 (m, 1H); 13C NMR (151 MHz,
CDCl3): δ = 129.5, 128.8, 128.58, 128.54, 123.0 (q, J = 273.7
Hz), 59.4, 31.5, 30.3 (q, J = 37.3 Hz); 19F NMR (376 MHz,
CDCl3): δ = ꢀ60.86 (d, J = 7.0 Hz), ꢀ66.26 (d, J = 6.3 Hz);
Anal. Calcd for C10H8F3NO2: C, 51.96; H, 3.49; N, 6.06.
Found: C, 51.87; H, 3.75; N, 6.68; MS (CI): m/z (%): 232.2
([M+H], 100%), 214.2 ([MꢀOH], 53%), 185.2 ([MꢀNO2],
59%); IR (KBr) = 3061, 2902,2323, 2116, 1555, 1439, 1363,
1269, 1139, 742, 697 cmꢀ1; HPLC: tR (major) = 5.3 min, tR
(minor) = 6.5 min.
EXPERIMENTAL SECTION
Unless otherwise noted, all commercially available
compounds were used as provided without further purification.
Chemicals used in this manuscript were purchased from Sigma
Aldrich and Alfa Aesar.
Solvents used in reactions were p.A. grade. Solvents for
chromatography were technical grade and distilled prior to
use. Analytical thinꢀlayer chromatography (TLC) was
performed on MachereyꢀNagel silicaꢀgel aluminium plates
with Fꢀ254 indicator, visualised by irradiation under UV light.
Column chromatography was performed using silicaꢀgel
Merck 60 (particle size 0.063 – 0.2 mm). Solvent mixtures are
understood as volume/volume.
1H NMR, 19F NMR and 13C NMR were recorded on a Varian
AV600 or AV400 spectrometer in CDCl3. Data are reported in
the following order: chemical shift (δ) in ppm; multiplicities
are indicated br (broadened singlet), s (singlet), d (doublet), t
(triplet), q (quartet), p (pentelet) m (multiplet); coupling
constants (J) are in Hertz (Hz). EI MS data were recorded on a
Shimadzu GCMS sytem (QP 2010 SE and GC2010plus, CPꢀ
Silꢀ8ꢀMS column, 30 m, 0.25 ꢁm ID, method: 60 °C for 5 min,
20 K/min to 300 °C and keep for 20 min). HRMS data were
recorded on a Finnigan MAT 95 using EI ionization at 70 eV
or on a ThermoFisher Scientific LTQ Orbitrap XL using ESI
ionization. CI MS data were recorded on a Finnigan SSQ 7000
using CI Ionization at 100 eV (methane). IR spectra were
recorded on a Perkin Elmerꢀ100 spectrometer and are reported
in terms of frequency of absorption (cmꢀ1). Elemental analysis
was performed on an Elementar VarioEL instrument.
1-methyl-4-((1R*,2R*,3R*)-2-nitro-3-(trifluoromethyl)cyclo-
propyl)benzene (4b). Compound 4b was prepared according to
general procedure and was obtained after column
chromatography (nꢀpentane ꢀ> nꢀpentane: diethyl ether 50:1)
1
as yellowish liquid in 93% yield (46 mg, d.r. 4:1). H NMR
(600 MHz, CDCl3): δ = 7.21 – 7.15 (m, 4H), 4.96 (dd, J = 4.7,
3.7 Hz) AND 4.83 (dd, J = 9.2, 3.7 Hz, 1H), 3.65 – 3.54 AND
3.43 – 3.32 (m, 1H), 3.25 – 3.17 AND 3.13 – 3.02 (m, 1H),
2.35 (s) AND 2.34 (s, 1H).; 13C NMR (151 MHz, CDCl3): δ =
138.8, 138.4, 129.6, 129.5, 128.48, 128.41, 126.4, 126.0,
123.0 (q, J = 273.8 Hz), 60.8, 59.5, 31.3 (q, J = 37.0 Hz), 21.1;
19F NMR (564 MHz, CDCl3) δ = δ ꢀ60.79 (d, J = 7.4 Hz), ꢀ
66.24 (d,
J = 6.5 Hz); HRMS (EI): m/z calc. for
[C11H10F3NO2]: 245.06582, found 245.06683; IR (KBr) =
3094, 3056, 2105, 1555, 1441, 1366, 1269, 1141, 1036, 813,
733, 675 cmꢀ1.
1-fluoro-4-((1R*,2R*,3R*)-2-nitro-3-(trifluoromethyl)cyclo-
propyl)benzene (4c). Compound 4c was prepared according to
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general procedure and was obtained after column for [C11H10F3NO3]: 261.06073, found 261.06067; IR (KBr) =
1
2
chromatography (nꢀpentane ꢀ> nꢀpentane: diethyl ether 50:1)
3056, 2940, 2112, 1613, 1554, 1517, 1442, 1365, 1251, 1140,
1030, 830, 734 cmꢀ1.
1
as yellowish liquid in 94% yield (47 mg, d.r. 4:1). H NMR
3
4
5
6
7
8
9
(600 MHz, CDCl3): δ = 7.33 – 7.27 (m, 2H), 7.10 – 7.01 (m,
2H), 4.95 (dd, J = 4.7, 3.7 Hz) AND 4.84 (dd, J = 9.1, 3.6 Hz,
1H), 3.68 – 3.51 AND 3.42 – 3.25 (m, 1H), 3.24 – 3.16 AND
3.14 – 3.03 (m, 1H); 13C NMR (151 MHz, CDCl3): δ = 163.4,
161.7, 130.4, 130.3, 122.9 (q, J = 273.9 Hz), 116.1, 116.09,
1-ethoxy-4-((1R*,2R*,3R*)-2-nitro-3-(trifluoromethyl)cyclo-
propyl)benzene (4g). Compound 4g was prepared according to
general procedure and was obtained after column
chromatography (nꢀpentane ꢀ> nꢀpentane: diethyl ether 20:1)
1
as yellowish liquid in 91% yield (50 mg, d.r. 3:1). H NMR
116.02, 115.9, 60.7, 59.5, 30.7, 30.2 (q, J = 37.3 Hz), 29.2; 19
F
(600 MHz, CDCl3): δ = 7.24 – 7.13 (m, 2H), 6.90 – 6.81 (m,
2H), 4.93 (dd, J = 4.7, 3.7 Hz) AND 4.81 (dd, J = 9.1, 3.7 Hz,
1H), 4.10 – 3.90 (m, 3H), 3.61 – 3.50 AND 3.38 – 3.30 (m,
1H), 3.22 – 3.15 AND 3.11 – 2.96 (m, 1H), 1.45 – 1.36 (m,
3H); 13C NMR (151 MHz, CDCl3): δ = 159.3, 159.0, 129.8,
129.7, 123.0 (q, J = 274.0 Hz), 121.1, 114.8, 114.7, 63.4, 59.7,
31.1, 30.4 (q, J = 37.0 Hz), 29.7, 14.7; 19F NMR (564 MHz,
CDCl3) δ = ꢀ60.73 (d, J = 7.3 Hz), ꢀ66.23 (d, J = 6.5 Hz);
HRMS (EI): m/z calc. for [C12H12F3NO3]: 275.07638, found
275.0766; IR (KBr) = 2922, 2330, 2092, 1890, 1747, 1547,
1366, 1255, 1141, 829 cmꢀ1.
NMR (564 MHz, CDCl3) δ = 19F NMR (, Chloroformꢀd) δ ꢀ
60.81 (d, J = 7.3 Hz), ꢀ66.24 (d, J = 6.4 Hz), ꢀ111.98 – ꢀ112.26
(m), ꢀ112.55 – ꢀ112.76 (m); HRMS (EI): m/z calc. for
[C10H7F4NO2]: 249.04074, found 249.04162; IR (KBr) = 3066,
2914, 2667, 2332, 2093, 1890, 1755, 1548, 1366,, 1246, 1142,
832, 737 cmꢀ1.
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1-chloro-4-((1R*,2R*,3R*)-2-nitro-3-(trifluoromethyl)cyclo-
propyl)benzene (4d). Compound 4d was prepared according to
general procedure and was obtained after column
chromatography (nꢀpentane ꢀ> nꢀpentane: diethyl ether 50:1)
1
as colorless liquid in 85% yield (45 mg, d.r. 6:1). H NMR
1-isopropyl-4-((1R*,2R*,3R*)-2-nitro-3-(trifluoromethyl)
cyclopropyl)benzene (4h). Compound 4h was prepared
according to general procedure and was obtained after column
chromatography (nꢀpentane ꢀ> nꢀpentane: diethyl ether 50:1)
(600 MHz, CDCl3): δ = 7.42 – 7.27 (m, 2H), 7.28 – 7.19 (m,
2H), 4.95 (dd, J = 4.7, 3.7 Hz) AND 4.85 (dd, J = 9.1, 3.6 Hz,
1H), 3.65 – 3.47 AND 3.39 – 3.30 (m, 1H), 3.23 – 3.17 AND
3.16 – 3.03 (m, 1H); 13C NMR (151 MHz, CDCl3): δ = 135.0,
134.6, 129.99, 129.96, 129.2, 129.1, 128.0, 122.8 (q, J = 274.0
Hz), 60.6, 59.3, 30.7, 30.2 (q, J = 37.4 Hz), 29.3, 27.5 (q, J =
38.9 Hz); 19F NMR (564 MHz, CDCl3) δ = δ ꢀ60.83 (d, J = 7.0
Hz), ꢀ66.24 (d, J = 6.2 Hz); HRMS (EI): m/z calc. for
[C10H7ClF3NO2]: 265.01119, found 265.01132; IR (KBr) =
3092, 2919, 2313, 1556, 1365, 1267, 1144, 1096, 1018, 925,
824, 735 cmꢀ1.
1
as yellowish liquid in 68% yield (37 mg, d.r. 3:1). H NMR
(600 MHz, CDCl3): δ = 7.24 – 7.17 (m, 4H), 4.96 (dd, J = 4.8,
3.7 Hz) AND 4.83 (dd, J = 9.2, 3.7 Hz, 1H), 3.65 – 3.54 AND
3.46 – 3.34 (m, 1H), 3.25 – 3.16 AND 3.15 – 3.02 (m, 1H),
2.90 (hept, J = 6.8 Hz, 1H), 1.27 – 1.21 (m, 6fH); 13C NMR
(151 MHz, CDCl3): δ = 149.7, 149.3, 128.59, 128.50, 127.0,
126.9, 126.7, 123.0 (q, J = 273.8 Hz), 60.9, 59.6, 33.7, 33.7,
31.4, 30.4 (q, J = 37.1 Hz), 29.9, 27.4 (q, J = 38.7 Hz), 23.8,
23.7; 19F NMR (564 MHz, CDCl3) δ = ꢀ60.75 (d, J = 7.2 Hz), ꢀ
1-((1R*,2R*,3R*)-2-nitro-3-(trifluoromethyl)cyclopropyl)-4-
(trifluoromethyl)benzene (4e). Compound 4e was prepared
according to general procedure and was obtained after column
chromatography (nꢀpentane ꢀ> nꢀpentane: diethyl ether 50:1)
66.26 (d,
J = 6.4 Hz); HRMS (EI): m/z calc. for
[C13H14F3NO2]: 273.09712 , found 273.09748; IR (KBr) =
2959, 2321, 2097, 1905, 1739, 1552, 1364, 12669, 1143, 837,
733 cmꢀ1.
1
as colorless liquid in 90% yield (54 mg, d.r. 5:1). H NMR
(600 MHz, CDCl3): δ = 7.64 (m, 2H), 7.50 – 7.36 (m, 2H),
5.01 (dd, J = 4.8, 3.7 Hz) AND 4.90 (dd, J = 9.1, 3.7 Hz, 1H),
3.76 – 3.61 AND 3.47 – 3.34 (m, 1H), 3.32 – 3.22 AND 3.22
– 3.08 (m, 1H); 13C NMR (151 MHz, CDCl3): δ = 133.5, 130.9
(q, J = 33.0 Hz), 129.17, 129.12, 126.2 – 125.3 (m), 123.6 (q,
J = 272.5 Hz), 122.79 (q, J = 274.1 Hz), 60.5, 59.1, 30.7, 30.2
(q, J = 37.5 Hz), 29.3, 27.5 (d, J = 38.9 Hz); 19F NMR (564
MHz, CDCl3) δ = ꢀ60.90 (d, J = 6.9 Hz), ꢀ62.88, ꢀ62.91, ꢀ
66.25 (d, J = 6.1 Hz); Anal. Calcd for C11H7F6NO2: C, 44.16;
H, 2.36; N, 4.68. Found: C, 44.31; H, 3.23; N, 5.17; MS (CI):
m/z (%): 300.2 ([M+H], 100%), 282.2 ([MꢀOH], 55%), 280.1
([MꢀF], 94%), 253.2 ([MꢀNO2], 38%); IR (KBr) = 3090, 2922,
1558, 1368, 1323, 1269, 1130, 837, 727 cmꢀ1.
4-((1R*,2R*,3R*)-2-nitro-3-(trifluoromethyl)cyclopropyl)-
1,1'-biphenyl (4i). Compound 4i was prepared according to
general procedure and was obtained after column
chromatography (nꢀpentane ꢀ> nꢀpentane: diethyl ether 50:1)
1
as yellowish solid in 87% yield (43 mg, d.r. 4:1). H NMR
(600 MHz, CDCl3): δ = 7.65 – 7.54 (m, 4H), 7.51 – 7.41 (m,
2H), 7.41 – 7.33 (m, 3H), 5.03 (dd, J = 4.8, 3.7 Hz) AND 4.88
(dd, J = 9.2, 3.7 Hz, 1H), 3.78 – 3.64 AND 3.54 – 3.37 (m,
1H), 3.34 – 3.24 AND 3.20 – 3.07 (m, 1H); 13C NMR (151
MHz, CDCl3): δ = 141.8, 141.4, 140.0, 129.08, 129.01, 128.8,
128.4, 127.9, 127.7, 127.6, 127.5, 127.08, 127.04, 123.0 (q, J
= 274.0 Hz), 60.9, 59.5, 31.2, 30.4 (q, J = 37.3 Hz), 29.8, 27.5
(q, J = 38.8 Hz); 19F NMR (564 MHz, CDCl3) δ = ꢀ60.72 (d, J
= 7.1 Hz), ꢀ66.20 (d, J = 6.2 Hz); HRMS (EI): m/z calc. for
[C16H12F3NO2]: 307.08147 , found 307.08117; m.p. = 106ꢀ111
°C; IR (KBr) = 3063, 2922, 1553, 1441, 1363, 1266, 1140,
1032, 838, 762, 693 cmꢀ1.
1-methoxy-4-((1R*,2R*,3R*)-2-nitro-3-(trifluoromethyl)cyclo-
propyl)benzene (4f). Compound 4f was prepared according to
general procedure and was obtained after column
chromatography (nꢀpentane ꢀ> nꢀpentane: diethyl ether 20:1)
1
as colorless liquid in 88% yield (46 mg, d.r. 3:1). H NMR
1-methoxy-2-((1R*,2R*,3R*)-2-nitro-3-(trifluoromethyl)cyclo-
propyl)benzene (4j). Compound 4j was prepared according to
general procedure and was obtained after column
chromatography (nꢀpentane ꢀ> nꢀpentane: diethyl ether 20:1)
(600 MHz, CDCl3): δ = 7.24 – 7.16 (m, 2H), 6.92 – 6.84 (m,
2H), 4.94 (dd, J = 4.7, 3.7 Hz, AND 4.81 (dd, J = 9.1, 3.7 Hz,
1H), 3.81 (s) AND 3.80 (s, 1H), 3.64 – 3.47 AND 3.40 – 3.29
(m, 1H), 3.23 – 3.15 AND 3.12 – 2.92 (m, 1H); 13C NMR (151
MHz, CDCl3): δ = 159.6, 129.8, 129.7, 122.6 (q, J = 400.1
Hz), 114.3, 114.2, 59.7, 55.2, 31.0, 30.4 (q, J = 37.2 Hz), 29.6,
27.5 (q, J = 38.4 Hz); 19F NMR (376 MHz, CDCl3) δ = ꢀ60.73
(d, J = 7.1 Hz), ꢀ66.23 (d, J = 6.4 Hz); HRMS (EI): m/z calc.
1
as colorless liquid in 56% yield (29 mg, d.r. 3:1). H NMR
(600 MHz, CDCl3): δ = 7.32 (m, 1H), 7.26 – 7.16 (m, 1H),
7.03 – 6.81 (m, 2H), 4.92 (dd, J = 5.0, 3.8 Hz) AND 4.89 (dd,
J = 9.0, 3.7 Hz, 1H) 3.87 (s) AND 3.79 (s, 1H), 3.52 – 3.46
ACS Paragon Plus Environment

The Journal of Organic Chemistry
AND 3.32 – 3.22 (m, 1H), 3.17 – 3.02 (m, 1H); 13C NMR (151
Page 6 of 8
1-bromo-3-((1R*,2R*,3R*)-2-nitro-3-(trifluoromethyl)cyclo-
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MHz, CDCl3): δ = 158.3, 158.1, 130.1, 129.9, 129.8, 128.7,
123.2 (d, J = 274.0 Hz), 120.6, 120.3, 118.1, 110.5, 110.4,
60.3, 59.6, 55.4, 30.2 (q, J = 37.2 Hz), 28.0, 26.7; 19F NMR
(564 MHz, CDCl3) δ = ꢀ61.43 (d, J = 7.4 Hz), ꢀ66.25 (d, J =
6.5 Hz); HRMS (EI): m/z calc. for [C11H10F3NO3]: 261.06073,
found 261.06111; IR (KBr) = 2933, 2334, 2092, 1895, 1747,
1551, 1461, 1362, 1261, 1141, 752 cmꢀ1.
propyl)benzene (4n). Compound 4n was prepared according to
general procedure and was obtained after column
chromatography (nꢀpentane ꢀ> nꢀpentane: diethyl ether 50:1)
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as yellowish liquid in 86% yield (53 mg, d.r. 5:1). H NMR
(600 MHz, CDCl3): δ = 7.53 – 7.42 (m, 2H), 7.29 – 7.18 (m,
2H), 4.96 (dd, J = 4.8, 3.7 Hz) AND 4.85 (dd, J = 9.1, 3.7 Hz,
1H), 3.79 – 3.54 AND 3.47 – 3.33 (m, 1H), 3.33 – 3.17 AND
3.19 – 2.97 (m, 1H); 13C NMR (151 MHz, CDCl3): δ = 132.1,
131.8, 131.7, 131.6, 130.4, 127.29, 127.22, 122.84, 122.83 (q,
J = 274.0 Hz), 60.6, 59.1, 30.6, 30.2 (q, J = 37.5 Hz); 19F
NMR (564 MHz, CDCl3) δ = ꢀ60.85 (d, J = 7.1 Hz), ꢀ66.24 (d,
J = 6.4 Hz); HRMS (EI): m/z calc. for [C10H7BrF3NO2]:
308.96068, found 308.96081; IR (KBr) = 3086, 2325, 1556,
1439, 1363, 1266, 1145, 1088, 890, 784, 675 cmꢀ1.
1-fluoro-2-((1R*,2R*,3R*)-2-nitro-3-(trifluoromethyl)cyclo-
propyl)benzene (4k). Compound 4k was prepared according to
general procedure and was obtained after column
chromatography (nꢀpentane ꢀ> nꢀpentane: diethyl ether 50:1)
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as yellowish liquid in 86% yield (43 mg, d.r. 4:1). H NMR
(600 MHz, CDCl3): δ = 7.40 – 7.32 (m, 1H), 7.30 – 7.22 (m,
1H), 7.20 – 7.03 (m, 2H), 5.02 (dd, J = 4.9, 3.8 Hz) AND 4.91
(dd, J = 8.9, 3.7 Hz, 1H), 3.59 – 3.52 AND 3.41 – 3.34 (m,
1H), 3.21 – 3.09 (m, 1H); 13C NMR (151 MHz, CDCl3): δ =
161.6 (d, J = 249.1 Hz), 130.7 (d, J = 8.3 Hz), 130.5 (d, J =
8.4 Hz), 130.2, 129.6, 124.4 (d, J = 3.7 Hz), 124.3 (d, J = 3.8
Hz), 122.8 (q, J = 273.9 Hz), 117.1 (d, J = 14.4 Hz), 115.9 (d,
J = 21.1 Hz), 115.7, 59.9, 58.8, 29.8 (q, J = 37.5 Hz), 25.9,
24.7; 19F NMR (564 MHz, CDCl3) δ = ꢀ61.69 (dd, J = 7.1, 3.4
Hz), ꢀ66.37 (d, J = 6.2 Hz), ꢀ114.87 – ꢀ115.31 (m), ꢀ115.64 – ꢀ
116.00 (m); HRMS (EI): m/z calc. for [C10H7F4NO2]:
249.04074, found 249.04156; IR (KBr) = 3067, 2921, 2678,
2334, 2094, 1747, 1553, 1457, 1367, 1258, 1146, 756 cmꢀ1.
1-methoxy-3-((1R*,2R*,3R*)-2-nitro-3-(trifluoromethyl)cyclo-
propyl)benzene (4o). Compound 4o was prepared according to
general procedure and was obtained after column
chromatography (nꢀpentane ꢀ> nꢀpentane: diethyl ether 20:1)
1
as a colorless liquid in 98% yield (51 mg, d.r. 3:1). H NMR
(600 MHz, CDCl3): δ = 7.35 – 7.25 (m, 1H), 6.97 – 6.76 (m,
3H), 4.96 (dd, J = 4.8, 3.7 Hz, AND 4.84 (dd, J = 9.2, 3.7 Hz,
1H), 3.81 (s) AND 3.80 (s, 1H), 3.65 – 3.60 AND 3.48 – 3.33
(m, 1H), 3.32 – 3.18 AND 3.18 – 3.03 (m, 1H); 13C NMR (151
MHz, CDCl3): δ =159.8, 130.9, 130.0, 129.9, 123.0 (q, J =
273.7 Hz), 114.5, 114.1, 113.8, 59.5, 55.2, 31.4, 30.3 (q, J =
37.3 Hz); 19F NMR (564 MHz, CDCl3) δ ꢀ60.87 (d, J = 7.0
Hz), ꢀ66.26 (d, J = 6.4 Hz); HRMS (EI): m/z calc. for
[C11H10F3NO3]: 261.06073, found 261.06070; IR (KBr) =
3057, 2936, 2326, 2093, 1744, 1561, 1455, 1363, 1263, 1145,
1047, 778, 692 cmꢀ1.
1-methyl-2-((1R*,2R*,3R*)-2-nitro-3-(trifluoromethyl)cyclo-
propyl)benzene (4l). Compound 4l was prepared according to
general procedure and was obtained after column
chromatography (nꢀpentane ꢀ> nꢀpentane: diethyl ether 50:1)
1
as yellowish liquid in 53% yield (26 mg, d.r. 3:1). H NMR
(600 MHz, CDCl3): δ = 7.25 – 7.21 (m, 1H), 7.17 – 7.04 (m,
3H), 4.97 (dd, J = 4.7, 3.7 Hz) AND 4.83 (dd, J = 9.2, 3.7 Hz,
1H), 3.66 – 3.56 AND 3.44 – 3.29 (m, 1H), 2.36 (s) AND 2.35
(s, 3H); 13C NMR (151 MHz, CDCl3): δ = 138.6, 129.6, 129.4,
129.29, 129.22, 128.8, 128.7, 125.6, 125.5, 123.0 (q, J = 273.8
Hz), 60.8, 59.5, 31.5, 30.3 (q, J = 37.0 Hz), 21.3; 19F NMR
(564 MHz, CDCl3) δ = ꢀ60.83 (d, J = 7.1 Hz), ꢀ66.25 (d, J =
6.2 Hz); HRMS (EI): m/z calc. for [C11H10F3NO2]: 245.06582,
found 245.06612; IR (KBr) = 3051, 2920, 2675, 2328, 2092,
1746, 1553, 1454, 1364, 1264, 1141, 929, 778, 700 cmꢀ1.
5-((1R*,2R*,3R*)-2-nitro-3-(trifluoromethyl)cyclopropyl)
benzo[d][1,3]dioxole (4p). Compound 4p was prepared
according to general procedure and was obtained after column
chromatography (nꢀpentane ꢀ> nꢀpentane: diethyl ether 20:1)
1
as a yellowish liquid in 91% yield (50 mg, d.r. 6:1). H NMR
(600 MHz, CDCl3): δ = 6.81 – 6.69 (m, 3H), 6.10 – 5.93 (m,
2H), 4.90 (dd, J = 4.6, 3.7 Hz) AND 4.80 (dd, J = 9.1, 3.7 Hz,
1H), 3.70 – 3.52 AND 3.44 – 3.26 (m, 1H), 3.27 – 3.12 AND
3.10 – 2.94 (m, 1H); 13C NMR (151 MHz, CDCl3): δ = 148.0,
147.8, 123.0 (q, J = 274.3 Hz), 122.9, 122.3, 122.0, 108.9,
108.8, 108.6, 108.5, 101.4, 60.8, 59.7, 31.3, 30.3 (q, J = 37.1
Hz), 29.8, 27.7 (q, J = 38.7 Hz); 19F NMR (564 MHz, CDCl3)
δ = ꢀ60.77 (d, J = 7.4 Hz), ꢀ66.25 (d, J = 6.4 Hz); HRMS (EI):
m/z calc. for [C11H8F3NO4]: 275.03999, found 275.04036; IR
(KBr) = 3061, 2909, 2311, 2083, 1744, 1553, 1467, 1364,
1244, 1138, 1036, 931, 820, 736 cmꢀ1.
1-nitro-2-((1R*,2R*,3R*)-2-nitro-3-(trifluoromethyl)cyclopro-
pyl)benzene (4m). Compound 4m was prepared according to
general procedure and was obtained after column
chromatography (nꢀpentane ꢀ> nꢀpentane: diethyl ether 10:1)
1
as yellowish solid in 89% yield (49 mg, d.r. 3:1). H NMR
(600 MHz, CDCl3): δ = 8.34 – 8.08 (m, 1H), 7.83 – 7.66 (m,
1H), 7.64 – 7.48 (m, 2H), 5.04 (dd, J = 9.0, 3.7 Hz) AND 4.99
(dd, J = 5.2, 3.7 Hz, 1H), 4.26 – 4.09 AND 3.70 – 3.57 (m,
1H), 3.48 – 3.36 AND 3.35 – 3.21 (m, 1H); 13C NMR (151
MHz, CDCl3): δ = 149.1, 134.0, 133.99, 131.91, 130.7, 130.2,
130.0, 125.8, 125.65, 125.61, 124.5 (q, J = 263.0 Hz), 60.8,
59.8, 30.4, 30.0 (q, J = 37.2 Hz), 29.3, 28.9 (m); 19F NMR
(564 MHz, CDCl3) δ = ꢀ62.08 (d, J = 7.1 Hz), ꢀ66.06 (d, J =
6.1 Hz); Anal. Calcd for C10H7F3N2O4: C, 43.49; H, 2.55; N,
10.14. Found: C, 43.55; H, 2.62; N, 10.06; MS (CI): m/z (%):
230.2 ([MꢀNO2], 9%), 186.2 ([Mꢀ2(NO2)], 16%), 166.1 ([Mꢀ
2(NO2)F], 90%), 117.1 ([Mꢀ2(NO2)CF3], 32%); m.p. = 66ꢀ69
°C; IR (KBr) = 3068, 2922, 1527, 1439, 1350, 1262,
1139,1031, 955, 835, 792, 737 cmꢀ1.
1,2-dichloro-4-((1R*,2R*,3R*)-2-nitro-3-(trifluoromethyl)
cyclopropyl)benzene (4q). Compound 4q was prepared
according to general procedure and was obtained after column
chromatography (nꢀpentane ꢀ> nꢀpentane: diethyl ether 50:1)
1
as a yellowish liquid in 90% yield (54 mg, d.r. 6:1). H NMR
(600 MHz, CDCl3): δ = 7.49 – 7.37 (m, 2H), 7.20 – 7.06 (m,
1H), 4.94 (dd, J = 4.8, 3.7 Hz) AND 4.85 (dd, J = 9.1, 3.7 Hz,
1H), 3.74 – 3.49 AND 3.47 – 3.29 (m, 1H), 3.24 – 2.97 (m,
1H); 13C NMR (151 MHz, CDCl3): δ = 133.2, 133.1, 130.9,
130.7, 130.6, 129.6, 127.9, 127.8, 122.7 (q, J = 274.2 Hz),
59.1, 30.4 (q, J = 37.4 Hz), 30.0; 19F NMR (564 MHz, CDCl3)
δ = ꢀ60.82 (d, J = 7.0 Hz), ꢀ66.23 (d, J = 6.1 Hz); HRMS (EI):
m/z calc. for [C10H6Cl2F3NO2]: 298.97222, found 298.97362;
IR (KBr) = 3094, 2918, 1556, 1444, 1363, 1266, 1139, 1034,
819, 737, 679 cmꢀ1.
ACS Paragon Plus Environment

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The Journal of Organic Chemistry
1,3-dimethoxy-5-((1R*,2R*,3R*)-2-nitro-3-(trifluoromethyl) calc. for [C9H7F3N2O2]: 232.04541, found 232.04644; IR
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cyclopropyl)benzene (4r). Compound 4r was prepared
according to general procedure and was obtained after column
chromatography (nꢀpentane ꢀ> nꢀpentane: diethyl ether 20:1)
(KBr) = 3441, 3036, 2324, 2097, 1741, 1556, 1370, 1265,
1142, 710 cmꢀ1.
tert-butyl 3-((1R*,2R*,3R*)-2-nitro-3-(trifluoromethyl)cyclo-
propyl)-1H-indole-1-carboxylate (4v). Compound 4v was
prepared according to general procedure and was obtained
after column chromatography (nꢀpentane ꢀ> nꢀpentane: diethyl
ether 10:1) as a yellowish liquid in 78% yield (58 mg, d.r.
1
as a colorless liquid in 96% yield (56 mg, d.r. 3:1). H NMR
(600 MHz, CDCl3): δ = 6.58 – 6.34 (m, 3H), 4.93 (dd, J = 4.7,
3.7 Hz) AND 4.82 (dd, J = 9.2, 3.6 Hz, 1H), 3.79 (s) AND
3.78 (s, 3H), 3.62 – 3.56 AND 3.40 – 3.31 (m, 1H), 3.23 –
3.15 AND 3.14 – 3.00 (m, 1H); 13C NMR (151 MHz, CDCl3):
δ = 161.07, 161.03, 131.6, 131.3, 123.2 (q, J = 272.7 Hz),
123.0 (q, J = 273.8 Hz), 106.8, 106.7, 100.5, 100.2, 60.7, 59.4,
55.39, 55.37, 31.6, 30.3 (q, J = 37.5 Hz), 30.0, 27.5 (q, J =
38.9 Hz); 19F NMR (564 MHz, CDCl3) δ = ꢀ60.91 (d, J = 7.1
Hz), ꢀ66.28 (d, J = 6.2 Hz); HRMS (EI): m/z calc. for
[C12H12F3NO4]: 291.07129, found 291.07112; IR (KBr) =
29053, 2314, 2093, 1742, 1573, 1442, 1364, 1258, 1152, 944,
840, 689 cmꢀ1.
1
3:1). H NMR (600 MHz, CDCl3): δ = 8.23 – 8.03 (m, 1H),
9
7.68 – 7.51 (m, 2H), 7.42 – 7.27 (m, 2H), 5.01 – 4.94 (m, 1H),
3.53 – 3.46 AND 3.45 – 3.33 (m, 1H), 3.27 – 3.14 (m, 1H),
1.68 (s, 9H); 13C NMR (151 MHz, CDCl3): δ = 149.2, 135.2,
129.4, 125.3, 125.2, 124.5, 123.0 (q, J = 273.6 Hz), 123.1,
118.5, 118.1, 115.6, 115.5, 109.6, 109.2, 84.5, 60.2, 59.3, 29.7
(q, J = 37.7 Hz), 28.1, 27.4 (q, J = 38.7 Hz), 23.2, 21.8; 19F
NMR (564 MHz, CDCl3) δ = ꢀ60.86 (d, J = 7.0 Hz), ꢀ66.16 (d,
J = 6.3 Hz); HRMS (EI): m/z calc. for [C17H17F3N2O4]:
370.11349 , found 370.11520; IR (KBr) = 3065, 2982, 1733,
1556, 1454, 1370, 1258, 1145, 914, 847, 741 cmꢀ1.
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2-((1R*,2R*,3R*)-2-nitro-3-(trifluoromethyl)cyclopropyl)
naphthalene (4s). Compound 4s was prepared according to
general procedure and was obtained after column
chromatography (nꢀpentane ꢀ> nꢀpentane: diethyl ether 50:1)
2-((1R*,2R*,3R*)-2-nitro-3-(trifluoromethyl)cyclopropyl)thio-
phene (4w). Compound 4w was prepared according to general
procedure and was obtained after column chromatography (nꢀ
pentane ꢀ> nꢀpentane: diethyl ether 50:1) as a yellowish liquid
in 80% yield (38 mg, d.r. 8:1). 1H NMR (600 MHz, CDCl3): δ
= 7.35 – 7.27 (m, 1H), 7.07 – 6.95 (m, 2H), 4.98 (t, J = 4.2
Hz) AND 4.83 (dd, J = 8.8, 3.9 Hz, 1H), 3.72 – 3.59 AND
3.49 – 3.39 (m, 1H), 3.34 – 3.23 AND 3.19 – 3.03 (m, 1H);
13C NMR (151 MHz, CDCl3): δ = 131.4, 127.7, 127.1, 126.4,
122.7 (q, J = 273.7 Hz), 60.6, 30.8 (q, J = 37.5 Hz), 26.2; 19F
NMR (564 MHz, CDCl3) δ = ꢀ60.94 (d, J = 7.0 Hz), ꢀ66.36 (d,
J = 6.5 Hz); Anal. Calcd for C8H6F3NO4S: C, 40.51; H, 2.00;
N, 5.79. Found: C, 39.93; H, 2.00; N, 6.02; MS (CI): m/z (%):
238.1 ([M], 41%), 221.1 ([MꢀO], 24%), 220.1 ([MꢀOH], 84%)
191.1 ([MꢀNO2], 100%); IR (KBr) = 3060, 2672, 2330, 2093,
1743, 1553, 1366, 1256, 1145, 848, 707 cmꢀ1.
1
as a colorless solid in 87% yield (49 mg, d.r. 3:1). H NMR
(600 MHz, CDCl3): δ = 7.88 – 7.74 (m, 4H), 7.57 – 7.49 (m,
2H), 7.44 – 7.33 (m, 1H), 5.12 (dd, J = 4.8, 3.7 Hz) AND 4.93
(dd, J = 9.1, 3.6 Hz, 1H), 3.94 – 3.77 AND 3.58 – 3.51 (m,
1H), 3.45 – 3.36 AND 3.38 – 3.00 (m, 1H); 13C NMR (151
MHz, CDCl3): δ = 133.0, 132.9, 128.9, 128.8, 128.1, 127.8,
127.7 (q, J = 2.4 Hz), 126.9, 126.7 (d, J = 5.8 Hz), 125.9,
125.7, 123.0 (d, J = 273.7 Hz), 60.9, 59.6, 31.7, 30.5 (q, J =
37.4 Hz), 27.6 (q, J = 38.8 Hz); 19F NMR (564 MHz, CDCl3) δ
= ꢀ60.73 (d, J = 7.1 Hz), ꢀ66.14 (d, J = 6.4 Hz); HRMS (EI):
m/z calc. for [C14H10F3NO2]: 281.06582, found 281.06609;
m.p. = 91ꢀ92°; IR (KBr) = 3098, 3061, 2300, 1552, 1437,
1363, 1270, 1136, 1035, 967, 947, 821, 750 cmꢀ1.
1-((1R*,2R*,3R*)-2-nitro-3-(trifluoromethyl)cyclopropyl)
naphthalene (4t). Compound 4t was prepared according to
general procedure and was obtained after column
chromatography (nꢀpentane ꢀ> nꢀpentane: diethyl ether 50:1)
Computational Data. All electronic structure calculations
were carried in the Gaussian09 (revision E01)[17] and QꢀChem
programs.[18] All molecular geometries were optimized at the
M06ꢀ2X/6ꢀ31+G(d) level of theory in the gas phase and in
conjunction with the SMD implicit solvation model to
1
as a colorless solid in 57% yield (32 mg, d.r. 4:1). H NMR
(600 MHz, CDCl3): δ = 8.11 – 8.05 (m, 1H), 7.93 – 7.85 (m,
2H), 5.18 (dd, J = 4.9, 3.6 Hz) AND 5.14 (dd, J = 8.6, 3.9 Hz,
1H), 3.95 (dd, J = 11.1, 4.9 Hz) AND 3.62 – 3.54 (m) AND
3.36 (dqd, J = 10.8, 7.1, 3.7 Hz, 2H); 13C NMR (151 MHz,
CDCl3): δ = 133.6, 131.9, 129.6, 129.4, 128.8, 126.8, 126.4,
125.6, 125.1, 125.0, 123.2, 59.3, 30.6 (m); 19F NMR (564
MHz, CDCl3) δ = ꢀ61.22 (d, J = 7.0 Hz), ꢀ65.93 (d, J = 6.0
Hz); HRMS (EI): m/z calc. for [C14H10F3NO2]: 281.06582,
found 281.06603; m.p. = 104ꢀ107 °C; IR (KBr) = 3109, 3044,
1551, 1435, 1364, 1262, 1142, 1105, 1029, 949, 865, 783,
749, 687 cmꢀ1.
simulate
the
solvent
(chloroform).[19]
Systematic
conformational searches were carried out by scanning each
rotatable bond (a, b and c) at 120o or 180o resolution (see
below).
3-((1R*,2R*,3R*)-2-nitro-3-(trifluoromethyl)cyclopropyl)
pyridine (4u). Compound 4u was prepared according to
general procedure and was obtained after column
chromatography (nꢀpentane ꢀ> nꢀpentane: diethyl ether 10:1)
Solvation free energies were computed from the difference
between the SCF energy of the solution and gas phase
optimized geometries so that the effect of geometrical
relaxation is included. Vibrational analyses confirmed that all
reactants and products have zero imaginary frequencies, and
that transition states are true firstꢀorder saddle points on the
potential energy surface. Intrinsic Reaction Coordinate (IRC)
calculations were also carried out to confirm that these are the
correct transition states connecting the reactants and products.
All thermal corrections (at 298 K) to the gas phase Gibbs free
energy were computed using the ideal gas molecular partition
1
as a yellowish liquid in 80% yield (37 mg, d.r. 8:1). H NMR
(600 MHz, CDCl3): δ = 8.78 – 8.53 (m, 2H), 7.68 – 7.56 (m,
1H), 7.39 – 7.30 (m, 1H), 5.02 (dd, J = 4.7, 3.7 Hz) AND 4.90
(dd, J = 9.0, 3.7 Hz, 1H), 3.74 – 3.59 AND 3.47 – 3.39 (m,
1H), 3.26 – 3.09 (m, 1H); 13C NMR (151 MHz, CDCl3): δ =
149.83, 149.82, 136.1, 123.5, 122.7 (q, J = 275.1 Hz) 58.7,
29.9 (q, J = 37.4 Hz), 28.6; 19F NMR (564 MHz, CDCl3) δ = ꢀ
60.83 (d, J = 7.0 Hz), ꢀ66.22 (d, J = 6.1 Hz); HRMS (EI): m/z
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[5] (a) Bos, M.; Poisson, T.; Pannecoucke, X.; Charette, A. B.;
function and the rigidꢀrotor harmonic oscillator approximation
(RRHO). G3(MP2)ꢀRAD(+) and RIMP2/augꢀccꢀpVTZ single
point calculations were performed on the gas phase optimized
geometries. The G3(MP2)ꢀRAD(+) is a modification of the
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6ꢀ31G(d) basis set were replaced with 6ꢀ31+G(d) so as to
provide an improved description of zwitterionic species. The
solution phase free energies were obtained as the sum of the
gas phase free energy and solvation free energy plus a
standard state correction (ꢂnRTln(RT/P) so that they
correspond to a reference state of 1 mol Lꢀ1 (See Scheme S1).
Unless stated otherwise, all reported free energies are relative
to the starting reagents (1a and ylide), and correspond to
RIMP2/augꢀccꢀpVTZ gas phase energies plus SMD solvation
free energies.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Stereochemical assignment, isomerization and reaction kinetics
data, reaction optimization data, computational details, copies of
NMR spectra and M06ꢀ2X/6ꢀ31+G(d) Cartesian coordinates.
AUTHOR INFORMATION
Corresponding Author
* rene.koenigs@rwthꢀaachen.de
* t.v.nguyen@unsw.edu.au
* hojm@ihpc.aꢀstar.edu.sg
ACKNOWLEDGMENT
This work was funded by the Excellence Initiative of the German
federal and state governments (R.M.K.). R.M.K. gratefully thank
the Fonds der Chemischen Industrie for generous support (Sachꢀ
kostenbeihilfe). L.M. thanks RWTH Aachen University for a
doctoral scholarship. T.V.N. thanks the Australian Research
Council for their financial support (grant DE150100517). J.H.
thanks A*STAR for support and NCI for computer time.
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