Oxidative Ring Contraction of Cyclobutenes: General Approach to Cyclopropylketones including Mechanistic Insights

Article abstract of DOI:10.1021/acs.joc.8b00297

An original oxidative ring contraction of easily accessible cyclobutene derivatives for the selective formation of cyclopropylketones (CPKs) under atmospheric conditions is reported. Comprehensive mechanistic studies are proposed to support this novel, yet unusual, rearrangement. Insights into the mechanism ultimately led to simplification and generalization of the ring contraction of cyclobutenes using mCPBA as an oxidant. This unique and functional group tolerant transformation proceeds under mild conditions at room temperature, providing access to a new library of polyfunctionalized motifs. With CPKs being attractive and privileged pharmacophores, the elaboration of such a simple and straightforward strategy represents a highly valuable tool for drug discovery and medicinal chemistry. Additionally, the described method was employed to generate a pool of bioactive substances and key precursors in a minimum number of steps.

Full text of DOI:10.1021/acs.joc.8b00297

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Oxidative Ring Contraction of Cyclobutenes – General
Approach to Cyclopropylketones Including Mechanistic Insights
Andreas N. Baumann, Franziska Schüppel, Michael Eisold,
Andrea Kreppel, Regina de Vivie-Riedle, and Dorian Didier
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 11 Apr 2018
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The Journal of Organic Chemistry
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Oxidative Ring Contraction of Cyclobutenes – General Approach to
Cyclopropylketones Including Mechanistic Insights.
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Andreas N. Baumann, Franziska Schüppel, Michael Eisold, Andrea Kreppel, Regina de VivieꢀRiedle*
and Dorian Didier*
Department of Chemistry and Pharmacy, LudwigꢀMaximiliansꢀUniversity, Butenandtstraße 5ꢀ13, 81377 Munich, Germany
Supporting Information Placeholder
ABSTRACT: Reported is an original oxidative ring contraction of easily accessible cyclobutene derivatives for the selective forꢀ
mation of cyclopropylketones (CPKs) under atmospheric conditions. Comprehensive mechanistic studies are proposed to support
this novel, yet unusual, rearrangement. Insights into the mechanism ultimately led to simplification and generalization of the ring
contraction of cyclobutenes using mCPBA as an oxidant. This unique and functional group tolerant transformation proceeds under
mild conditions at room temperature, providing access to a new library of polyfunctionalized motifs. With CPKs being attractive
and privileged pharmacophores, the elaboration of such a simple and straightforward strategy represents a highly valuable tool for
drug discovery and medicinal chemistry. Additionally, the described method was employed to generate a pool of bioactive subꢀ
stances
and
key
precursors
in
a
minimum
number
of
steps.
have described an efficient, general and regioselective route to
cyclobutenes via the intermediate formation of an easilyꢀ
accessible cyclobutenylmetal species CB-M (Scheme 1a) from
bromobutynes 1.3 This oneꢀpot generated CB-M was then
engaged either in a direct crossꢀcoupling reaction with aryl
halides, or in a relayed sequence involving intermediate forꢀ
mation of iodocyclobutenes 2. The synthetic approach to funcꢀ
tionalized cyclobutenes 3 was studied in depth, leading to a
unique library of diversified arylꢀ, heteroarylꢀ, alkynylꢀ and
vinylꢀcyclobutenes. While CB-M could be used in oneꢀpot
sequences to form challenging alkylidenecyclobutanes,4 vinylꢀ
cyclobutenes were transformed into strained fused ring sysꢀ
tems.5 Interestingly, when vinylꢀcyclobutene 3a was left under
atmospheric conditions (Scheme 1b) a formal oxidative ring
contraction was observed and cyclopropylketone (CPK) 4a
was isolated in 46% yield.
INTRODUCTION
Fourꢀmembered carbocyclic architectures, especially cycloꢀ
butenes, have recently become a source of inspiration for
dependable synthetic methodologies, due to their inherent ring
strain.1
Scheme 1. Our access path to cyclobutenes (a) and the first
observation of oxidative ring contraction (b).
Notably, CPKꢀbased pharmacophores can be found in a numꢀ
ber of bioactive substances (Figure 1, AꢀF)6 by exalting cruꢀ
cial hydrophobic interactions.7 Efficient strategies that allow
for a rapid and selective construction of these strained pharꢀ
macophores represent valuable tools for drug discovery and
high throughput screenings.
Surprisingly, only few methods are described concerning the
synthesis of such structures possessing aromatic, heteroaroꢀ
While most documented strategies are based on [2+2]ꢀ
cycloadditions and transition metalꢀcatalyzed processes,2 we
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matic or vinylic substituents, and those require in most cases a
Page 2 of 19
RESULTS AND DISCUSSION
1
2
3
large number of steps, with low functional group tolerance
On the mechanism of the oxidative ring contraction
with O2
After the first observation of ring contraction of cyclobutenes
under air, we became interested in the generalization and
application of such an uncommon reaction.13 We thus started
investigating the mechanism of the transformation to underꢀ
stand, and ultimately optimize, the synthesis of CPKs from
cyclobutenes. Here we propose a mechanism for the oxidative
addition of O2 onto cyclobutenes, inspired by the early findꢀ
ings of Priesnitz et al.13a Fundamental mechanistic assumpꢀ
tions were addressed both experimentally and by quantum
chemical calculations, the details of which can be found at the
end of the manuscript. We describe and compare hereafter,
two alternative routes that can be envisioned for the formation
of CPKs.
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As the reaction readily occurs under air, we propose that cyꢀ
clobutene (E)ꢀ3 is first oxidized by the presence of triplet O2,
giving the biradical species [G] (Scheme 2). Importantly, we
noticed that starting from either (E)ꢀ3 or (Z)ꢀ3 derivatives led
to the same (E)ꢀ4 isomer. Firstly, the consideration of this
allows for explaining the double bond isomerization through
an intermediate πꢀallyl radical species, the equilibrium being
displaced toward the thermodynamic E product [G]. Two
paths can then be described: in path 1a, a ring contraction
takes place resulting in [H], which leads to formation of the
dioxirane [I]. As dioxiranes are very reactive species, we
assumed that a fast epoxidation occurs, consuming an equimoꢀ
lar amount of the starting material 3. However, a second route
(path 1b) can be described, where G reacts in a concerted
radical epoxidation with a molecule of the cyclobutene subꢀ
strate 3, giving the same intermediate 5 as path 1a. In parallel,
path 2 can be followed, in which a 1,2ꢀdioxetane [J] is interꢀ
Figure 1. CPK-containing bioactive substances.6
So far, formation of gemꢀdisubstituted cyclopropanes has been
achieved by employing preformed carbonylated cycloproꢀ
panes,8 double alkylations with dihaloethanes,9 Coreyꢀ
Chaykovsky cyclopropanations,10 αꢀarylation of cyclopropyl
nitriles,11 or more recently, via transition metal catalyzed
oxidative cyclopropanations of alkynes.12 Intrigued by the
simplicity of our innovative sequence, when compared to
functional group sensitive reported processes, we took on the
challenge of generalizing the access to these important modꢀ
ules.
mediary formed, as the product of
a formal [2+2]ꢀ
cycloaddition. A subsequent ringꢀopening reaction undergoes
the formation of 1,4ꢀdiketone 6.
Scheme 2. Proposed mechanism for the oxidative ring contraction of cyclobutenes (path 1) and oxidative ring opening (path 2).
Taking into account that a carbonꢀshift of substituted epoxides
can be triggered by addition of a Lewis acid, or under thermal
conditions (Meinwald rearrangement),13ꢀ14 optimizations were
undertaken to favor the exclusive formation of the oxidative
ring contraction product 4 (Table 1). Particular observations of
Formation of CPKs vs 1,4-Diketones under atmospheric
conditions
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such cyclobutene oxide rearrangements have been reported in
1
2
the past, but in most cases with low efficiency and versatiliꢀ
ty.15
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9
Performing the reaction neat on air led to uncomplete converꢀ
sion while pure oxygen favored the formation of 1,4ꢀdiketone
6a (entries 1, 2), as recently exemplified by Loh and coꢀ
workers.16 Similar ratios were observed when H2O was used as
a solvent in the presence of O2 (entry 3), and prolonged reacꢀ
tion times were noted when solubilizing substrates in EtOAc
(entry 4). In the absence of air (nitrogen atmosphere), no oxiꢀ
dation was observed leaving the starting material unreacted
(entry 5). Addition of TEMPO or BHT to the solution preꢀ
vented the reaction ꢀ supporting the assumption of an initial
radical addition of O2 to the unsaturated system (entries 6 and
7) ꢀ and the starting material was recovered. Taking the reacꢀ
tion under air up to 100 °C afforded full conversion of the
starting cyclobutene in 3 h, furnishing exclusively the monoꢀ
oxidized compound 4a, supporting the intermediate formation
of cyclobutene oxide 5, undergoing a dyotropic rearrangement
at higher temperatures (entry 8).
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Surprisingly, when arylꢀcyclobutene (3e) was subjected to
similar conditions, none of the corresponding CPK 4e could be
detected, even in prolonged reaction time (further optimizaꢀ
tions will be disclosed later).
As depicted in Table 1, the use of pure oxygen favored a forꢀ
mal [2+2]ꢀcycloaddition, giving a majority of 1,4ꢀdiketone 6.
The scope of this transformation was briefly explored, as such
motifs present synthetic applications in organic chemistry.16
Vinylcyclobutenes 3 were submitted to an atmosphere of
dioxygen, furnishing diketones 6a-f in moderate yields
(Scheme 4). Moreover, 6e was employed in a PaalꢀKnorr
condensation to undergo the formation of triꢀsubstituted furan
7 in 87% yield.
Table 1. Condition optimizations.
entry oxidant solvent temp.
(° C)
t
conv. 4a:6a[a]
(h)
(%)
Scheme 4. Synthetic scope of 1,4-diketone formation
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3
4
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8
air
neat
rt
24
2
50
98
92
>99
0
87:13
30:70
38:62
77:23
ꢀ
O2
neat
rt
O2
H2O
rt
2
air
ꢀ[b]
air[c]
air[d]
air
EtOAc
neat
rt
48
20
20
20
3
rt
EtOAc
EtOAc
neat
rt
0
ꢀ
rt
0
ꢀ
100
89
>99:1
[a] conversion of the starting material and ratios determined by
GC. [b] under N2. [c] TEMPO (1 equiv.) was added. [d] BHT (1
equiv.) was added.
Through a favored path 1 under thermal conditions (see
Scheme 2), the exclusive formation of the desired product is
the result of two converging and complementary reactions: 1)
the consumption of the dioxirane [I] giving the ketone 4 along
with the epoxide 5; 2) the Meinwald rearrangement of the
latter epoxide under thermal conditions.
Selective formation of CPKs with oxidants
With optimized conditions in hand for airꢀpromoted oxidative
ring contraction, cyclobutene 3aꢀc led to CPKs 4aꢀc in good
yields up to 66%. When chiral cyclobutene 3d was used, 4d
was isolated with a good diastereoisomeric ratio (dr = 8:1
determined by 13C NMR, Scheme 3).
Overcoming the limitation of the ring contraction to styryl
systems required developing additional optimizations. Diverse
oxidizing reagents were tested for the transformation of 3a and
3e into 4a and 4e, respectively (Table 2)
Scheme 3. Representative examples of air-promoted oxida-
tive ring contraction
Table 2. Condition optimizations.
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entry
R
oxidant
temp.
t
conv.
(%)[a]
>99[c]
1
2
3
4
5
6
7
8
(° C)
rt
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2
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4
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9
DMDO[b]
mCPBA[d]
mCPBA[d]
mCPBA[d]
mCPBA[e]
tꢀBuOOH[d] rt
AcOOH[d]
3h
0
10min
10min
10min
18h
>99
>99
>99
75[f]
traces
33
rt
p-Tol
pꢀTol
pꢀTol
pꢀTol
pꢀTol
pꢀTol
rt
rt
18h
9
rt
rt
rt
18h
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[g]
H2O2
18h
traces
70[h]
NaOCl[h]
18h
[a] conversion of the starting material and proportions deterꢀ
mined by GC/NMR. [b] acetone from the inꢀsitu generation of
DMDO. [c] many side products observed. [d] 1 equiv., in CH2Cl2
[e] NaHCO3 (2 equiv.) was added to the reaction. [f] 75% converꢀ
sion of the starting material, but in a 50:50 ratio of epoxidation
product and desired product 4, see SI [g] 5 equiv., NaOH (0.1
equiv.), in MeOH. [h] (R,R)ꢀJacobsen’s catalyst (5 mol%): 70%
conversion of the starting material, but in a 30:70 ratio of epoxiꢀ
dation product and desired product 4, see SI.
Even though DMDO afforded full conversion of 3a at room
temperature (entry 1, Table 2), many overoxidized side prodꢀ
ucts were observed. When mCPBA was used (entries 2, 3),
complete consumption of the starting material was observed,
giving the desired ring contracted product independently from
the temperature.17 Interestingly, only the most activated double
bond (cyclobutene) reacted during the reaction, leaving both
allyl and vinyl groups untouched. Moreover, the airꢀstable
substrate 3e furnished the rearranged product 4e under these
optimized and mild conditions. We assumed that the Meinꢀ
wald rearrangement was assisted by the presence of mꢀ
chlorobenzoic acid, released by the epoxidation reaction. To
test this hypothesis, a similar experiment (entry 5) was conꢀ
ducted in the presence of NaHCO3. If 75% conversion were
observed, the ringꢀcontraction was partially inhibited by the
presence of the base, as the cyclobutene oxide was observed in
a 50:50 ratio with the desired cyclopropylketone, thus supportꢀ
ing the intermediary epoxide formation as well as the assisꢀ
tance of the acid in the ring contraction process. Furthermore,
the scope of oxidants was evaluated. While alkylperoxide or
hydrogen peroxide did not promote any oxidation, leaving the
starting material unreacted (entry 6, 8), peracetic acid afforded
33% of conversion after 18h (entry 7). At last, Jacobsen’s
catalyst was employed in the presence of sodium hypochlorite
(entry 9) and could convert 70% of the starting cyclobutene 3e
in 18h. However, the uncontracted cyclobutene oxide was
detected in 30:70 ratio with the desired product 4, supporting
the need for acidic conditions in the Meinwald rearrangement.
[a] mCPBA (1 equiv.). [b] BF3·OEt2 (1 equiv.) was added to the
reaction mixture. [c] The product was obtained from the correꢀ
sponding 3ꢀNH2C6H4 derivative. [d] The aldehyde was obtained
after hydrolysis, starting from the corresponding 1,3ꢀdioxolane
(see supporting information).
To establish the scope of the transformation, a range of cycloꢀ
butenes was engaged in the oxidative ring contraction under
reꢀoptimized conditions. First, 3e – which remained unaffected
under an atmospheric environment – furnished the desired
CPK 4e in 86% yield (Scheme 5). Likewise, an electroenꢀ
riched substrate led to the expected ringꢀcontracted product 4f
in similar yield, and a crystal structure was obtained to conꢀ
firm the presence of the cyclopropylketone scaffold.18
Vinylcyclobutenes, the oxidative ring contraction of which
was established with air, underwent smooth conversion to
CPKs 4a-c and 4g-o with peracids in similar to high yields (up
to 89%).
Noteworthy, the very simple CPKꢀcontaining skeleton 4p was
found to possess a moderate activity against tumor cells HL60
(IC50 = 15 ꢀM; see SI). In all cases, only the internal strained
alkene reacted with the oxidant, leaving additional double
bonds intact. In a second instance, arylꢀsubstituted cycloꢀ
butenes were subjected to oxidation, yielding the correspondꢀ
Scheme 5. Representative examples of mCPBA-promoted
oxidative ring contraction
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Employing similar oxidative conditions, cyclobutenes 3ae-ai
ing adducts 4q-u and 4w. While electronꢀdonor substituents
1
2
3
4
5
6
7
8
underwent a direct ringꢀcontraction (4q-r, 4w), the addition of
a Lewis acid (BF3·OEt2) was needed to drive the reaction to
completion with electronꢀwithdrawing groups (4s-u). Altꢀ
hough an alkynyl derivative also furnished the desired prodꢀ
uct, a lower yield was obtained (4v, 45%). Finally, we pushed
the methodology further to test the versatility of the process
when using heteroarylated cyclobutenes. Dibenzofuryl, fluorꢀ
opyridyl, dimethyloxazolyl and benzylpyrazolyl substituents
were tolerated, and the corresponding compounds 4w-z were
isolated in good yields up to 75%. Interestingly, the presence
of a sulphur atom in the aromatic core (thiophenyl) did not
affect the course of the transformation, giving the derivative
4ab in good yield (69%), the aromatic ring remaining unoxꢀ
idized. Finally, different approaches were employed to introꢀ
duce phenylꢀ and ethylphenyl moieties on the starting cyclobuꢀ
tene.19ꢀ20 Their oxidation in the presence of mCPBA led to
diversely substituted cyclopropylketones 4ac and 4ad, thus
extending the scope of the oxidative ring contraction to aryl
and alkyl groups.
underwent rapid ring contraction, providing CPKs 4ae-ai in
good to excellent yields (up to 92%, 4ae). The diastereoselecꢀ
tivity of the transformation seems to depend on the nature of
the substrate. Only moderate to low diastereomeric ratios were
observed (dr up to 2.3:1). We attributed the deficiency in
stereoselectivity to a fast epoxidation, the shielding effect of
the R1 chain playing only a minor role in the stereodifferentiaꢀ
tion of the double bond. Decreasing the temperature to ꢀ40 °C
slightly improved the diastereoselectivity for the ring contracꢀ
tion to 2.6:1 dr (4ae).
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Synthesis of bioactive targets
To further explore the synthetic utility of our methodology, we
set out to access bioactive substances or their related precurꢀ
sors (Scheme 7).
A
common starting material (4ꢀ
bromobutyne) was utilized to begin these syntheses. Cyclobuꢀ
tene iodides were formed in a oneꢀpot process through lithiaꢀ
tion/carboalumination/iodolysis and after simple extraction,
reacted using a palladiumꢀcatalyzed Negishi or Suzuki crossꢀ
coupling reaction to afford the corresponding arylated cycloꢀ
butenes. Further oxidation with mCPBA was performed on
crude materials, giving CPKs 4r, 4w and 4aj in good yields
(68 to 86%). At first, postꢀderivatization was achieved on the
methylketone moiety of 4r by enolization / electrophilic trapꢀ
ping employing 2ꢀpyridylsulfonylfluoride to provide the dehyꢀ
drogenase inhibitor B in a single step. Second, modification of
the methylketone was carried out through haloform reaction
with CCl4, providing cyclopropylcarboxylic acids 8a-b in
quantitative yields. Importantly, 8b stands as the precursor in
the Lumacaftor (E) synthesis (potent drug against cystic fibroꢀ
sis in combination with Ivacaftor).6g Preꢀderivatization was
also envisioned and applied to the synthesis of an analog strucꢀ
ture of the herbicide C providing the deoxyꢀC herbicide in
43% yield over two steps. Initial Suzuki crossꢀcoupling of
previously iodinated CB-M (see Scheme 1) with (2ꢀ
methoxyphenyl)boronic acid resulted in the corresponding
cyclobutene 9 in 77%. Upon exposure of 9 to BBr3, followed
by nucleophilic substitution on dichloropyridazine, 10 was
obtained and directly employed in the final oxidative ring
contraction without purification, completing the synthesis of
deoxyꢀC 11 in 43% yield over two steps.
Next, we investigated the oxidative ring contraction of chiral
cyclobutenes (Scheme 6).
Scheme 6. Representative examples of mCPBA-promoted
oxidative ring contraction
[a] ꢀ40 °C to rt, 3h.
Scheme 7. Straightforward syntheses and formal synthesis of bioactive substances through oxidative ring contraction.
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Sequence to access cyclopropyl-aldehydes
To ensure a broader applicability of the method, we finally
assembled a sequence for the formation of cyclopropylaldeꢀ
hydes. To achieve that goal, commercially available cyclobuꢀ
tanone 12 was submitted to nucleophilic addition of an arꢀ
ylmetal species and the resulting alcoholate was further acetyꢀ
lated. βꢀElimination on 15 in the presence of lithium bromide
after exchanging the solvent to dimethylformamide furnished
arylated cyclobutene 16. With a sufficient purity, 16 was furꢀ
ther engaged without purification in the oxidative ring contracꢀ
tion in the presence of mCPBA, giving the desired rearranged
compounds 13a-f (Scheme 8). Employing diversely substitutꢀ
ed aromatic structures showcases the efficient formation of a
range of cyclopropylaldehydes in six steps from commercial
sources and with a sole purification step, in moderate to good
yields (34 to 69%).
The energies of the discussed reaction scheme were then obꢀ
COMPUTATIONAL ANALYSIS
tained by applying the CASPT2 routine of the program packꢀ
age Molcas 8.223 with the ANOꢀLꢀVDZP basis set on the
optimized structures. It is a common procedure to do geometry
optimizations on a low level of theory, as e.g. DFT, and then
correct the calculated energies using singleꢀpoint calculations
at a higher level of theory, as e.g. the CASPT2, to include
nondynamic and dynamic electron correlation.24 Investigating
the mechanism proposed in Scheme 2 computationally, we
need to describe diradicalic structures. To do this correctly, we
use the multiꢀreference method CASPT2. A more detailed
description of the computational methods is given in the supꢀ
porting information. Specific options for the CASPT2 calculaꢀ
tions, as the chosen active space, are discussed there. For
completeness, we also show the results at the B3LYP level of
theory.
The proposed mechanism of the oxidative ring contraction of
cyclobutene 3 (Scheme 2) was investigated theoretically for a
better understanding. DFT with the B3LYP functional and the
6ꢀ31G(d) basis set of the program package Gaussian1621 was
used generally for all geometry optimizations. Only geometry
point TSDK1 was computed at the CASSCF/6ꢀ31G(d) level of
theory with the program package Molpro201222 for a correct
description of the state.
Scheme 8. Direct access to cyclopropyl-aldehydes from
commercially available cyclobutanone.
Scheme 9. Barrier for the addition of triplet oxygen (3O2)
to cyclobutene 3 at the CASPT2/ANO-L-VDZP level of
theory. The labels in brackets correspond to the nomencla-
ture used in Scheme 2. The given energies are referenced
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to the energy of the educts, cyclobutene 3 and 3O2, separat-
ed at 10 Angstrom. Additionally, the numbering of im-
portant atoms used in the following discussion is shown.
Figure 2. Single occupied orbitals of the S0/T1 state at a)
GS1, b) TSDK1 and c) TSCPX showing the diradicalic
character at this geometry points.
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Scheme 10 summarizes the results for the reaction pathways
path 1a, path 1b and path 2 discussed in Scheme 2. In path 1a,
first proposed by Priesnitz13a, the predicted dioxirane [I]
(GSCP2) is reached in a stepwise process. First, the cyclobuꢀ
tene ring is rearranged to a cyclopropane ring to form GSCP1
[H]. The CꢀC bond between C1 and C4 is broken and a bond
between C2 and C4 is built in one step via TSCP1. This is
followed by the formation of the second CꢀO bond between
C1 and O2 via TSCP2 to form dioxirane [I]. For the next step,
Priesnitz proposed that cyclobutene 3 is epoxidized by dioxꢀ
irane [I]. This step via TSCP3 leads to the product CPK 4
(GSCP4) and the intermediate, epoxide 5 (GSCP3). 5 can
form another CPK 4 molecule via TSCP4 which corresponds
to a Meinwald rearrangement.13ꢀ14 The first step of path 1a has
a high barrier of 31.5 kcal/mol to TSCP1 accounting for a total
barrier of 49.3 kcal/mol which makes this pathway highly
unlikely. Apparently, the rearrangement of the carbon bonds
forming a cyclopropane ring from a cyclobutene ring is unfeaꢀ
sible at this point of the reaction path.
The first step of the mechanism (Scheme 9) is the same for
both observed products, cyclopropane 4 and diketone 6. Triꢀ
plet oxygen (3O2) adds to the CꢀC double bond of the cyclobuꢀ
tene ring forming a CꢀO bond between C1 and O1 to generate
the diradical GS1. The barrier for this addition lies with
24.4 kcal/mol in the possible range for a slow reaction at room
temperature. At GS1 the occupied T1 state and the S0 state,
both have the equivalent electronic diradicalic character and
lie energetically close with Δꢀ ꢁ 0.001 eV. Figure 2 a shows
the two single occupied orbitals of the S0 and T1 state to conꢀ
firm the diradicalic character. One electron is localized at the
oxygen atom O2 and the second is delocalized over the allylic
positions C2 and C6. The S0 and T1 states remain energetically
close and keep their electronic character along the reaction
path to the corresponding next transition state of each investiꢀ
gated pathway (Figure 2 b and c). Calculations of the spin
orbit coupling suggest that intersystem crossing is possible in
those regions. A detailed discussion and the calculated values
are given in the supporting information. In the following disꢀ
cussion, we expect that intersystem crossing took place and all
points are evaluated in the singlet ground state S0.
In Scheme 2 another mechanistic pathway to cyclobutene 3
was proposed (path 1b). Here, a direct epoxidation takes place
after the addition of 3O2 without formation of the cyclopropane
ring. The diradical GS1 can epoxidize cyclobutene 3 via
TSCPX to form two molecules of intermediate epoxide 5
(GSCP3). The next step of this pathway is the same as of
path 1a. CPK 4 (GSCP4) is built via Meinwald rearrangement
of epoxide 5. The barrier to TSCPX is with a value of
9.1 kcal/mol a lot of smaller than the barrier to TSCP1 which
makes path 1b the favored pathway towards cyclobutene 4.
The second transition state of this path (TSCP4) can be
reached via a barrier of 32.1 kcal/mol, the largest barrier of
this pathway. In the following, only the here proposed novel
path 1b is discussed as reaction pathway leading to the product
4.
Scheme 10. Reaction scheme for path 1a, path 1b and path 2 of the oxidative ring contraction of cyclobutene 3 at the
CASPT2/ANO-L-VDZP level of theory. The labels in brackets correspond to the nomenclature used in Scheme 2. The struc-
tures are shown without the phenyl ring. The energies are referenced to the energy of the educts, cyclobutene 3 and 3O2,
separated at 10 Angstrom.
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The reaction towards the second product, diketone 6, is deꢀ
scribed with path 2. Here, the first transition state (TSDK1)
leads to a formation of a four membered ring between the
oxygen molecule and the two carbon atoms of the CꢀC double
bond. This intermediate, dioxetane [G] (GSDK1), corresponds
to a classical [2+2] cycloꢀaddition product between 3O2 and an
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The Journal of Organic Chemistry
General considerations. Commercially available starting materiꢀ
alkene. The barrier for this step accounts for 13.6 kcal/mol. In
als were used without further purification unless otherwise stated.
All reactions were carried out under N2 atmosphere in flameꢀdried
glassware. Syringes, which were used to transfer anhydrous solꢀ
vents or reagents, were purged with nitrogen prior to use. CH2Cl2
was predried over CaCl2 and distilled from CaH2. THF was reꢀ
fluxed and distilled from sodium benzophenone ketyl under nitroꢀ
gen. Et2O was predried over CaCl2 and passed through activated
Al2O3 (the solvent purification system SPSꢀ400ꢀ2 from Innovative
Technologies Inc.). Toluene was predried over CaCl2 and distilled
from, CaH2. Chromatography purifications were performed using
silica gel (SiO2, 0.040ꢀ0.063 mm, 230ꢀ400 mesh ASTM) from
Merck. The spots were visualized under UV (254 nm) or by stainꢀ
ing the TLC with KMnO4 solution (K2CO3, 10 g – KMnO4, 1.5 g
– H2O, 150 mL – NaOH 10% in H2O, 1.25 mL), PAA: pꢀ
anisaldehyde solution (conc. H2SO4, 10 mL – EtOH, 200 mL –
AcOH, 3 mL – pꢀanisaldehyde, 4 mL). Diastereoisomeric ratios
1
2
3
4
5
6
7
8
the second step, the bonds of the fourꢀmembered dioxetane
ring are rearranged via a sixꢀmembered transition state
(TSDK2) to form diketone 6 (GSDK2). The corresponding
barrier (23.4 kcal/mol) is of the same magnitude as the barrier
for the first addition of 3O2 to 3 (step 1).
Comparing both pathways (path 1b and path 2) first confirms
that the formation of both products is possible and secondly
reveals a difference in 4.3 kcal/mol for the corresponding first
barriers in favor of reaction path 1b. This also results in a
difference of the same value in the total barriers of both pathꢀ
ways. Thirdly, diketone 6 is the more stable product lying
14.1 kcal/mol lower than CPK 4.
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In contrast to dioxetane [J], the intermediate epoxide 5 could
be detected experimentally. This can be explained by the fact,
that 5 (GSCP3) is around 38.1 kcal/mol more stabilized than
[J] (GSDK1). Furthermore, comparison of the corresponding
barriers to each next step reveals that the barrier to TSCP4 is
around 8.7 kcal/mol larger than the barrier to TSDK2. This
means, the Meinwald rearrangement via TSCP4 to generate
CPK 4 happens on a slower timeꢀscale so that intermediate 5
can be detected under the given experimental conditions. The
rearrangement towards 6 is expected to happen at the same
1
1
were determined by H NMR and 13C NMR. 13C and H NMR
spectra were recorded on VARIAN Mercury 200, BRUKER ARX
300, VARIAN VXR 400 S and BRUKER AMX 600 instruments.
Chemical shifts are reported as δ values in ppm relative to residuꢀ
al solvent peak (1HꢀNMR) or solvent peak (13CꢀNMR) in deuterꢀ
1
ated chloroform (CDCl3: δ 7.26 ppm for HꢀNMR and δ 77.16
ppm for 13CꢀNMR). Abbreviations for signal coupling are as
follows: s (singlet), d (doublet), t (triplet), q (quartet), quint (quinꢀ
tet), m (multiplet) and br (broad). Reaction endpoints were deterꢀ
mined by GC monitoring of the reactions. Gas chromatography
was performed with machines of Agilent Technologies 7890,
using a column of type HP 5 (Agilent 5% phenylmethylpolysiloxꢀ
ane; length: 15 m; diameter: 0.25 mm; film thickness: 0.25 ꢁm) or
HewlettꢀPackard 6890 or 5890 series II, using a column of type
HP 5 (HewlettPackard, 5% phenylmethylpolysiloxane; length: 15
m; diameter: 0,25 mm; film thickness: 0.25 ꢁm). High resolution
mass spectra (HRMS) and low resolution mass spectra (LRMS)
were recorded on Finnigan MAT 95Q or Finnigan MAT 90 inꢀ
strument or JEOL JMSꢀ700. Infrared spectra were recorded on a
Perkin 281 IR spectrometer and samples were measured neat
(ATR, Smiths Detection DuraSample IR II Diamond ATR). The
absorption bands were reported in wave numbers (cmꢀ1) and
abbreviations for intensity are as follows: vs (very strong; maxiꢀ
mum intensity), s (strong; above 75% of max. intensity), m (meꢀ
dium; from 50% to 75% of max. intensity), w (weak; below 50%
of max. intensity) and br (broad). Melting points were determined
on a Büchi Bꢀ540 apparatus and uncorrected. Single crystals were
grown in small quench vials with a volume of 5.0 mL from slow
evaporation of dichloromethane/hexanes mixtures at room temꢀ
perature. Suitable single crystals were then introduced into perꢀ
fluorinated oil and mounted on top of a thin glass wire. Data
collection was performed at 100 K with a Bruker D8 Venture
TXS equipped with a Spellman generator (50 kV, 40 mA) and a
Kappa CCD detector operating with MoꢀKα radiation (l = 0.71071
Å).
3
timeꢀscale than the initial attack of O2 to 3 since the barriers
are of the same height.
All computational results are in good agreement with the
experimental product distributions under different reaction
conditions. Using thermodynamical conditions with a low
reaction temperature and a long reaction time leads preferenꢀ
tially to the more stable product diketone 6. In contrast, using
kinetic conditions with a high reaction temperature and a short
reaction time leads to CPK 4 whose pathway has the lower
overꢀall barrier. Furthermore, the observation of better yields
of diketone 6 when the reaction is conducted under pure oxyꢀ
gen atmosphere (in contrast to the normal atmospheric condiꢀ
tions) can be explained by the theoretical results. The decisive
transition state for the formation of CPK 4 (TSCPX) is a twoꢀ
molecule transition state between GS1 and educt cyclobutene
3. When more oxygen is available for the first reaction step,
3
the addition of O2 to 3, less reaction partner for GS1 is availꢀ
able to form epoxide 5 (GSCP2).
In summary, the proposed as well as observed intermediates
are verified and the complete proposed reaction mechanism is
strongly supported by the theoretical study.
CONCLUSIONS
We have demonstrated a novel and efficient airꢀpromoted
oxidative ring contraction of easilyꢀgenerated vinyl cycloꢀ
butenes. Combining theoretical studies with experimental
investigations finally led to proposing a new mechanistic path
for the formation of αꢀsubstituted cyclopropylketones. These
modules possessing interesting pharmacological properties, a
general and selective sequence was designed starting from
readily available substrates, allowing the synthesis of a wide
variety of functionalized scaffolds. Such a straightforward
approach undoubtedly opens an entire platform for high
throughput screening in drug discovery processes.
sꢀBuLi and tꢀBuLi were purchased as solutions in cyclohexꢀ
ane/hexanes mixtures from Rockwood Lithium GmbH. The
commercially available Grignard reagents MeMgCl, PhMgCl and
nꢀBuMgCl were also purchased from Rockwood Lithium GmbH,
as solutions in THF.
The concentration of organometallic reagent from commercially
purchased and synthesized reagents was determined either by
titration of isopropyl alcohol using the indicator 4ꢀ
(phenylazo)diphenylamine in THF for Grignard reagents or using
the indicator Nꢀbenzylbenzamide in THF for organolithium reaꢀ
gents.
[sꢀBuLi] = 1.31
M in cyclohexane (titration with isopropanol /
Experimental Section
1,10ꢀphenanthroline), purchased from Rockwood Lithium GmbH.
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[iꢀPrMgClꢂLiCl] = 1.1
from Rockwood Lithium GmbH. [nꢀBuLi] = 2.44
ane (titration with isopropanol / 1,10ꢀphenanthroline), purchased
from Rockwood Lithium GmbH.
M
in THF (titration with iodine), purchased
in cyclohexꢀ
solution, extracted with hexanes, dried with MgSO4 and filtered.
M
1
2
3
4
The solvent was removed under reduced pressure and the crude
mixture was purified over silica with hexanes as eluent (Rf = 0.7
(hexane, UV, KMnO4, PAA). (2ꢀ(2ꢀiodocyclobutꢀ1ꢀenꢀ1ꢀ
yl)ethyl)benzene was then used in the following crossꢀcoupling
reaction. Therefore LiCl (1.1 eq.) and Mg (1.6 eq.) were dried
General procedure A for the synthesis of cyclobutenes 3:[3]
To cyclobuteneꢀiodides 2 in THF (0.2 M) were consecutively
5
6
7
8
9
under inert atmosphere followed by adding THF (0.4
M), and one
added Pd(dppf)Cl2ꢂCH2Cl2 (4 mol%), the appropriate organoboꢀ
ronic acid (1.0 – 2.0 eq.) and a 1M solution of NaOH (3.0 eq.).
The mixture was stirred at ambient temperature until TLC showed
full consumption of the starting iodide 2 (20 min up to overnight).
The reaction was quenched by addition of water, extracted with
Et2O (3 × 20 mL) and dried over MgSO4. The crude product was
concentrated under reduced pressure and finally filtrated through
a short silica column to remove palladium salts. Crude materials
were used without further purification.
drop of dibromoethane. The mixture was heated once to reflux to
activate the Grignard. After cooling back to room temperature to
the mixture was added B(OiꢀPr)3 (1.5 eq.). According to that (2ꢀ
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(2ꢀiodocyclobutꢀ1ꢀenꢀ1ꢀyl)ethyl)benzene (0.5
M) was added
dropwise to the reaction. After 2 h a cloudy suspension has been
formed. To the suspension was then added Pd(dppf)Cl2 dichloroꢀ
methane adduct (4 mol%), 1ꢀiodoꢀ4ꢀmethoxybenzene (0.80 eq.)
and an aqueous solution of sodium hydroxide (1.5 eq. 1.00 M).
General procedure B for the synthesis of cyclopropylketones
The reaction mixture stirred overnight and then extracted with
diethyl ether (3 × 20 mL), washed with a saturated aqueous soluꢀ
tion of sodium chloride (20 mL), dried with magnesium sulfate,
filtered, concentrated and purified via flash column chromatogꢀ
raphy to provide 3ad (0.27 mmol, 72 mg, 55%) as colorless oil. Rf
= 0.20 (hexane, UV, KMnO4, PAA). 1H NMR (400 MHz, CDCl3)
δ 7.35 – 7.18 (m, 7H), 6.89 – 6.82 (m, 2H), 3.82 (s, 3H), 2.86 (dd,
J = 9.6, 6.4 Hz, 2H), 2.75 – 2.67 (m, 2H), 2.65 – 2.59 (m, 2H),
2.51 – 2.42 ppm (m, 2H). 13C NMR (101 MHz, CDCl3) δ 158.4,
142.2, 139.7, 137.3, 129.3, 128.5, 128.4, 126.9, 126.0, 113.9,
55.4, 33.7, 32.1, 27.7, 26.1 ppm. LRMS (DEP/EIꢀOrbitrap):
m/z (%):264.1 (30), 249.1 (40), 235.0 (5), 221.1 (5), 203.1 (2).
HRMS (EIꢀOrbitrap): m/z: [M]+ Calcd for C19H20O+: 264.1514;
found: 264.1507. IR (DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ: 3059(w),
3024(w), 1780(w), 1726(w), 1670(s), 1614(vw), 1597(m),
1578 cmꢀ1 (w).
4,11): To cyclobutenes 3 in CH2Cl2 (0.1
M) was added mCPBA in
CH2Cl2 (0.3 , 1.0 eq.) at 0 °C. The reaction was checked after
M
10 min by TLC and another portion of mCPBA (0.5 eq.) was
added if the reaction was not complete. This step was repeated
until full conversion of the substrates. The reaction was the treated
by addition of NaOH (1 M) and extracted with CH2Cl2
(3 × 20 mL). Volatiles were removed under reduced pressure and
the crude product purified by chromatography. Ba) The desired
products 4,11 were obtained analytically pure. Bb) In the case of
4s,t,u,y,ac,ad, aj the epoxide intermediate 5 was obtained after
chromatography, as it did not undergo ring contraction. In such
cases, intermediates were dissolved in Et2O (0.3 M) and BF3ꢂOEt2
(1.0 eq.) was added. As completion of the rearrangement was
observed after 10 min, the final products could be purified by
chromatography after extraction.
General procedure C for the synthesis of cyclopropylaldehydes
(13). To arylꢀhalide (1.05 eq) in THF (0.33
wise nꢀBuLi (1.1 eq., 2.44 ) at ꢀ78 °C under inert atmosphere
and the mixture was stired for 15 min at this temperature. Cycloꢀ
butanone 12 (1 eq) in THF (1 ) was added at ꢀ78 °C, the reaction
M) was added dropꢀ
M
(E)-3-Methyl-1-(1-styrylcyclopropyl)but-3-en-1-one
(4a):
Using 1ꢀiodoꢀ2ꢀ(2ꢀmethylallyl)cyclobutꢀ1ꢀene (2a) and (E)ꢀ
styrylboronic acid according to general procedure A and Ba proꢀ
vided 4a (0.20 mmol, 45 mg, 79%) as colorless oil.Rf = 0.80
(hexane/EtOAc 9:1, UV, KMnO4, PAA). 1H NMR (400 MHz,
CDCl3) δ 7.42 – 7.31 (m, 4H), 7.29 – 7.22 (m, 1H), 6.83 (d, J =
15.8 Hz, 1H), 6.42 (d, J = 15.8 Hz, 1H), 4.96 – 4.93 (m, 1H), 4.77
– 4.75 (m, 1H), 3.33 (s, 2H), 1.76 (t, J = 1.1 Hz, 3H), 1.50 (dd, J =
6.9, 3.7 Hz, 2H), 1.15 ppm (dd, J = 7.1, 3.9 Hz, 2H). 13C NMR
(101 MHz, CDCl3) δ 207.8, 139.5, 136.9, 131.4, 128.8, 128.2,
127.8, 126.3, 114.8, 49.9, 33.8, 22.9, 19.8 ppm. LRMS (DEP/EIꢀ
Orbitrap): m/z (%): 226.2 (3), 211.2 (12), 184.1 (21), 141.1 (31),
128.1 (100). HRMS (EIꢀOrbitrap): m/z: [M]+ Calcd for
C16H18O+: 226.1358; found: 226.1353. IR (DiamondꢀATR, neat)
ꢂꢃꢄꢅꢆ: 3080(vw), 3027(w), 2920(w), 2852(w), 1690(s), 1646(w),
1600 cmꢀ1 (w).
M
stirred for 30 min before warming to room temperature. Ac2O
(2 eq.) was added at ꢀ78 °C, and the reaction was allowed to warm
to room temperature and stirred for 2h. Volatiles were removed
under vacuum and DMF (0.5 M) was added, followed by LiBr
(10 eq.) and the mixture was heated to 100 °C and let stir for 2 h.
After completion of the transformation, monitoring by TLC, the
mixture was allowed to cool down to room temperature, washed
with water and brine and extracted with EtOAc. The organic
phase was dried over MgSO4 and the solvent removed under
reduced pressure. To crude cyclobutenes 16 in CH2Cl2 (0.1
M)
was added mCPBA in CH2Cl2 (1.0 eq., 0.3 ) at 0 °C. The reacꢀ
M
tion was checked after 10 mins by TLC and another portion of
mCPBA (0.5 eq.) was added if the reaction was not complete.
This was repeated once if need be. The reaction was quenched by
addition of NaOH (1 M) and extracted with CH2Cl2 (3 × 20 mL).
The solvent was evaporated under reduced pressure and the crude
product purified by chromatography.
(E)-1-(1-Styrylcyclopropyl)ethanone (4b): Using 1ꢀiodoꢀ2ꢀ
methylcyclobutꢀ1ꢀene (2b) and (E)ꢀstyrylboronic acid according
to general procedure A and Ba provided 4b (0.35 mmol, 65 mg,
70%) as colorless oil. 4b was also obtained by following proceꢀ
dure A and subjecting the crosscoupling product to air at 100 °C
for three hours (58%). Rf = 0.5 (hexane/EtOAc 9:1, UV, KMnO4,
PAA). 1H NMR (400 MHz, CDCl3) δ 7.33 – 7.28 (m, 2H), 7.27 –
7.22 (m, 2H), 7.20 – 7.14 (m, 1H), 6.76 (d, J = 15.9 Hz, 1H), 6.31
(d, J = 15.9 Hz, 1H), 2.17 (s, 3H), 1.42 (dd, J = 6.6, 4.2 Hz, 1H),
1.09 ppm (dd, J = 7.3, 3.8 Hz, 1H). 13C NMR (101 MHz, CDCl3)
δ 208.1, 136.9, 130.6, 128.8, 128.4, 127.8, 126.3, 33.9, 28.4,
19.6 ppm. LRMS (DEP/EIꢀOrbitrap): m/z (%): 186.1 (40), 171.1
(10), 157.1 (15), 143.1 (40), 128.1 (100). HRMS (EIꢀOrbitrap):
Experimental Data
1-Methoxy-4-(2-phenethylcyclobut-1-en-1-yl)benzene (3ad):19
To a solution of (C5H5)2ZrCl2 (1 eq.) in THF (0.2 M) was added
EtMgBr (2 eq.) at ꢀ78 °C. The reaction mixture was warmed up to
ꢀ40 °C and stirred for 1 h. To the mixture was added (4ꢀchlorobutꢀ
3ꢀynꢀ1ꢀyl)benzene (1 eq.) in THF (5
M) at ꢀ78 °C. The mixture
was stirred for 1 h at room temperature. After cooling back to ꢀ
40 °C the reaction was quenched with iodide (2 eq.) and let warm
to room temperature. The mixture was poured on ice/1
M HCl
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The Journal of Organic Chemistry
m/z: [M]+ Calcd for C13H14O+: 186.1045; found: 186.1039. IR
(DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ: 2968(w), 2940(w), 2924(w),
1
(DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ: 3082(vw), 3058(vw), 3026(w),
2832(w), 1692(m), 1586(m) cmꢀ1. mp (°C): 81ꢀ82.
3006(w), 2926(vw), 1688(s), 1646(w), 1600 cmꢀ1 (w).
2
3
4
5
6
7
8
9
(E)-1-(1-(4-(Trifluoromethyl)styryl)cyclopropyl)ethanone (4g):
Using 2b and (E)ꢀ(4ꢀ(trifluoromethyl)styryl)boronic acid accordꢀ
ing to general procedure A and Ba provided 4g (0.19 mmol,
49 mg, 78%) as colorless oil. Rf = 0.4 (hexane/EtOAc 9:1, UV,
(E)-1-(1-(4-Methylstyryl)cyclopropyl)ethanone (4c): Using 2b
and (E)ꢀ(4ꢀmethylstyryl)boronic acid according to general proceꢀ
dure A and Ba provided 4c (0.17 mmol, 33 mg, 66%) as colorless
oil. 4c was also obtained by following procedure A and subjecting
the crosscoupling product to air at 100 °C for three hours (66%).
1
KMnO4, PAA). H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.1
Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 6.99 (d, J = 15.9 Hz, 0H), 6.38
(d, J = 15.9 Hz, 0H), 2.23 (s, 1H), 1.55 (dd, J = 7.0, 4.3 Hz, 1H),
1.21 ppm (dd, J = 6.6, 3.9 Hz, 1H). 13C NMR (101 MHz, CDCl3)
δ 207.3, 140.4 (q, J = 1.3 Hz), 131.3, 129.3 (q, J = 32.6 Hz),
128.7, 126.5, 125.7 (q, J = 3.8 Hz), 122.9 (q, J = 271.7 Hz), 34.0,
27.9, 19.7 ppm. LRMS (DEP/EIꢀOrbitrap): m/z (%): 254.1 (46),
225.1 (23), 191.1 (22). HRMS (EIꢀOrbitrap): m/z: [M]+ Calcd for
C14H13F3O+: 254.0918; found: 254.0913. IR (DiamondꢀATR,
neat) ꢂꢃꢄꢅꢆ: 3044(vw), 3012(vw), 2932(vw), 1692(m), 1648(w),
1616(w) cmꢀ1.
1
Rf = 0.5 (hexane/EtOAc 9:1, UV, KMnO4, PAA). H NMR (400
MHz, CDCl3) 7.30 – 7.26 (m, 2H), 7.18 – 7.10 (m, 2H), 6.77 (d, J
= 15.8 Hz, 1H), 6.36 (d, J = 15.8 Hz, 1H), 2.34 (s, 3H), 2.25 (s,
3H), 1.48 (dd, J = 6.7, 4.0 Hz, 2H), 1.15 ppm (dd, J = 7.2, 3.6 Hz,
2H). 13C NMR (101 MHz, CDCl3) δ 208.4, 137.6, 134.1, 130.6,
129.5, 127.4, 126.2, 33.9, 28.5, 21.3, 19.5 ppm. LRMS (DEP/EIꢀ
Orbitrap): m/z (%): 200.1 (42), 185.1 (13), 157.1 (50), 142.1
(100). HRMS (EIꢀOrbitrap): m/z: [M]+ Calcd for C14H16O+:
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
200.1201; found: 200.1192. IR (DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ
:
3088(vw), 3022(w), 2922(w), 2864(vw), 1690(vs), 1650(w),
1612(w), 1572(vw), 1560(vw), 1540(vw) cmꢀ1.
(E)-1-(1-(4-Chlorostyryl)cyclopropyl)ethanone (4h): Using 2b
and (E)ꢀ(4ꢀchlorostyryl)boronic acid according to general proceꢀ
dure A and Ba provided 4h (0.08 mmol, 17 mg, 31%) as colorless
1-((1R,2R)-2-Pentyl-1-((E)-styryl)cyclopropyl)ethanone (4d):
Using 1ꢀiodoꢀ2ꢀmethylꢀ3ꢀpentylcyclobutꢀ1ꢀene (2c) and (E)ꢀ
styrylboronic acid according to general procedure A and Ba proꢀ
vided 4d (0.35 mmol, 65 mg, 70%) as colorless oil. 4d was also
1
oil. Rf = 0.45 (hexane/EtOAc 9:1, UV, KMnO4, PAA). H NMR
(400 MHz, CDCl3) δ 7.33 – 7.26 (m, 4H), 6.83 (d, J = 15.9 Hz,
1H), 6.32 (d, J = 15.9 Hz, 1H), 2.22 (s, 3H), 1.51 (dd, J = 7.2, 4.4
Hz, 2H), 1.17 ppm (dd, J = 7.4, 3.6 Hz, 2H). 13C NMR (101
MHz, CDCl3) δ 207.7, 135.4, 133.3, 129.2, 129.2, 128.9, 127.5,
33.9, 28.1, 19.5 ppm. LRMS (DEP/EIꢀOrbitrap): m/z (%): 220.0
(46), 191.0 (11), 177.0 (30), 162.0 (21), 142.1 (100). HRMS (EIꢀ
Orbitrap): m/z: [M]+ Calcd for C13H13ClO+: 220.0655; found:
220.0647. IR (DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ: 3022(vw), 2926(vw),
1690(vs), 1646(w) cmꢀ1.
obtained by following procedure
A and subjecting the
crosscoupling product to air at 100 °C for three hours (88%). Rf =
0.6 (hexane/EtOAc 9:1, UV, KMnO4, PAA). 1H NMR (400 MHz,
CDCl3) δ 7.41 – 7.29 (m, 4H), 7.26 – 7.22 (m, 1H), 6.74 (d, J =
15.8 Hz, 1H), 6.39 (d, J = 15.8 Hz, 1H), 2.33 (s, 3H), 1.59 (dd, J
= 6.8, 4.1 Hz, 1H), 1.49 – 1.24 (m, 9H), 1.21 (dd, J = 8.3, 4.2 Hz,
1H), 0.88 ppm (t, J = 6.6 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
206.3, 137.0, 130.6, 130.2, 128.8, 127.7, 126.3, 39.5, 35.0, 31.7,
30.6, 29.6, 27.1, 22.8, 21.0, 14.2 ppm. LRMS (DEP/EIꢀOrbitrap):
m/z (%): 256.1 (8), 213.2 (15), 160.1 (50). HRMS (EIꢀOrbitrap):
m/z: [M]+ Calcd for C18H24O+: 256.1827; found: 256.1823. IR
(E)-1-(1-(4-Methoxystyryl)cyclopropyl)ethanone (4i): Using 2b
and (E)ꢀ(4ꢀmethoxystyryl)boronic acid according to general proꢀ
cedure A and Ba provided 4i (0.22 mmol, 48 mg, 89%) as colorꢀ
less oil. Rf = 0.4 (hexane/EtOAc 9:1, UV, KMnO4, PAA). 1H
NMR (400 MHz, CDCl3) δ 7.38 – 7.28 (m, 2H), 6.91 – 6.82 (m,
2H), 6.67 (d, J = 15.9 Hz, 1H), 6.34 (d, J = 15.8 Hz, 1H), 3.81 (s,
3H), 2.25 (s, 3H), 1.58 (s, 4H), 1.47 (dd, J = 6.9, 4.3 Hz, 3H),
1.14 ppm (dd, J = 7.5, 3.6 Hz, 3H). 13C NMR (101 MHz, CDCl3)
δ 208.6, 159.4, 130.3, 129.7, 127.5, 126.2, 114.2, 55.5, 33.9, 28.6,
19.5 ppm. LRMS (DEP/EIꢀOrbitrap): m/z (%): 216.0 (95), 201.0
(22), 173.0 (81), 158.0 (100), 141.1 (35). HRMS (EIꢀOrbitrap):
(DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ
: 3645(m), 1738(w), 1481(w),
1467(m), 1441(s), 1429(vs) cmꢀ1.
3-Methyl-1-(1-(p-tolyl)cyclopropyl)but-3-en-1-one (4e): Using
2a and 4,4,5,5ꢀtetramethylꢀ2ꢀ(pꢀtolyl)ꢀ1,3,2ꢀdioxaborolane acꢀ
cording to general procedure A and Ba provided 4e (0.22 mmol,
46 mg, 86%) as colorless oil. Rf = 0.45 (hexane/EtOAc 9:1, UV,
1
KMnO4, PAA). H NMR (400 MHz, CDCl3) δ 7.28 – 7.24 (m,
+
2H), 7.15 (d, J = 7.8 Hz, 2H), 4.88 – 4.79 (m, 1H), 4.57 – 4.53
(m, 1H), 3.02 (s, 2H), 2.36 (s, 3H), 1.63 (s, 3H), 1.60 (dd, J = 7.1,
3.2 Hz, 2H), 1.15 ppm (dd, J = 7.2, 3.2 Hz, 2H). 13C NMR (101
MHz, CDCl3) δ 208.8, 139.7, 137.9, 137.3, 131.1, 129.4, 114.4,
50.1, 37.1, 22.8, 21.3, 19.2 ppm. LRMS (DEP/EIꢀOrbitrap): m/z
(%): 214.1 (8), 159.1 (26), 131.1 (100). HRMS (EIꢀOrbitrap):
m/z: [M]+ Calcd for C15H18O+: 214.1358; found: 214.1354. IR
m/z: [M]+ Calcd for C14H16O2 : 216.1150; found: 216.1153.
(E)-1-(1-(4-Fluorostyryl)cyclopropyl)ethanone (4j): Using 2b
and (E)ꢀ(4ꢀfluorostyryl)boronic acid according to general proceꢀ
dure A and Ba provided 4j (0.13 mmol, 27 mg, 53%) as colorless
1
oil. Rf = 0.45 (hexane/EtOAc 9:1, UV, KMnO4, PAA). H NMR
(400 MHz, CDCl3) δ 7.40 – 7.28 (m, 2H), 7.06 – 6.96 (m, 2H),
6.75 (d, J = 15.9 Hz, 1H), 6.34 (d, J = 15.9 Hz, 1H), 2.23 (s, 3H),
1.49 (dd, J = 7.0, 3.6 Hz, 2H), 1.16 ppm (dd, J = 7.2, 3.7 Hz, 2H).
13C NMR (101 MHz, CDCl3) δ 208.0, 162.4 (d, J = 246.9 Hz),
133.1 (d, J = 3.4 Hz), 129.4, 128.2 (d, J = 2.3 Hz), 127.8 (d, J =
8.0 Hz), 115.7 (d, J = 21.6 Hz), 33.9, 28.2, 19.4 ppm. LRMS
(DEP/EIꢀOrbitrap): m/z (%): 204.1 (34), 175.0 (11), 161.1 (39),
146.0 (100). HRMS (EIꢀOrbitrap): m/z: [M]+ Calcd for
C13H13FO+: 204.0950; found: 204.0946. IR (DiamondꢀATR, neat)
(DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ
: 3080(vw), 2974(w), 2922(w),
2252(vw), 1776(w), 1692(s), 1650(w) cmꢀ1.
3-Methyl-1-(1-(3,4,5-trimethoxyphenyl)cyclopropyl)but-3-en-
1-one (4f): Using 2a and (3,4,5ꢀtrimethoxyphenyl)boronic acid
according to general procedure A and Ba provided 4f (0.22 mmol,
62 mg, 86%) as colorless solid. Rf = 0.35 (hexane/EtOAc 8:2,
1
UV, KMnO4, PAA). H NMR (400 MHz, CDCl3) δ 6.58 (s, 2H),
4.84 (t, J = 1.6 Hz, 1H), 4.59 (dq, J = 2.0, 1.0 Hz, 1H), 3.86 (s,
6H), 3.85 (s, 3H), 3.06 (s, 2H), 1.69 – 1.55 (m, 3H), 1.58 (dd, J =
6.7, 3.5 Hz, 2H), 1.17 ppm (dd, J = 7.0, 3.5 Hz, 2H). 13C NMR
(101 MHz, CDCl3) δ 208.4, 153.2, 139.8, 137.5, 136.4, 114.4,
108.0, 61.1, 56.3, 49.7, 38.0, 22.9, 19.3 ppm. LRMS (DEP/EIꢀ
Orbitrap): m/z (%): 290.1 (67), 275.1 (45), 235.1 (10), 207.1
(100), 192.1 (29), 176.1 (84), 161.1 (50). HRMS (EIꢀOrbitrap):
ꢂꢃꢄꢅꢆ: 3040(vw), 3008(vw), 2926(vw), 1690(s), 1652(w),
1602(m) cmꢀ1.
(E)-1-(1-(2-([1,1'-Biphenyl]-4-yl)vinyl)cyclopropyl)-3-
methylbut-3-en-1-one (4k): Using 2a and (E)ꢀ(2ꢀ([1,1'ꢀ
biphenyl]ꢀ4ꢀyl)vinyl)boronic acid according to general procedure
A and Ba provided 4k (0.15 mmol, 44 mg, 58%) as colorless oil.
1
+
Rf = 0.5 (hexane/EtOAc 9:1, UV, KMnO4, PAA). H NMR (400
m/z: [M]+ Calcd for C17H22O4 : 290.1518; found: 290.1514. IR
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MHz, CDCl3) δ 7.66 – 7.55 (m, 4H), 7.50 – 7.41 (m, 4H), 7.38 –
(E)-1-(1-(4-Fluorostyryl)cyclopropyl)-3-methylbut-3-en-1-one
7.32 (m, 1H), 6.88 (d, J = 15.8 Hz, 1H), 6.46 (d, J = 15.8 Hz, 1H),
4.99 – 4.93 (m, 1H), 4.82 – 4.76 (m, 1H), 3.35 (s, 2H), 1.78 (s,
3H), 1.53 (dd, J = 7.0, 4.0 Hz, 2H), 1.17 ppm (dd, J = 7.0, 3.0 Hz,
2H). 13C NMR (101 MHz, CDCl3) δ 207.7, 140.7, 140.6, 139.5,
135.9, 130.9, 128.9, 128.3, 127.5, 127.5, 127.0, 126.8, 114.8,
49.9, 33.9, 23.0, 19.8 ppm. LRMS (DEP/EIꢀOrbitrap): m/z
(%):302.1 (37), 287.1 (45), 260.1 (41), 247.1 (100), 233.1 (11),
219.1 (61), 204.1 (83), 191.0 (47), 178.1 (53). HRMS (EIꢀ
Orbitrap): m/z: [M]+ Calcd for C22H22O+: 302.1671; found:
302.1665. IR (DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ: 3078(vw), 3056(vw),
3028(w), 2972(vw), 2914(vw), 1688(s), 1646(w), 1602(w),
1582(vw) cmꢀ1.
(4o): Using 2a and (E)ꢀ(4ꢀfluorostyryl)boronic acid according to
general procedure A and Ba provided 4o (0.14 mmol, 34 mg,
56%) as colorless oil. Rf = 0.6 (hexane/EtOAc 9:1, UV, KMnO4,
PAA). 1H NMR (400 MHz, CDCl3) δ 7.37 – 7.30 (m, 2H), 7.07 –
6.97 (m, 2H), 6.74 (d, J = 15.9 Hz, 1H), 6.37 (d, J = 15.8 Hz, 1H),
4.97 – 4.92 (m, 1H), 4.79 – 4.73 (m, 1H), 3.31 (s, 3H), 1.75 (app
t, 3H), 1.50 (dd, J = 7.4, 3.8 Hz, 2H), 1.13 ppm (dd, J = 7.4, 3.3
Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 207.7, 162.5 (d, J =
247.0 Hz), 139.5, 133.1 (d, J = 3.4 Hz), 130.2, 128.0 (d, J = 2.3
Hz), 127.8 (d, J = 7.9 Hz), 115.7 (d, J = 21.6 Hz), 114.8, 49.8,
33.8, 22.9, 19.7 ppm. LRMS (DEP/EIꢀOrbitrap): m/z (%):
244.1(100). HRMS (EIꢀOrbitrap): m/z: [M]+ Calcd for
C16H17FO+: 244.1263; found: 244.1261. IR (DiamondꢀATR, neat)
ꢂꢃꢄꢅꢆ: 3078(vw), 2992(vw), 2936(vw), 1692(s), 1652(w), 1602(w)
cmꢀ1.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(E)-3-Methyl-1-(1-(4-(trifluoromethyl)styryl)cyclopropyl)but-
3-en-1-one
(4l):
Using
2a
and
(E)ꢀ(4ꢀ
(trifluoromethyl)styryl)boronic acid according to general proceꢀ
dure A and Ba provided 4l (0.14 mmol, 40 mg, 54%) as colorless
(E)-1-(1-(2-([1,1'-Biphenyl]-4-yl)vinyl)cyclopropyl)ethanone
(4p): Using 2b and (E)ꢀ(2ꢀ([1,1'ꢀbiphenyl]ꢀ4ꢀyl)vinyl)boronic acid
according to general procedure A and Ba provided 4p
1
oil. Rf = 0.5 (hexane/EtOAc 9:1, UV, KMnO4, PAA). H NMR
(400 MHz, CDCl3) δ 7.57 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.1 Hz,
2H), 6.97 (d, J = 15.9 Hz, 1H), 6.42 (d, J = 15.8 Hz, 1H), 4.97 –
4.93 (m, 1H), 4.79 – 4.71 (m, 1H), 3.29 (s, 2H), 1.76 (s, 3H), 1.55
(0.20 mmol, 53 mg, 81%) as white solid. Rf = 0.45 (hexꢀ
ane/EtOAc 9:1, UV, KMnO4, PAA). 1H NMR (400 MHz, CDCl3)
δ 7.68 – 7.54 (m, 4H), 7.50 – 7.39 (m, 4H), 7.38 – 7.32 (m, 1H),
6.90 (d, J = 15.9 Hz, 1H), 6.42 (d, J = 15.9 Hz, 1H), 2.27 (s, 3H),
1.52 (dd, J = 7.0, 3.9 Hz, 2H), 1.19 ppm (dd, J = 7.5, 3.7 Hz, 2H).
13C NMR (101 MHz, CDCl3) δ 208.1, 140.7, 140.5, 135.9, 130.1,
128.9, 128.6, 127.5, 127.5, 127.0, 126.8, 34.0, 28.4, 19.6 ppm.
LRMS (DEP/EIꢀOrbitrap): m/z (%): 262.2 (100), 247.1 (5), 219.1
(80). HRMS (EIꢀOrbitrap): m/z: [M]+ Calcd for C19H18O+:
(dd, J = 6.7, 3.4 Hz, 2H), 1.18 ppm (dd, J = 7.3, 3.5 Hz, 2H). 13
C
NMR (101 MHz, CDCl3) δ 207.0, 140.4 (q, J = 1.4 Hz), 139.3,
131.1, 129.6, 129.5 (q, J = 32.4 Hz), 126.5, 125.8 (q, J = 3.8 Hz),
124.3 (q, J = 271.5 Hz), 114.9, 49.6, 33.9, 22.9, 19.9 ppm. LRMS
(DEP/EIꢀOrbitrap): m/z (%): 294.1 (8), 279.1 (30), 252.2 (35),
239.2 (11), 211.1 (34), 191.1 (100). HRMS (EIꢀOrbitrap): m/z:
[M]+ Calcd for C17H17F3O+: 294.1231; found: 294.1225. IR
(DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ: 3080(vw), 2976(vw), 2918(vw),
1692(m), 1648(w) cmꢀ1.
262.1358; found: 262.1352. IR (DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ
:
3028(w), 2924(w), 2854(vw), 1688(s), 1644(w), 1600(w) cmꢀ1.
1-(1-(4-Phenoxyphenyl)cyclopropyl)ethanone (4q): Using 2b
and (4ꢀphenoxyphenyl)boronic acid according to general proceꢀ
dure A and Ba provided 4q (0.10 mmol, 24 mg, 38%) as colorless
(E)-1-(1-(4-Chlorostyryl)cyclopropyl)-3-methylbut-3-en-1-one
(4m): Using 2a and (E)ꢀ(4ꢀchlorostyryl)boronic acid according to
general procedure A and Ba provided 4m (0.11 mmol, 29 mg,
46%) as colorless oil. Rf = 0.5 (hexane/EtOAc 9:1, UV, KMnO4,
PAA). 1H NMR (400 MHz, CDCl3) δ 7.29 (app s, 4H), 6.81 (d, J
= 15.8 Hz, 1H), 6.35 (d, J = 15.9 Hz, 1H), 4.97 – 4.90 (m, 1H),
4.78 – 4.72 (m, 1H), 3.30 (s, 3H), 1.75 (s, 2H), 1.51 (dd, J = 7.4,
3.9 Hz, 2H), 1.14 ppm (dd, J = 7.7, 3.2 Hz, 2H). 13C NMR (101
MHz, CDCl3) δ 207.4, 139.4, 135.4, 133.4, 130.0, 128.9, 128.9,
127.5, 114.8, 49.7, 33.8, 22.9, 19.8 ppm. LRMS (DEP/EIꢀ
Orbitrap): m/z (%): 260.1 (5), 245.1 (14), 218.1 (33), 205.0 (12),
177.0 (22). HRMS (EIꢀOrbitrap): m/z: [M]+ Calcd for
C16H17ClO+: 260.0968; found: 260.0966. IR (DiamondꢀATR,
neat) ꢂꢃꢄꢅꢆ: 3080(vw), 3028(vw), 3014(vw), 2974(w), 2942(vw),
2916(w), 1690(vs), 1646(m), 1592(w) cmꢀ1.
1
oil. Rf = 0.5 (hexane/EtOAc 9:1, UV, KMnO4, PAA). H NMR
(400 MHz, CDCl3) δ 7.39 – 7.33 (m, 2H), 7.33 – 7.30 (m, 2H),
7.17 – 7.08 (m, 1H), 7.05 – 7.01 (m, 2H), 7.00 – 6.95 (m, 2H),
2.03 (s, 3H), 1.60 (dd, J = 6.5, 3.5 Hz, 2H), 1.17 ppm (dd, J = 6.9,
3.5 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 209.3, 157.0, 156.8,
135.9, 132.2, 130.0, 123.7, 119.3, 118.8, 37.0, 29.6, 19.1 ppm.
LRMS (DEP/EIꢀOrbitrap): m/z (%): 252.1 (100), 209.1 (35)
+
HRMS (EIꢀOrbitrap): m/z: [M]+ Calcd for C17H16O2 : 252.1150;
found: 252.1145. IR (DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ: 3040(w),
3010(w), 1692(s), 1590(m) cmꢀ1.
1-(1-(4-Chlorophenyl)cyclopropyl)ethanone (4r): Using 2a and
(4ꢀchlorophenyl)boronic acid according to general procedure A
and Ba provided 4r (0.22 mmol, 42 mg, 86%) as colorless oil. Rf
= 0.5 (hexane/EtOAc 9:1, UV, KMnO4, PAA). 1H NMR (400
MHz, CDCl3) δ 7.34 – 7.28 (m, 1H), 2.00 (s, 1H), 1.61 (dd, J =
6.8, 3.9 Hz, 1H), 1.15 ppm (dd, J = 7.0, 3.5 Hz, 1H). 13C NMR
(101 MHz, CDCl3) δ 208.3, 139.7, 133.5, 132.2, 128.9, 37.1, 29.4,
18.9 ppm. HRMS (EIꢀOrbitrap): m/z: [M]+ Calcd for
C11H11ClO+: 194.0498; found: 194.0496.
(E)-1-(1-(4-Methoxystyryl)cyclopropyl)-3-methylbut-3-en-1-
one (4n): Using 2a and (E)ꢀ(4ꢀmethoxystyryl)boronic acid acꢀ
cording to general procedure A and Ba provided 4n (0.15 mmol,
39 mg, 61%) as colorless oil. Rf = 0.5 (hexane/EtOAc 9:1, UV,
1
KMnO4, PAA). H NMR (400 MHz, CDCl3) δ 7.34 – 7.29 (m,
2H), 6.90 – 6.84 (m, 2H), 6.66 (d, J = 15.8 Hz, 1H), 6.37 (d, J =
15.9 Hz, 1H), 4.97 – 4.91 (m, 1H), 4.77 – 4.72 (m, 1H), 3.82 (s,
3H), 3.33 (s, 2H), 1.75 (app t, 3H), 1.47 (dd, J = 7.0, 4.0 Hz, 2H),
1.11 ppm (dd, J = 7.3, 3.4 Hz, 2H). 13C NMR (101 MHz, CDCl3)
δ 208.2, 159.4, 139.6, 131.1, 129.7, 127.5, 125.9, 114.7, 114.2,
55.5, 50.0, 33.8, 23.0, 19.7 ppm. LRMS (DEP/EIꢀOrbitrap): m/z
(%): 256.1 (31), 241.1 (12), 214.1 (28), 201.1 (87), 173.1 (76),
158.1 (100), 141.1 (40), 128.1 (58), 115.1 (82), 102.0 (186.1 (40),
1-(1-(4-Bromophenyl)cyclopropyl)ethanone (4s): Using 2b and
(4ꢀbromophenyl)boronic acidaccording to general procedure A
and Bb provided 4s (0.18 mmol, 42 mg, 70%) as colorless oil. Rf
= 0.5 (hexane/EtOAc 9:1, UV, KMnO4, PAA). 1H NMR (400
MHz, CDCl3) δ 7.50 – 7.46 (m, 2H), 7.26 – 7.22 (m, 2H), 2.00 (s,
3H), 1.61 (dd, J = 6.5, 3.8 Hz, 2H), 1.15 ppm (dd, J = 7.0, 4.0 Hz,
2H). 13C NMR (101 MHz, CDCl3) δ 208.4, 140.2, 132.6, 131.9,
121.6, 37.2, 29.4, 18.9 ppm. LRMS (DEP/EIꢀOrbitrap): m/z (%):
238.0 (38), 195.0 (13), 116.1 (100). HRMS (EIꢀOrbitrap): m/z:
[M]+ Calcd for C11H1179BrO+: 237.9993; found: IR (Diamondꢀ
+
171.1 (10). HRMS (EIꢀOrbitrap): m/z: [M]+ Calcd for C17H20O2 :
256.1463; found: 256.1465. IR (DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ
:
2967(w), 2944(w), 2934(w), 2916(w), 1723(w), 1690(m),
1652(w), 1606(m), 1576(w), 1528(w), 1511(vs) cmꢀ1.
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The Journal of Organic Chemistry
ATR, neat) ꢂꢃꢄꢅꢆ
:
237.9987. 2958(m), 2918(vs), 2850(s),
2H), 1.13 ppm (dd, J = 6.9, 3.5 Hz, 2H). 13C NMR (101 MHz,
1
2
3
4
5
6
7
8
2212(m), 1740(m) cmꢀ1.
CDCl3) 209.4, 147.8, 147.0, 135.1, 124.1, 111.2, 108.4, 101.3,
37.4, 29.5, 19.3 ppm. LRMS (DEP/EIꢀOrbitrap): m/z (%): 204.1
(70), 161.0 (30). HRMS (EIꢀOrbitrap): m/z: [M]+ Calcd for
1-Methyl-4-(3-nitrophenyl)-5-oxabicyclo[2.1.0]pentane
(5t):
+
Using 2b and 4,4,5,5ꢀtetramethylꢀ2ꢀ(3ꢀnitrophenyl)ꢀ1,3,2ꢀ
dioxaborolane according to general procedure A and B provided
intermediate 5t (0.17 mmol, 34 mg, 66%) as colorless oil. Rf = 0.8
(hexane/EtOAc 9:1, UV, KMnO4, PAA). 1H NMR (400 MHz,
CDCl3) δ 8.17 (t, J = 1.9 Hz, 1H), 8.13 (ddd, J = 8.1, 2.3, 1.2 Hz,
1H), 7.63 (dt, J = 7.7, 1.4 Hz, 1H), 7.53 (t, J = 7.9 Hz, 1H), 2.71 –
2.62 (m, 1H), 2.15 – 1.94 (m, 3H), 1.50 ppm (s, 3H). 13C NMR
(101 MHz, CDCl3) δ 148.5, 137.3, 132.2, 129.4, 122.5, 121.4,
71.9, 68.5, 30.5, 27.3, 13.9 ppm. LRMS (DEP/EIꢀOrbitrap): m/z
(%): 205.1 (40), 190.0 (100), 159.1 (20). HRMS (EIꢀOrbitrap):
C12H12O3 : 204.0786; found: 204.0774.
1-(1-(Dibenzo[b,d]furan-4-yl)cyclopropyl)ethanone (4x): Using
2b and dibenzo[b,d]furanꢀ4ꢀylboronic acid according to general
procedure A and Ba provided 4x (0.19 mmol, 50 mg, 75%) as
colorless oil. Rf = 0.5 (hexane/EtOAc 9:1, UV, KMnO4, PAA). 1H
NMR (400 MHz, CDCl3) δ 7.98 (ddd, J = 7.7, 1.4, 0.7 Hz, 1H),
7.92 (dd, J = 7.6, 1.4 Hz, 1H), 7.62 (dt, J = 8.3, 0.9 Hz, 1H), 7.49
(ddd, J = 8.3, 7.3, 1.3 Hz, 1H), 7.41 (td, J = 7.2, 1.2 Hz, 1H), 7.36
(dd, J = 7.5, 1.0 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 2.03 (s, 3H),
1.80 (dd, J = 6.8, 3.9 Hz, 2H), 1.34 ppm (dd, J = 7.1, 3.7 Hz, 2H).
13C NMR (101 MHz, CDCl3) δ 208.5, 156.3, 155.9, 128.9, 127.5,
125.3, 124.6, 124.3, 123.1, 123.0, 120.9, 120.2, 112.1, 32.6, 29.2,
19.3 ppm. LRMS (DEP/EIꢀOrbitrap): m/z (%): 250.1 (100), 207.1
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
m/z: [M]+ Calcd for C11H11NO3 : 205.0739; found: 205.0733.
1-(1-(3-Nitrophenyl)cyclopropyl)ethanone (4t): Treating 5t
with BF3ꢂOEt2 (see general procedure Bb) resulted in ring conꢀ
traction, yielding 4t (0.17 mmol, 34 mg, quant.) as slightly yellow
solid. Using 2b and 3ꢀAminobenzeneboronic acid hydrochloride
according to general procedure A and Bb provided directly oxiꢀ
dized 4t (0.19 mmol, 39 mg, 77%). Rf = 0.5 (hexane/EtOAc 9:1,
+
(97). HRMS (EIꢀOrbitrap): m/z: [M]+ Calcd for C17H14O2 :
250.0994; found: 250.0995. IR (DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ
:
3056(vw), 3010(w), 1692(s), 1630(vw), 1586(w) cmꢀ1.
1
UV, KMnO4, PAA). H NMR (400 MHz, CDCl3) δ 8.22 (t, J =
1-(1-(2-Fluoropyridin-3-yl)cyclopropyl)ethanone (4y): Using
2b and 2ꢀfluoroꢀ3ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀ
yl)pyridine according to general procedure A and Bb provided 4y
(0.16 mmol, 29 mg, 65%) as colorless oil. Rf = 0.2 (hexꢀ
ane/EtOAc 9:1, UV, KMnO4, PAA). 1H NMR (400 MHz, CDCl3)
δ 8.18 (ddd, J = 4.9, 2.0, 1.1 Hz, 1H), 7.73 (ddd, J = 9.5, 7.4, 2.0
Hz, 1H), 7.20 (ddd, J = 7.4, 4.9, 1.7 Hz, 1H), 2.04 (s, 3H), 1.71
2.0 Hz, 1H), 8.17 (ddd, J = 8.2, 2.3, 1.1 Hz, 1H), 7.71 (ddd, J =
7.6, 1.7, 1.1 Hz, 1H), 7.55 (t, J = 7.9 Hz, 1H), 2.01 (s, 3H), 1.71
(dd, J = 7.2, 3.6 Hz, 2H), 1.25 (dd, J = 7.2, 3.6 Hz, 2H). 13C
NMR (101 MHz, CDCl3) δ 206.7, 148.5, 143.1, 137.2, 129.8,
125.7, 122.8, 37.6, 28.8, 18.6 ppm. LRMS (DEP/EIꢀOrbitrap):
m/z (%): 205.1 (85), 146.0 (10), 115.1 (100). HRMS (EIꢀ
Orbitrap): m/z: [M]+ Calcd for C11H11NO3 : 205.0739; found:
(dd, J = 7.1, 4.1 Hz, 2H), 1.19 ppm (dd, J = 7.4, 3.9 Hz, 2H). 13
C
+
205.0734. IR (DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ: 3096(vw), 3008(vw),
NMR (101 MHz, CDCl3) δ 206.1, 163.1 (d, J = 240.8 Hz), 147.0
(d, J = 14.8 Hz), 142.4 (d, J = 4.8 Hz), 123.4 (d, J = 29.3 Hz),
121.8 (d, J = 4.4 Hz), 31.9 (d, J = 3.2 Hz), 28.2 (d, J = 1.3 Hz),
18.6 ppm. LRMS (DEP/EIꢀOrbitrap): m/z (%): 179.1 (100), 136.0
(88). HRMS (EIꢀOrbitrap): m/z: [M]+ Calcd for C10H10FNO+:
1700(m), 1688(m), 1534(s) cmꢀ1. mp (°C): 106ꢀ107.
3-(1-Acetylcyclopropyl)benzaldehyde (4u): Using 2b and 2ꢀ(3ꢀ
(1,3ꢀdioxolanꢀ2ꢀyl)phenyl)ꢀ4,4,5,5ꢀtetramethylꢀ1,3,2ꢀ
dioxaborolane according to general procedure A and Bb directly
provided deprotected 4u (0.15 mmol, 27 mg, 58%) as colorless
179.0746; found: 179.0741. IR (DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ
:
3012(vw), 1696(s), 1636(vw), 1606(m), 1578(w) cmꢀ1.
1
oil. Rf = 0.2 (hexane/EtOAc 9:1, UV, KMnO4, PAA). H NMR
(400 MHz, CDCl3) δ 10.03 (s, 1H), 7.89 (t, J = 1.7 Hz, 1H), 7.82
(dt, J = 7.6, 1.5 Hz, 1H), 7.65 (ddd, J = 7.7, 1.9, 1.2 Hz, 1H), 7.54
(t, J = 7.6 Hz, 1H), 2.00 (s, 3H), 1.67 (dd, J = 6.8, 4.2 Hz, 2H),
1.22 ppm (dd, J = 7.1, 3.7 Hz, 2H). 13C NMR (101 MHz, CDCl3)
δ 207.7, 192.2, 142.4, 137.1, 136.9, 131.5, 129.6, 129.4, 37.5,
29.2, 18.7 ppm. LRMS (DEP/EIꢀOrbitrap): m/z (%): 188.1 (100).
1-(1-(3,5-Dimethylisoxazol-4-yl)cyclopropyl)ethanone
(4z):
Using 2b and (3,5ꢀdimethylisoxazolꢀ4ꢀyl)boronic acid according
to general procedure A and Ba provided 4z (0.13 mmol, 24 mg,
53%) as colorless oil. Rf = 0.25 (hexane/EtOAc 9:1, UV, KMnO4,
1
PAA). H NMR (400 MHz, CDCl3) δ 2.37 (s, 3H), 2.24 (s, 3H),
2.04 (s, 3H), 1.65 (dd, J = 7.0, 3.0 Hz, 2H), 1.02 ppm (dd, J = 6.7,
3.4 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 207.6, 167.9, 160.6,
114.1, 28.8, 25.1, 18.8, 11.5, 10.5 ppm. LRMS (DEP/EIꢀ
Orbitrap): m/z (%): 179.1 (11), 136.1 (61). HRMS (EIꢀOrbitrap):
m/z: [MꢀH]+ Calcd for C10H12NO2+ : 178.0863; found: 178.0859.
+
HRMS (EIꢀOrbitrap): m/z: [M]+ Calcd for C12H12O2 : 188.0837;
found: 188.0831. IR (DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ: 3010(w),
1758(w), 1720(m), 1692(vs), 1604(w), 1586(w) cmꢀ1.
1-(1-(Phenylethynyl)cyclopropyl)ethanone
(4v):
((2ꢀ
Methylcyclobutꢀ1ꢀenꢀ1ꢀyl)ethynyl) according to general proceꢀ
dure Ba provided 4v (0.11 mmol, 21 mg, 45%) as colorless oil. Rf
= 0.5 (hexane/EtOAc 9:1, UV, KMnO4, PAA). 1H NMR (400
MHz, CDCl3) δ 7.46 – 7.39 (m, 2H), 7.34 – 7.29 (m, 3H), 2.57 (s,
3H), 1.62 (dd, J = 8.2, 3.2 Hz, 2H), 1.39 ppm (dd, J = 8.1, 3.1 Hz,
2H). 13C NMR (101 MHz, CDCl3) δ 206.2, 131.7, 128.5, 128.3,
123.2, 90.4, 80.7, 29.7, 23.7, 23.4 ppm. LRMS (DEP/EIꢀ
Orbitrap): m/z (%): 184.1 (84), 141.1 (83). HRMS (EIꢀOrbitrap):
m/z: [M]+ Calcd for C13H12O+: 184.0888; found: 184.0883. IR
1-(1-(1-Benzyl-1H-pyrazol-4-yl)cyclopropyl)ethanone (4aa):
Using 2b and 1ꢀbenzylꢀ3ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ
2ꢀyl)ꢀ1Hꢀpyrazole according to general procedure A and Ba proꢀ
vided 4aa (0.17 mmol, 41 mg, 69%) as colorless oil. Rf = 0.1
(hexane/EtOAc 9:1, UV, KMnO4, PAA). 1H NMR (400 MHz,
CDCl3) δ 7.49 (d, J = 0.8 Hz, 1H), 7.39 – 7.31 (m, 4H), 7.24 –
7.20 (m, 2H), 5.28 (s, 2H), 2.08 (s, 3H), 1.53 (dd, J = 7.4, 3.7 Hz,
2H), 1.07 ppm (dd, J = 7.4, 3.7 Hz, 2H). 13C NMR (101 MHz,
CDCl3) δ 208.9, 140.4, 136.4, 129.8, 129.0, 128.3, 127.8, 122.5,
56.3, 28.9, 27.5, 19.4 ppm. LRMS (DEP/EIꢀOrbitrap): m/z (%):
240.1 (38), 197.1 (22), 91.1 (100). HRMS (EIꢀOrbitrap): m/z:
[M]+ Calcd for C15H16N2O+: 240.1263; found: 240.1257. IR
(DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ
: 2958(w), 2930(w), 1706(vs),
1598(w) cmꢀ1.
1-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropyl)ethanone
(4w):
(DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ: 3090(w), 3008(w), 2940(w),
Using 2b and benzo[d][1,3]dioxolꢀ5ꢀylboronic acid according to
general procedure A and Ba provided 4w (0.17 mmol, 35 mg,
68%) as colorless oil. Rf = 0.4 (hexane/EtOAc 9:1, UV, KMnO4,
PAA). 1H NMR (400 MHz, CDCl3) δ 6.86 – 6.81 (m, 2H), 6.80 –
6.75 (m, 1H), 5.97 (s, 2H), 2.03 (s, 3H), 1.56 (dd, J = 7.0, 3.1 Hz,
1718(m), 1690(vs) cmꢀ1.
1-(1-(5-Methylthiophen-2-yl)cyclopropyl)ethanone
(4ab):
Using 2b and (5ꢀmethylthiophenꢀ2ꢀyl)boronic acid according to
general procedure A and Ba provided 4ab (0.17 mmol, 31 mg,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 19
69%) as colorless oil. Rf = 0.6 (hexane/EtOAc 9:1, UV, KMnO4,
PAA). H NMR (400 MHz, CDCl3) δ 6.77 (d, J = 3.4 Hz, 1H),
CDCl3) δ 209.4, 142.0, 137.2, 135.0, 131.4, 129.4, 128.6, 128.4,
1
125.9, 42.2, 35.7, 33.0, 29.9, 29.7, 25.3, 21.3 ppm. LRMS
(DEP/EIꢀOrbitrap): m/z (%): 278.1 (100). HRMS (EIꢀOrbitrap):
m/z: [M]+ Calcd for C20H22O+: 278.1671; found: 278.1660. IR
1
2
3
4
5
6
7
8
6.60 (dq, J = 3.4, 1.1 Hz, 1H), 2.46 (d, J = 1.1 Hz, 3H), 2.17 (s,
3H), 1.62 (dd, J = 7.2, 3.7 Hz, 2H), 1.26 ppm (dd, J = 7.2, 3.7 Hz,
2H). 13C NMR (101 MHz, CDCl3) δ 208.6, 142.7, 140.1, 128.0,
124.9, 31.8, 29.1, 21.1, 15.6 ppm. LRMS (DEP/EIꢀOrbitrap): m/z
(%): 180.1 (90), 165.0 810), 137.0 (100), 122.0 (23). HRMS (EIꢀ
Orbitrap): m/z: [M]+ Calcd for C10H12OS+: 180.0609; found:
180.0608. IR (DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ: 3010(w), 2920(w),
1698(vs) cmꢀ1.
(DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ
: 3026(w), 3000(w), 2924(w),
2858(w), 1690(vs) cmꢀ1.
1-((1R*,2R*)-2-Phenethyl-1-((E)-styryl)cyclopropyl)ethanone
((R*)-4af): Using 2d and (E)ꢀstyrylboronic acid according to
general procedure A and Ba provided (R*)-4af (0.11 mmol,
31 mg, 43%) as colorless oil. Rf = 0.8 (hexane/EtOAc 9:1, UV,
9
1
Phenyl(1-phenylcyclopropyl)methanone
(4ac):
1,2ꢀ
KMnO4, PAA). H NMR (400 MHz, CDCl3) δ 7.37 – 7.23 (m,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
diphenylcyclobutꢀ1ꢀene (3ac) for the following rearrangement
was synthesized according to the literature.20 Using 3ac according
to general Bc provided 4ac (0.36 mmol, 80 mg, 72%) as yellowꢀ
7H), 7.23 – 7.16 (m, 3H), 6.68 (d, J = 15.8 Hz, 1H), 6.35 (d, J =
15.8 Hz, 1H), 2.74 – 2.54 (m, 2H), 2.21 (s, 3H), 1.83 – 1.73 (m,
2H), 1.60 (dd, J = 7.5, 4.1 Hz, 1H), 1.52 – 1.41 (m, 1H), 1.22 ppm
(dd, J = 8.6, 4.1 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 206.3,
141.7, 136.9, 130.9, 129.9, 128.8, 128.8, 128.5, 127.8, 126.2,
126.1, 39.4, 36.1, 34.2, 30.6, 28.6, 21.1 ppm. LRMS (DEP/EIꢀ
Orbitrap): m/z (%): 290.1 (5), 199.1 (10). HRMS (EIꢀOrbitrap):
m/z: [M]+ Calcd for C21H22O+: 290.1671; found: 290.1660. IR
1
ish oil. Rf = 0.5 (hexane/EtOAc 95:5, UV, KMnO4, PAA). H
NMR (400 MHz, CDCl3) δ 7.91 – 7.84 (m, 2H), 7.53 – 7.23 (m,
8H), 1.79 (dd, J = 7.3, 4.1 Hz, 2H), 1.48 ppm (dd, J = 7.0, 3.9 Hz,
2H). 13C NMR (101 MHz, CDCl3) δ 200.5, 141.1, 137.1, 132.1,
129.5, 128.7, 128.1, 128.0, 126.7, 35.2, 16.4 ppm. LRMS
(DEP/EIꢀOrbitrap): m/z (%): 222.1 (80), 193.1 (5), 165 (10),
105.0 (100). HRMS (EIꢀOrbitrap): m/z: [M]+ Calcd for
C16H14O+: 222.1045; found: 222.1039.
(DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ
: 3060(w), 3026(m), 3000(w),
2920(w), 1692(vs), 1644(w), 1602(w) cmꢀ1.
1-((1S*,2R*)-2-Phenethyl-1-((E)-styryl)cyclopropyl)ethanone
((S*)-4af): Using 2d and (E)ꢀstyrylboronic acid according to
general procedure A and Ba provided (S*)-4af (0.08 mmol,
24 mg, 33%) as colorless oil. Rf = 0.7 (hexane/EtOAc 9:1, UV,
1-(1-(4-Methoxyphenyl)cyclopropyl)-3-phenylpropan-1-one
(4ad): Using 3ad according to general Bc provided 4ad
(0.16 mmol, 45 mg, 85%) as colorless oil. Rf = 0.65 (hexꢀ
ane/EtOAc 8:2, UV, KMnO4, PAA). 1H NMR (400 MHz, CDCl3)
δ 7.23 (tq, J = 6.7, 6.6, 3.4, 3.2 Hz, 4H), 7.18 – 7.13 (m, 1H), 7.09
– 7.04 (m, 2H), 6.87 – 6.83 (m, 2H), 3.81 (s, 3H), 2.78 (t, J = 7.6
Hz, 2H), 2.60 (t, J = 7.6 Hz, 2H), 1.57 (dd, J =7.2, 3.5 Hz, 2H),
1.11 ppm (dd, J = 7.2, 3.5 Hz, 2H).13C NMR (101 MHz, CDCl3)
δ 210.5, 159.0, 141.5, 132.8, 132.1, 128.5, 128.5, 126.0, 114.1,
55.4, 43.5, 36.6, 30.3, 19.2 ppm. LRMS (DEP/EIꢀOrbitrap): m/z
(%): 280.0 (60), 189.1 (30), 161.0 (70). HRMS (EIꢀOrbitrap):
1
KMnO4, PAA). H NMR (400 MHz, CDCl3) δ 7.36 – 7.25 (m,
7H), 7.24 – 7.18 (m, 1H), 7.15 – 7.09 (m, 2H), 6.39 (d, J = 15.8
Hz, 1H), 6.21 (d, J = 15.8 Hz, 1H), 2.77 – 2.59 (m, 2H), 2.16 (s,
3H), 1.77 – 1.62 (m, 2H), 1.62 – 1.53 (m, 2H), 1.03 ppm (dd, J =
6.2, 3.6 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 208.4, 141.8,
136.8, 134.3, 128.8, 128.8, 128.5, 127.9, 126.4, 126.1, 125.6,
39.4, 36.1, 32.4, 30.6, 29.3, 21.9 ppm. LRMS (DEP/EIꢀOrbitrap):
m/z (%): 290.1 (4), 199.1 (53), 141.1 (10). HRMS (EIꢀOrbitrap):
m/z: [M]+ Calcd for C21H22O+: 290.1671; found: 290.1663. IR
+
m/z: [M]+ Calcd for C19H20O2 : 280.1463; found: 280.1458. IR
(DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ
:
3086(vw), 3026(w), 3003(w),
(DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ: 3060(w), 3025(w), 2998(w),
2955(w), 2952(w), 2934(w), 2931(w), 2923(vw), 2835(vw),
2926(w), 2922(w), 2919(w), 2859(w), 1729(w), 1691(vs),
1716(w), 1689(s), 1651(vw), 1610(m), 1579 cmꢀ1 (w).
1655(w), 1643(w), 1602(w) cmꢀ1.
1-((1R*,2R*)-2-Phenethyl-1-(p-tolyl)cyclopropyl)ethanone
1-((1R*,2R*)-1-(Furan-3-yl)-2-phenethylcyclopropyl)ethanone
((R*)-4ag): Using 2d and furanꢀ3ꢀylboronic acid according to
general procedure A and Ba provided (R*)-4ag (0.085 mmol,
21 mg, 33%) as colorless oil. Rf = 0.5 (hexane/EtOAc 9:1, UV,
((R*)-4ae):
Using
(2ꢀ(3ꢀiodoꢀ2ꢀmethylcyclobutꢀ2ꢀenꢀ1ꢀ
yl)ethyl)benzene (2d) and 4,4,5,5ꢀtetramethylꢀ2ꢀ(pꢀtolyl)ꢀ1,3,2ꢀ
dioxaborolane according to general procedure A and Ba provided
(R*)-4ae (0.15 mmol, 42 mg, 60%) as colorless oil. Rf = 0.7
(hexane/EtOAc 9:1, UV, KMnO4, PAA). 1H NMR (400 MHz,
CDCl3) δ 7.32 – 7.27 (m, 2H), 7.24 – 7.17 (m, 5H), 7.15 – 7.11
(m, 2H), 2.80 – 2.71 (m, 1H), 2.69 – 2.61 (m, 1H), 2.35 (s, 3H),
1.95 (s, 3H), 1.91 – 1.80 (m, 2H), 1.76 – 1.66 (m, 2H), 1.15 –
1.05 ppm (m, 1H). 13C NMR (101 MHz, CDCl3) δ 207.3, 141.8,
139.6, 137.2, 130.5, 129.4, 128.6, 128.5, 126.0, 42.6, 36.4, 32.1,
30.9, 28.5, 21.6, 21.2 ppm. LRMS (DEP/EIꢀOrbitrap): m/z (%):
278.1 (2), 187.1 (10), 173.1 (15), 148.1 (100). HRMS (EIꢀ
Orbitrap): m/z: [M]+ Calcd for C20H22O+: 278.1671; found:
278.1662. IR (DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ: 3086(vw), 3062(vw),
3026(w), 3000(w), 2922(w), 2860(w), 1688(vs), 1654(vw),
1604(w) cmꢀ1.
1
KMnO4, PAA). H NMR (400 MHz, CDCl3) δ 7.36 (dd, J = 1.7
Hz, 1H), 7.32 – 7.24 (m, 3H), 7.23 – 7.16 (m, 3H), 6.30 (dd, J =
1.8, 0.9 Hz, 1H), 2.74 – 2.56 (m, 2H), 2.06 (s, 3H), 1.92 – 1.72
(m, 2H), 1.63 (dd, J = 7.3, 3.5 Hz, 1H), 1.61 – 1.53 (m, 1H),
1.03 ppm (dd, J = 8.2, 3.5 Hz, 1H). 13C NMR (101 MHz, CDCl3)
δ 206.9, 143.2, 141.6, 141.4, 128.7, 128.5, 127.3, 126.1, 112.1,
36.2, 33.1, 32.2, 30.5, 28.2, 21.6 ppm. LRMS (DEP/EIꢀOrbitrap):
m/z (%): 254.1 (3), 163.0 (29). HRMS (EIꢀOrbitrap): m/z: [M]+
+
Calcd for C17H18O2 : 254.1307; found: 254.1299. IR (Diamondꢀ
ATR, neat) ꢂꢃꢄꢅꢆ: 3026(w), 3002(w), 2924(w), 2860(w), 1770(m),
1690(s), 1602(w) cmꢀ1.
1-((1R*,2S*)-1-(Furan-3-yl)-2-phenethylcyclopropyl)ethanone
((S*)-4ag): Using 2d and furanꢀ3ꢀylboronic acid according to
general procedure A and Ba provided (S*)-4ag (0.08 mmol,
19 mg, 30%) as colorless oil. Rf = 0.4 (hexane/EtOAc 9:1, UV,
1-((1R*,2S*)-2-Phenethyl-1-(p-tolyl)cyclopropyl)ethanone
((S*)4ae): Using 2d and 4,4,5,5ꢀtetramethylꢀ2ꢀ(pꢀtolyl)ꢀ1,3,2ꢀ
dioxaborolane according to general procedure A and Ba provided
(S*)-4ae (0.08 mmol, 23 mg, 32%) as colorless oil. Rf = 0.6 (hexꢀ
ane/EtOAc 9:1, UV, KMnO4, PAA). 1H NMR (400 MHz, CDCl3)
δ 7.25 – 7.20 (m, 2H), 7.15 (s, 5H), 7.09 – 7.06 (m, 2H), 2.77 –
2.58 (m, 2H), 2.35 (s, 3H), 1.99 – 1.92 (m, 1H), 1.97 (s, 3H), 1.79
– 1.67 (m, 1H), 1.60 (ddd, J = 8.8, 3.6, 0.8 Hz, 1H), 1.00 (dd, J =
6.8, 3.6 Hz, 1H), 0.91 – 0.79 ppm (m, 1H). 13C NMR (101 MHz,
1
KMnO4, PAA). H NMR (400 MHz, CDCl3) δ 7.42 (dd, J = 1.7
Hz, 1H), 7.30 (dd, J = 1.5, 0.9 Hz, 1H), 7.28 – 7.21 (m, 2H), 7.20
– 7.13 (m, 1H), 7.12 – 7.07 (m, 2H), 6.33 (dd, J = 1.8, 0.9 Hz,
1H), 2.75 – 2.59 (m, 2H), 2.11 (s, 3H), 1.94 – 1.81 (m, 1H), 1.68
– 1.58 (m, 2H), 1.28 – 1.17 (m, 1H), 0.93 ppm (dd, J = 6.9, 3.6
Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 208.6, 143.3, 142.6,
141.9, 128.5, 128.5, 126.0, 122.6, 112.9, 35.6, 33.1, 32.2, 29.8,
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The Journal of Organic Chemistry
29.4, 25.0 ppm. LRMS (DEP/EIꢀOrbitrap): m/z (%): 254.1 (29),
117.1 (17). HRMS (EIꢀOrbitrap): m/z: [M]+ Calcd for C17H18O2 :
Orbitrap): m/z: [M]+ Calcd for C17H24O+: 244.1827; found:
+
1
244.1821. IR (DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ: 3000(w), 2956(m),
254.1307; found: 254.1299. IR (DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ
:
2928(m), 2858(m), 1692(vs) cmꢀ1.
2
3
4
3025(w), 2932(w), 2926(w), 2923(w), 1758(vs), 1688(vs),
1635(w), 1627(w), 1602(w) cmꢀ1.
(E)-8-Methyl-1-(4-(trifluoromethyl)phenyl)nona-1,8-diene-3,6-
dione (6a): Using 2c and (E)ꢀ(4ꢀ(trifluoromethyl)styryl)boronic
acid according to general procedure A and C provided 6a
(0.10 mmol, 31 mg, 40%) as colorless oil. Rf = 0.28 (hexꢀ
ane/EtOAc 9:1, UV, KMnO4, PAA). 1H NMR (400 MHz, CDCl3)
δ 7.64 (s, 4H), 7.58 (d, J = 16.2 Hz, 1H), 6.81 (d, J = 16.2 Hz,
1H), 4.97 (s, 1H), 4.86 (s, 1H), 3.20 (s, 2H), 2.98 (t, J = 6.1 Hz,
2H), 2.87 (t, J = 6.1 Hz, 2H), 1.77 ppm (s, 3H). 13C NMR (101
MHz, CDCl3) δ 207.4, 198.3, 140.8, 139.3, 138.0, 132.0 (q, J =
32.7 Hz), 128.5, 128.1, 126.0 (q, J = 3.8 Hz), 123.9 (q, J = 272.2
Hz), 115.4, 52.4, 35.6, 34.7, 22.8 ppm. LRMS (DEP/EIꢀ
Orbitrap): m/z (%): 310.2 (2), 255.1 (100), 227.1 (30), 199.1 (62).
5
6
7
8
1-((1R*,2R*)-2-Phenethyl-1-(3,4,5-
trimethoxyphenyl)cyclopropyl)ethanone ((R*)-4ah): Using 2d
and (3,4,5ꢀtrimethoxyphenyl)boronic acid according to general
procedure A and Ba provided (R*)-4ah (0.07 mmol, 26 mg, 43%)
as colorless oil. Rf = 0.4 (hexane/EtOAc 8:2, UV, KMnO4, PAA).
1H NMR (400 MHz, CDCl3) δ 7.32 – 7.27 (m, 2H), 7.25 – 7.16
(m, 3H), 6.46 (s, 2H), 3.83 (s, 3H), 3.82 (s, 6H), 2.70 (t, J = 7.3
Hz, 2H), 1.98 (s, 3H), 1.93 – 1.80 (m, 2H), 1.77 – 1.67 (m, 2H),
1.10 ppm (dd, J = 7.8, 2.9 Hz, 1H). 13C NMR (101 MHz, CDCl3)
δ 207.1, 153.3, 141.6, 138.1, 137.3, 128.6, 128.6, 126.1, 107.4,
61.0, 56.3, 43.5, 36.2, 31.7, 30.6, 28.1, 21.7 ppm. LRMS
(DEP/EIꢀOrbitrap): m/z (%): 354.2 (26), 311.2 (17), 263.1 (10),
219.1 (919, 181.1 (100), 165.1 (24). HRMS (EIꢀOrbitrap): m/z:
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
HRMS (EIꢀOrbitrap): m/z: [M]+ Calcd for C17H17F3O2 :
310.1181; found: 310.1168. IR (DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ
:
2973(vw), 2917(vw), 2854(vw), 1714(m), 1694(m), 1670(m),
+
1616(m) cmꢀ1.
[M]+ Calcd for C22H26O4 : 354.1831; found: 354.1819. IR (Diaꢀ
mondꢀATR, neat) ꢂꢃꢄꢅꢆ: 2998(w), 2936(w), 2838(vw), 1688(m)
cmꢀ1.
(E)-1-Cyclohexyl-8-methylnona-1,8-diene-3,6-dione
(6b):
Using 2a and (E)ꢀ(2ꢀcyclohexylvinyl)boronic acid according to
general procedure A and C provided 6b (0.12 mmol, 29 mg, 48%)
as slightly yellow oil. Rf = 0.50 (hexane/EtOAc 9:1, UV, KMnO4,
1-((1R*,2S*)-2-Phenethyl-1-(3,4,5-
trimethoxyphenyl)cyclopropyl)ethanone ((S*)-4ah): Using 2d
and (3,4,5ꢀtrimethoxyphenyl)boronic acid according to general
procedure A and Ba provided (S*)-4ah (0.03 mmol, 12 mg, 20%)
as colorless oil. Rf = 0.3 (hexane/EtOAc 8:2, UV, KMnO4, PAA).
1H NMR (400 MHz, CDCl3) δ 7.29 – 7.20 (m, 2H), 7.19 – 7.13
(m, 1H), 7.12 – 7.07 (m, 2H), 6.47 (s, 2H), 3.86 (s, 3H), 3.85 (s,
6H), 2.79 – 2.61 (m, 2H), 2.02 (s, 3H), 2.01 – 1.93 (m, 1H), 1.81
– 1.69 (m, 1H), 1.57 (dd, J = 9.0, 3.7 Hz, 1H), 1.00 (dd, J = 6.8,
3.7 Hz, 1H), 0.98 – 0.88 ppm (m, 1H). 13C NMR (101 MHz,
CDCl3) δ 208.9, 153.3, 141.9, 137.4, 133.6, 128.5, 128.5, 126.0,
108.3, 61.1, 56.3, 43.1, 35.7, 33.0, 29.6, 29.5, 25.4 ppm. LRMS
(DEP/EIꢀOrbitrap): m/z (%): 354.2 (100), 339.2 (39), 207.1 (17),
1
PAA). H NMR (400 MHz, CDCl3) δ 6.80 (dd, J = 16.1, 6.8 Hz,
1H), 6.05 (dd, J = 16.1, 1.3 Hz, 1H), 4.95 (s, 1H), 4.84 (s, 1H),
3.18 (s, 2H), 2.85 (t, J = 6.3 Hz, 2H), 2.77 (t, J = 6.2 Hz, 2H),
2.23 – 2.07 (m, 1H), 1.76 (s, 3H), 1.83 – 1.60 (m, 4H), 1.34 –
1.05 ppm (m, 6H). 13C NMR (101 MHz, CDCl3) δ 207.6, 199.1,
152.7, 139.2, 127.5, 115.1, 52.3, 40.6, 35.3, 33.5, 31.7, 25.9, 25.7,
22.6 ppm. LRMS (DEP/EIꢀOrbitrap): m/z (%): 248.3 (2), 193.2
+
(23). HRMS (EIꢀOrbitrap): m/z: [M]+ Calcd for C16H24O2 :
248.1776; found: 248.1772. IR (DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ
:
2926(vs), 2853(m), 1717(m), 1698(m), 1674(s), 1650(w),
1628(m) cmꢀ1.
+
189.1 (22). HRMS (EIꢀOrbitrap): m/z: [M]+ Calcd for C22H26O4 :
(E)-7-Phenylhept-6-ene-2,5-dione (6c): Using 2b and (E)ꢀ
styrylboronic acid according to general procedure A and C proꢀ
vided 6c (0.13 mmol, 25 mg, 50%) as colorless oil. Rf = 0.10
(hexane/EtOAc 9:1, UV, KMnO4, PAA). 1H NMR (400 MHz,
CDCl3) δ 7.59 (d, J = 16.2 Hz, 1H), 7.56 – 7.51 (m, 2H), 7.42 –
7.36 (m, 3H), 6.76 (d, J = 16.2 Hz, 1H), 2.98 (dd, J = 6.6, 5.5 Hz,
2H), 2.83 (dd, J = 6.9, 5.7 Hz, 2H), 2.24 ppm (s, 3H). 13C NMR
(101 MHz, CDCl3) δ 207.5, 198.6, 143.0, 134.5, 130.7, 129.1,
128.4, 126.1, 37.2, 34.3, 30.2 ppm. LRMS (DEP/EIꢀOrbitrap):
m/z (%): 202.1 (4), 144.1 (24), 131.1 (100). HRMS (EIꢀOrbitrap):
354.1831; found: 354.1822. IR (DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ
:
3000(w), 2936(w), 1688(m) cmꢀ1.
1-((1R*,2R*)-2-Pentyl-1-(p-tolyl)cyclopropyl)ethanone ((R*)-
4ai): Using 2c and 4,4,5,5ꢀtetramethylꢀ2ꢀ(pꢀtolyl)ꢀ1,3,2ꢀ
dioxaborolane according to general procedure A and Ba provided
(R*)-4ai (0.18 mmol, 21 mg, 55%) as colorless oil. Rf = 0.6 (hexꢀ
ane/EtOAc 9:1, UV, KMnO4, PAA). 1H NMR (400 MHz, CDCl3)
δ 7.25 – 7.21 (m, 2H), 7.16 – 7.12 (m, 2H), 2.35 (s, 3H), 1.98 (s,
3H), 1.71 – 1.65 (m, 2H), 1.52 – 1.40 (m, 3H), 1.37 – 1.24 (m,
5H), 1.11 – 1.03 (m, 1H), 0.93 – 0.84 ppm (m, 3H). 13C NMR
(101 MHz, CDCl3) δ 207.4, 139.9, 137.1, 130.6, 129.4, 42.6, 32.8,
31.8, 30.8, 30.0, 26.8, 22.8, 21.6, 21.3, 14.2 ppm. LRMS
(DEP/EIꢀOrbitrap): m/z (%): 244.2 (56), 187.1 (10), 160.1 (14).
HRMS (EIꢀOrbitrap): m/z: [M]+ Calcd for C17H24O+: 244.1827;
found: 244.1820. IR (DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ: 3000(w),
2956(m), 2924(m), 2858(m), 1692(vs) cmꢀ1.
+
m/z: [MꢀH]+ Calcd for C13H13O2 : 201.0910; found: 201.0912.
IR (DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ: 2908(w), 1714(vs), 1690(s),
1664(vs), 1614(vs) cmꢀ1.
(E)-Tridec-6-ene-2,5-dione (6d): Using 2b and (E)ꢀoctꢀ1ꢀenꢀ1ꢀ
ylboronic acid according to general procedure A and C provided
6d (0.12 mmol, 25 mg, 48%) as colorless oil. Rf = 0.13 (hexꢀ
ane/EtOAc 9:1, UV, KMnO4, PAA). 1H NMR (400 MHz, CDCl3)
δ 6.87 (dt, J = 15.9, 6.9 Hz, 1H), 6.10 (d, J = 15.9 Hz, 1H), 2.84
(t, J = 6.3 Hz, 2H), 2.75 (t, J = 6.3 Hz, 2H), 2.21 (dd, J = 13.6, 7.0
Hz, 2H), 2.21 (s, 3H), 1.52 – 1.38 (m, 2H), 1.37 – 1.21 (m, 6H),
0.88 ppm (t, J = 6.6 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
207.6, 198.8, 148.2, 130.1, 37.1, 33.6, 32.7, 31.7, 30.2, 29.0, 28.2,
22.7, 14.2 ppm. HRMS (ESIꢀquadrupole pos): m/z: [M]+ Calcd
1-((1R*,2S*)-2-Pentyl-1-(p-tolyl)cyclopropyl)ethanone ((S*)-
4ai): Using 2c and 4,4,5,5ꢀtetramethylꢀ2ꢀ(pꢀtolyl)ꢀ1,3,2ꢀ
dioxaborolane according to general procedure A and Ba provided
(S*)-4ai (0.08 mmol, 9 mg, 24%) as colorless oil. Rf = 0.55 (hexꢀ
ane/EtOAc 9:1, UV, KMnO4, PAA). 1H NMR (400 MHz, CDCl3)
δ 7.16 (s, 4H), 2.36 (s, 3H), 1.96 (s, 3H), 1.93 – 1.84 (m, 1H),
1.61 (ddd, J = 8.8, 3.5, 0.7 Hz, 1H), 1.49 – 1.31 (m, 3H), 1.27 –
1.16 (m, 4H), 1.01 (dd, J = 6.9, 3.5 Hz, 1H), 0.87 – 0.78 (m, 3H),
0.57 – 0.44 ppm (m, 1H). 13C NMR (101 MHz, CDCl3) δ 209.7,
137.0, 135.3, 131.4, 129.3, 42.2, 31.7, 30.8, 30.3, 29.9, 29.1, 25.6,
22.7, 21.3, 14.2 ppm. LRMS (DEP/EIꢀOrbitrap): m/z (%): 244.2
(100), 187.1 (12), 169.1 (12), 160.1 (20), 145.1 (43). HRMS (EIꢀ
+
for C13H22O2 : 210.1620; found: 210.1622. IR (DiamondꢀATR,
neat) ꢂꢃꢄꢅꢆ: 2956(m), 2926(s), 2871(m), 2857(m), 1718(vs),
1700(vs), 1675(vs), 1630(s) cmꢀ1.
(E)-3-Phenethyl-7-(p-tolyl)hept-6-ene-2,5-dione (6e): Using 2d
and (E)ꢀ(4ꢀmethylstyryl)boronic acid according to general proceꢀ
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Page 16 of 19
dure A and C provided 6e (0.11 mmol, 34 mg, 43%) as colorless
oil. Rf = 0.3 (hexane/EtOAc 9:1, UV, KMnO4, PAA). H NMR
ly added iPrMgClꢂLiCl (1.1 M in THF) and stirred at aforesaid
1
temperature for 60 minutes. The so obtained (2,2ꢀ
difluorobenzo[d][1,3]dioxolꢀ5ꢀyl)magnesium bromide was subseꢀ
quently transmetallated to zinc by addition of a zinc chloride
1
2
3
4
5
6
7
8
(400 MHz, CDCl3) δ 7.53 (d, J = 16.2 Hz, 1H), 7.47 – 7.41 (m,
2H), 7.34 – 7.27 (m, 2H), 7.23 – 7.14 (m, 5H), 6.68 (d, J = 16.2
Hz, 1H), 3.29 – 3.14 (m, 2H), 2.84 – 2.71 (m, 1H), 2.68 – 2.54
(m, 2H), 2.38 (s, 3H), 2.29 (s, 3H), 2.03 – 1.90 (m, 1H), 1.84 –
1.69 ppm (m, 1H). 13C NMR (101 MHz, CDCl3) δ 211.4, 198.5,
143.1, 141.2, 141.1, 131.6, 129.7, 128.6, 128.4, 128.3, 126.2,
124.9, 46.6, 42.1, 33.4, 33.1, 30.0, 21.6 ppm. LRMS (DEP/EIꢀ
Orbitrap): m/z (%): 320.1 (2), 216.1 (26), 145.1 (100). HRMS
solution (1.0
M in THF) and stirring for another 60 minutes at ꢀ
10 °C. The resulting zinc species was subjected to a Negishi
crossꢀcoupling[3] with 2b to obtain 12.
1-(1-(2,2-Difluorobenzo[d][1,3]dioxol-5-
yl)cyclopropyl)ethanone (4aj): Using 12 according to Bb proꢀ
vided 4aj (0.49 mmol, 118 mg, 49%) as colorless oil. Rf = 0.5
(hexane/EtOAc 9:1, UV, KMnO4, PAA). 1H NMR (400 MHz,
CDCl3) δ 7.12 – 7.06 (m, 2H), 7.02 (dd, J = 7.9, 0.7 Hz, 1H), 2.01
(s, 3H), 1.61 (dd, J = 6.8, 3.9 Hz, 2H), 1.16 ppm (dd, J = 7.1, 3.9
Hz, 2H). 13C NMR (101 MHz, CDCl3) 208.0, 143.8, 143.1, 137.4,
131.8 (t, J = 255.5 Hz), 126.2, 112.1, 109.5, 37.6, 29.1, 19.1 ppm.
LRMS (DEP/EIꢀOrbitrap): m/z (%): 240.0 (100), 197.0 (32),
131.0 (40), 103.1 (76). HRMS (EIꢀOrbitrap): m/z: [M]+ Calcd for
+
(EIꢀOrbitrap): m/z: [M]+ Calcd for C22H24O2 : 320.1776; found:
9
320.1768. IR (DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ: 3056(w), 3026(w),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2924(w), 2860(w), 1710(vs), 1686(s), 1656(s), 1602(vs) cmꢀ1.
(E)-3-Phenethyl-7-phenylhept-6-ene-2,5-dione (6f): Using 2d
and (E)ꢀstyrylboronic acid according to general procedure A and
C provided 6f (0.12 mmol, 37 mg, 48%) as colorless oil. Rf = 0.3
(hexane/EtOAc 9:1, UV, KMnO4, PAA). 1H NMR (400 MHz,
CDCl3) δ 7.60 – 7.51 (m, 3H), 7.43 – 7.37 (m, 3H), 7.33 – 7.27
(m, 2H), 7.25 – 7.15 (m, 3H), 6.72 (d, J = 16.3 Hz, 1H), 3.29 –
3.16 (m, 2H), 2.84 – 2.71 (m, 1H), 2.71 – 2.53 (m, 2H), 2.29 (s,
3H), 2.06 – 1.92 (m, 1H), 1.84 – 1.71 ppm (m, 1H). 13C NMR
(101 MHz, CDCl3) δ 211.5, 198.6, 143.1, 141.3, 134.5, 130.7,
129.1, 128.7, 128.5, 128.4, 126.3, 125.9, 46.7, 42.2, 33.5, 33.2,
30.1 ppm. LRMS (DEP/EIꢀOrbitrap): m/z (%): 306.0 (2), 202.1
(40), 159.0 (10), 131.0 (100). HRMS (EIꢀOrbitrap): m/z: [M]+
+
C12H10F2O3 : 240.0598; found: 240.0581.
1-(2,2-Difluorobenzo[d][1,3]dioxol-5-
yl)cyclopropanecarboxylic acid (8b): To a solution of 4aj (0.33
mmol) in CCl4 (0.66 mL) and CH2Cl2 (0.33 mL) was added benꢀ
zyltriethylammonium chloride (20 mg) followed by a dropwise
addition of a 50% solution of NaOH (0.5 ml). The mixture was
then stirred for 16h at rt. Water was added, and the mixture was
extracted with EtOAc, concentrated under vacuum and purified on
silica gel, providing 8b (0.33 mmol, 80 mg, quant.) as white solid.
+
Calcd for C21H22O2 : 306.1620; found: 306.1620. IR (Diamondꢀ
ATR, neat) ꢂꢃꢄꢅꢆ: 3060(w), 3026(w), 2928(w), 2860(w), 1708(s),
1
1688(m), 1658(s), 1610(s) cmꢀ1.
Rf = 0.3 (hexane/EtOAc 6:4, UV, KMnO4, PAA). H NMR (400
MHz, CDCl3) δ 7.08 – 7.03 (m, 2H), 6.98 (d, J = 8.2 Hz, 1H),
1.69 (dd, J = 7.2, 4.3 Hz, 2H), 1.25 ppm (dd, J = 7.2, 3.8 Hz, 2H)
(COOH not observed). 13C NMR (101 MHz, CDCl3) 180.7,
143.6, 143.1, 134.9, 131.8 (t, J = 253.2 Hz), 125.8, 112.2, 109.1,
28.8, 17.9 ppm. LRMS (DEP/EIꢀOrbitrap): m/z (%): 242.0 (68),
224.0 (16), 196.0 (35). HRMS (EIꢀOrbitrap): m/z: [M]+ Calcd for
1-(1-(4-Chlorophenyl)cyclopropyl)-2-(pyridin-2-
ylsulfonyl)ethanone (B): 4r was transformed to 6a according to a
literature procedure.[25] Purification by chromatography afforded
B (0.06 mmol, 20 mg, 40%) as colorless oil. Rf = 0.5 (hexꢀ
ane/EtOAc 5:5, UV, KMnO4, PAA). 1H NMR (400 MHz, CDCl3)
δ 8.70 (dt, J = 4.8, 1.2 Hz, 1H), 8.05 (dt, J = 7.9, 1.1 Hz, 1H),
7.97 (td, J = 7.7, 1.7 Hz, 1H), 7.55 (ddd, J = 7.6, 4.7, 1.2 Hz, 1H),
7.40 – 7.29 (m, 4H), 4.47 (s, 2H), 1.64 (dd, J = 7.3, 4.1 Hz, 2H),
1.27 ppm (dd, J = 7.1, 3.5 Hz, 2H). 13C NMR (101 MHz, CDCl3)
δ 198.5, 157.1, 150.1, 138.3, 137.2, 134.5, 132.5, 129.5, 127.6,
122.3, 59.5, 38.0, 20.5 ppm. LRMS (DEP/EIꢀOrbitrap): m/z (%):
335.0 (3), 243.0 (13), 229.1 (11), 193.1 (43), 158.1 (21). HRMS
(EIꢀOrbitrap): m/z: [MꢀH]+ Calcd for C16H13ClNO3S+ : 334.0299;
found: 334.0288. IR (DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ: 2918(w),
1696(s), 1580(w) cmꢀ1.
+
C11H8F2O4 : 242.0391; found: 242.0382. IR (DiamondꢀATR,
neat) ꢂꢃꢄꢅꢆ: 2886(w), 2840(w), 1678(vs) cmꢀ1. mp (°C): 179ꢀ180.
3-Chloro-6-(2-(2-methylcyclobut-1-en-1-
yl)phenoxy)pyridazine
methoxyphenyl)boronic acid according to general procedure A
provided 9. The product was dissolved in CH2Cl2 (1.0 ) and
treated with a solution of BBr3 in CH2Cl2 (1.0 eq., 1.0 ) at 30 °C.
(10):
Using
2b
and
(2ꢀ
M
M
After 5 min TLC indicated completion of the reaction. The reacꢀ
tion mixture was slowly poured onto ice cold water and subseꢀ
quently extracted with CH2Cl2 (3 × 20 mL) and dried over magꢀ
nesium sulfate. After evaporation of solvents and purification by
1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (8a):
To a solution of 4w (0.1 mmol) in CCl4 (0.2 mL) and CH2Cl2
(0.1 mL) was added benzyltriethylammonium chloride (6 mg)
followed by a dropwise addition of a 50% solution of NaOH
(0.15 ml). The mixture was then stirred for 16h at rt. Water was
added, and the mixture was extracted with EtOAc, concentrated
under vacuum and purified on silica gel, providing 8a (0.1 mmol,
26 mg, quant.) as white solid. Rf = 0.3 (hexane/EtOAc 6:4, UV,
chromatography, pure 13 was dissolved in DMF (1.0 M).To the
solution was added NaH (1.1 eq., 60 % dispersion in mineral oil)
and 3,6ꢀdichloropyridazine. After stirring for 30 min at ambient
temperature, TLC indicated full consumption of the starting mateꢀ
rials. The reaction mixture was extracted with Et2O (3 × 20 mL),
washed with a saturated aqueous solution of LiCl (20 mL) and
Brine (20 mL). After drying the organic phase over magnesium
sulfate and evaporation of solvents, chromatography afforded
pure 10 as colorless oil. Most fractions contained impurities, a
yield was therefore not determined. Rf = 0.3 (hexane/EtOAc 8:2,
1
KMnO4, PAA). H NMR (400 MHz, CDCl3) δ 6.83 (d, J = 1.6
Hz, 1H), 6.80 (dd, J = 7.9, 1.7 Hz, 1H), 6.73 (dd, J = 6.4, 3.3 Hz,
1H), 5.94 (s, 2H), 1.62 (dd, J = 7.0, 4.1 Hz, 3H), 1.22 ppm (dd, J
= 6.9, 3.6 Hz, 2H) (COOH not observed). 13C NMR (101 MHz,
CDCl3) 181.2, 147.4, 147.0, 132.7, 123.8, 111.3, 108.1, 101.2,
28.7, 17.8 ppm. LRMS (DEP/EIꢀOrbitrap): m/z (%): 206.1 (100),
1
UV, KMnO4, PAA). H NMR (400 MHz, CDCl3) δ 7.35 (d, J =
9.2 Hz, 1H), 7.36 – 7.33 (m, 1H), 7.18 – 7.12 (m, 2H), 7.02 – 6.98
(m, 1H), 6.96 (d, J = 9.1 Hz, 1H), 2.46 – 2.41 (m, 2H), 2.24 –
2.20 (m, 2H), 1.80 – 1.77 ppm (m, 3H). 13C NMR (101 MHz,
CDCl3) δ 165.5, 151.8, 149.6, 142.5, 133.9, 131.4, 129.0, 129.0,
128.0, 126.0, 122.4, 119.2, 31.0, 28.9, 16.6 ppm. HRMS (EIꢀ
Orbitrap): m/z: [M]+ Calcd for C15H13ClN2O+: 272.0716; found:
272.0714.
+
161.0 (61). HRMS (EIꢀOrbitrap): m/z: [M]+ Calcd for C11H10O4 :
206.0579; found: 206.0570. IR (DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ
:
3014(w), 2894(w), 2594(w), 1684(vs) cmꢀ1. mp (°C): 157ꢀ158.
2,2-Difluoro-5-(2-methylcyclobut-1-en-1-
yl)benzo[d][1,3]dioxole (12): To a solution of 5ꢀbromoꢀ2,2ꢀ
difluorobenzo[d][1,3]dioxole in THF (0.5 ) at –10 °C was slowꢀ
M
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The Journal of Organic Chemistry
(400 MHz, CDCl3) δ 9.42 (s, 1H), 8.04 – 7.97 (m, 1H), 7.94 –
1-(1-(2-((6-Chloropyridazin-3-
yl)oxy)phenyl)cyclopropyl)ethanone (11): Using 10 (also imꢀ
pure fractions) according to general procedure Ba provided 11
(1.00 mmol, 288 mg, 43% over two steps) as colorless oil. Rf =
0.1 (hexane/EtOAc 8:2, UV, KMnO4, PAA). 1H NMR (400 MHz,
CDCl3) δ 7.49 (d, J = 9.1 Hz, 1H), 7.45 – 7.36 (m, 2H), 7.29 (dd,
J = 7.5, 1.3 Hz, 1H), 7.19 (dd, J = 8.0, 1.3 Hz, 1H), 7.18 (d, J =
9.1 Hz, 1H), 2.08 (s, 3H), 1.43 (dd, J = 6.9, 3.8 Hz, 2H), 1.08 ppm
(dd, J = 7.2, 3.9 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 208.2,
164.8, 153.3, 152.4, 132.9, 131.8, 131.8, 129.3, 126.4, 122.5,
120.2, 33.5, 28.9, 18.1 ppm. LRMS (DEP/EIꢀOrbitrap): m/z (%):
272.1 (9), 237.1 (100), 222.1 (30), 209.1 (15), 194.1 (18), 183.0
(10), 165.0 (12). HRMS (EIꢀOrbitrap): m/z: [M]+ Calcd for
C15H12ClN2O+ ([MꢀOH]+): 271.0638; found: 271.0635. IR (Diaꢀ
mondꢀATR, neat) ꢂꢃꢄꢅꢆ: 3066(w), 2972(w), 1754(w), 1692(m),
1642(w), 1614(w), 1606(w) cmꢀ1.
7.81 (m, 2H), 7.58 – 7.45 (m, 4H), 1.88 – 1.78 (m, 2H), 1.54 –
1.47 ppm (m, 2H).13C NMR (101 MHz, CDCl3) δ 201.7, 134.2,
134.0, 133.3, 129.0, 128.8, 128.5, 126.6, 126.1, 125.5, 124.4,
35.7, 17.2 ppm. LRMS (DEP/EIꢀOrbitrapꢀOrbitrap): m/z (%):
196.1 (90), 178.1 (10), 165.1 (100), 152.1 (90), 139.1 (20).
HRMS (EIꢀOrbitrap): m/z: [M]+ Calcd for C14H12O+: 196.0888;
found: 196.0883. IR (DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ: 3044(w),
3007(vw), 2819(vw), 2732(vw), 2702(vw), 1780(vw), 1702(s),
1595(w) cmꢀ1.
1
2
3
4
5
6
7
8
9
1-([1,1'-Biphenyl]-4-yl)cyclopropane-1-carbaldehyde
(13d):
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Using 4ꢀbromoꢀ1,1'ꢀbiphenyl and cyclobutanone according to
general procedure C provided 13d (0.57 mmol, 133 mg, 57%) as
colorless oil. Rf = 0.45 (hexane/EtOAc 9:1, UV, KMnO4, PAA).
1H NMR (400 MHz, CDCl3) δ 9.29 (s, 1H), 7.64 – 7.57 (m, 4H),
7.51 – 7.35 (m, 5H), 1.63 (dd, J = 4.1 Hz, 2H), 1.47 ppm (dd, J =
4.3 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 201.0, 140.8, 140.7,
136.5, 130.6, 128.9, 127.5, 127.2, 37.3, 16.2 ppm. HRMS (EIꢀ
Orbitrap): m/z: [M]+ Calcd for C16H14O+: 222.1045; found:
222.1048. IR (DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ: 1677(m), 1498(m),
1440(w), 1427(w) cmꢀ1.
(E)-2-Methyl-5-(4-methylstyryl)-3-phenethylfuran (7): 6e was
dissolved in toluene (0.1
M) and P4O10 (3.0 eq.) was added. The
reaction mixture was heated to 100 °C for 24 hours in a pressure
tube. After cooling to room temperature, the reaction was
quenched with water, extracted with Et2O (3 × 20 mL), washed
with Brine (20 mL) and dried over magnesium sulfate. The organꢀ
ic phase was concentrated under reduced pressure and purified by
column chromatography. 7 was obtained (0.10 mmol, 29 mg,
1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-
carbaldehyde
(13e):
Using
5ꢀbromoꢀ2,2ꢀ
1
87%) as colorless oil. Rf = 0.2 (hexane, UV, KMnO4, PAA). H
difluorobenzo[d][1,3]dioxole and cyclobutanone according to
general procedure C. provided 13e (0.5 mmol, 105 mg, 50%) as
colorless oil. Rf = 0.5 (hexane/EtOAc 9:1, UV, KMnO4, PAA). 1H
NMR (400 MHz, CDCl3) δ 9.07 (s, 1H), 7.09 – 6.89 (m, 3H),
1.59 (dd, J = 4.1 Hz, 2H), 1.41 ppm(dd, J = 3.7 Hz, 2H).13C
NMR (101 MHz, CDCl3) δ 200.0, 143.9, 143.4, 133.5, 131.81 (t,
J = 255.5 Hz), 125.6, 111.8, 109.5 ppm. LRMS (DEP/EIꢀ
OrbitrapꢀOrbitrap): m/z (%): 226.1 (80), 207.0 (5), 197.1 (15),
182.0 (5), 170.9 (5). HRMS (EIꢀOrbitrap): m/z: [M]+ Calcd for
NMR (400 MHz, CDCl3) δ 7.36 – 7.32 (m, 2H), 7.31 – 7.26 (m,
2H), 7.23 – 7.11 (m, 5H), 6.90 (d, J = 16.2 Hz, 1H), 6.75 (d, J =
16.2 Hz, 1H), 6.13 (s, 1H), 2.81 (dd, J = 8.7, 6.7 Hz, 2H), 2.62
(dd, J = 8.7, 6.7 Hz, 2H), 2.34 (s, 3H), 2.10 ppm (s, 3H). 13C
NMR (101 MHz, CDCl3) 150.8, 147.9, 141.8, 137.2, 134.7,
129.5, 128.7, 128.4, 126.2, 126.1, 125.2, 120.6, 115.9, 110.9,
36.8, 27.1, 21.4, 11.6 ppm. LRMS (DEP/EIꢀOrbitrap): m/z (%):
302.1 (100), 211.1 (42), 169.1 (35). HRMS (EIꢀOrbitrap): m/z:
[M]+ Calcd for C22H22O+: 302.1671; found: 302.1670.
+
C11H8F2O3 : 226.0442; found: 226.0435.
1-(4-Bromophenyl)cyclopropane-1-carbaldehyde (13f): Using
1ꢀbromoꢀ4ꢀiodobenzene and cyclobutanone according to general
procedure C. provided 13f (0.69 mmol, 155 mg, 69%) as colorless
1-(p-Tolyl)cyclopropane-1-carbaldehyde (13a): Using 1ꢀbromoꢀ
4ꢀmethylbenzene and cyclobutanone according to general proceꢀ
dure C provided 13a (8.4 mmol, 1.346 g, 69%) as colorless oil. Rf
= 0.5 (hexane/EtOAc 9:1, UV, KMnO4, PAA). 1H NMR (400
MHz, CDCl3) δ 9.28 (s, 1H), 7.26 – 7.13 (m, 4H), 2.38 (s, 3H),
1.57 (dd, J = 3.9 Hz, 2H), 1.40 ppm (dd, 2H). 13C NMR (101
MHz, CDCl3) δ 201.4, 137.5, 134.6, 130.0, 129.4, 37.2, 21.2,
16.2 ppm. LRMS (DEP/EIꢀOrbitrapꢀOrbitrap): m/z (%): 160.1
(100), 145.1 (20). HRMS (EIꢀOrbitrap): m/z: [M]+ Calcd for
C11H12O+: 160.0888; found: 160.0882. IR (DiamondꢀATR, neat)
1
oil. Rf = 0.5 (hexane/EtOAc 9:1, UV, KMnO4, PAA). H NMR
(400 MHz, CDCl3) δ 9.14 (s, 1H), 7.51 – 7.47 (m, 2H), 7.20 –
7.16 (m, 2H), 1.58 (dd, J = 6.9, 5.0 Hz, 2H), 1.39 ppm (dd, J =
7.8, 4.1 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 200.3, 136.5,
131.9, 131.9, 131.8, 37.2, 15.9 ppm. LRMS (DEP/EIꢀOrbitrapꢀ
Orbitrap): m/z (%): 226.0 (30), 197.0 (5), 181.9 (5). HRMS (EIꢀ
Orbitrap): m/z: [M]+ Calcd for C10H9BrO+: 223.9837; found:
223.9830. IR (DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ: 1682(vs), 1488(m),
1429(m), 1420(m) cmꢀ1.
ꢂꢃꢄꢅꢆ
:
3010(w), 2923(w), 2919(w), 2822(vw), 2818(vw),
1705(vs), 1517(m) cmꢀ1.
1-(4-Methoxyphenyl)cyclopropane-1-carbaldehyde
(13b):
Using 1ꢀbromoꢀ4ꢀmethoxybenzene and cyclobutanone according
to general procedure C provided 13b (0.34 mmol, 60 mg, 34%) as
colorless oil. Rf = 0.4 (hexane/EtOAc 9:1, UV, KMnO4, PAA). 1H
NMR (400 MHz, CDCl3) δ 9.22 (s, 1H), 7.25 – 7.20 (m, 2H),
6.93 – 6.87 (m, 2H), 3.81 (s, 3H), 1.54 (dd, J = 3.9 Hz, 2H),
1.37 ppm (dd, J = 3.5 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ
201.5, 159.1, 131.4, 129.6, 114.1, 55.4, 37.0, 16.2 ppm. LRMS
(DEP/EIꢀOrbitrapꢀOrbitrap): m/z (%): 176.1 (100), 161.1 (10),
ASSOCIATED CONTENT
Supporting Information
1H and 13C NMR spectra for all new compounds and Xꢀray crysꢀ
tallographic data of compounds 4f and 4t, and computational
details can be found in the Supporting Information.
The Supporting Information is available free of charge on the
ACS Publications website.
147.1 (70), 132.1 (15). HRMS (EIꢀOrbitrap): m/z: [M]+ Calcd
+
for C11H12O2 : 176.0837; found: IR (DiamondꢀATR, neat) ꢂꢃꢄꢅꢆ
:
AUTHOR INFORMATION
Corresponding Author
176.0831. 3003(vw), 2958(vw), 2836(w), 2708(vw), 1780(vw),
1703(s), 1611(m), 1579(w), 1514(vs) cmꢀ1.
*dorian.didier@cup.uniꢀmuenchen.de
*regina.de_vivie@cup.uniꢀmuenchen.de
1-(Naphthalen-1-yl)cyclopropane-1-carbaldehyde (13c): Using
1ꢀbromonaphthalene and cyclobutanone according to general
procedure C provided 13c (0.58 mmol, 114 mg, 58%) as colorless
1
ACKNOWLEDGMENT
oil. Rf = 0.4 (hexane/EtOAc 9:1, UV, KMnO4, PAA). H NMR
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 19
d) Berger, M. D.; Hammerschmidt, F.; Qian, R.; Hahner, S.; Schirbel,
Generous support from the Fonds der chemischen Industrie, the
Deutsche Forschungsgemeinschaft (DFG Grant No. DI 2227/2ꢀ1)
and the SFB749 is greatly acknowledged. We kindly thank Dr.
Peter Mayer for Xꢀray measurements and Martina Stadler for
bioassays.
A.; Stichelberger, M.; Schibli, R.; Yu, J.; Arion, V. B.; Woschek, A.;
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min, A.; Stamos, D. J. Org. Chem. 2013, 78, 780. c) Gololobov, Y.
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1987, 43, 2609.
[11] a) Klapars, A.; Waldman, J. H.; Campos, K. R.; Jensen, M. S.;
Mclaughling, M.; Chung, J. Y. L.; Cvetovich, R. J.; Chen, C. J. Org.
Chem. 2005, 70, 10186. b) Caron, S.; Vasquez, E.; Wojcik, J. M. J.
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Chem. Commun. 2015, 51, 12819.
[13] For early studies of cyclobutene oxide rearrangements, see: a)
Heine, H.ꢀG.; Hartmann, W.; Knops, H.ꢀJ.; Priesnitz, U. Tetrahedron
Lett. 1983, 24, 2635. b) Conia, J. M. Angew. Chem. 1968, 80, 578. c)
Garin, D. L. J. Org. Chem. 1971, 36, 1697.
[14] For seminal studies and recent examples, see: a) Meinwald, J.;
Labana, S. S.; Chadha, M. S. J. Am. Chem. Soc. 1963, 85, 582. b)
Rickborn, B. in Comprehensive Organic Synthesis, Vol. 3 (Eds.: B.
M. Trost, I. Fleming, G. Pattenden), Pergamon, Oxford, 1991, 733. c)
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D'Amico, D. C. J. Am. Chem. Soc. 1995, 117, 7379. f) Pace, V.;
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Chem. Int. Ed. 2017, 56, 12677.
[15] a) Criegee, R.; Noll, N. Liebigs Ann. Chem. 1959, 627, 1ꢀ14; b)
Shabarov, Y. S.; Blagodatskikh, S. A.; Levina, M. I.; Fedotov, A. N.
Z. Org. Khim. 1975, 11, 1223; c) Kurita, J.; Sakai, H.; Tsuchiya, T. J.
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Matturro, M. G.; Okarma, P. J.; Jason, M. E.; Dailey, W. P.; Burgꢀ
maier, G. J.; Bailey, W. F.; Warner, P. Tetrahedron 1986, 42, 1895ꢀ
1902; e) Kurita, J.; Sakai, H.; Tsuchiya, T. Chem. Pharm. Bull. 1988,
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1996, 52, 15103ꢀ15116; g) Lescop, C.; Huet, F. Tetrahedron 2000,
56, 2995ꢀ3003. h) Ripoll, J.ꢀL.; Conia, J.ꢀM. Bull. Soc. Chim. Fr.
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[16] A [4+2]ꢀcycloaddition of the diene with O2 is assumed to be
responsible for the formation of 1,4ꢀdiketones. For a recent example,
see: Shen, L.; Zhao, K.; Doitomi, K.; Ganguly, R.; Li, Y.ꢀX.; Shen,
Z.ꢀL.; Hirao, H.; Loh, T.ꢀP. J. Am. Chem. Soc. 2017, 139, 13570.
[17] See supporting information.
1
2
3
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