Donor-Acceptor Bicyclopropyls as 1,6-Zwitterionic Intermediates: Synthesis and Reactions with 4-Phenyl-1,2,4-triazoline-3,5-dione and Terminal Acetylenes

Article abstract of DOI:10.1021/acs.joc.0c02293

The bicyclopropyl system activated by incorporation of donor and acceptor groups in the presence of Lewis acids was used as a synthetic equivalent of 1,6-zwitterions. Opening of both cyclopropane rings in 2′-aryl-1,1′-bicyclopropyl-2,2-dicarboxylates (D-A bicyclopropyl, ABCDs) in the presence of GaI3 + Bu4N+GaI4- results in 5-iodo-5-arylpent-2-enylmalonates as products of HI formal 1,6-addition to the bicyclopropyl system. The use of GaCl3 or GaBr3 as a Lewis acid and terminal aryl or alkyl acetylenes as 1,6-zwitterion interceptors allows the alkyl substituent to be grown to give the corresponding acyclic 7-chloro(bromo)-hepta-2,6-dienylmalonates. The reaction of ABCDs with 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) catalyzed by Yb(OTf)3 also results in the opening of both cyclopropane rings. The reaction products are tetrahydropyridazine derivatives - (7,9-dioxo-1,6,8-triazabicyclo[4.3.0]non-3-en-2-ylmethyl)malonates - containing one more PTAD moiety in the malonyl group.

Full text of DOI:10.1021/acs.joc.0c02293

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Donor−Acceptor Bicyclopropyls as 1,6-Zwitterionic Intermediates:
Synthesis and Reactions with 4‑Phenyl-1,2,4-triazoline-3,5-dione
and Terminal Acetylenes
Konstantin V. Potapov,† Dmitry A. Denisov,† Valeriia V. Glushkova, Roman A. Novikov,*,†
and Yury V. Tomilov*
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ABSTRACT: The bicyclopropyl system activated by incorpora-
tion of donor and acceptor groups in the presence of Lewis acids
was used as a synthetic equivalent of 1,6-zwitterions. Opening of
both cyclopropane rings in 2′-aryl-1,1′-bicyclopropyl-2,2-dicarbox-
ylates (D−A bicyclopropyl, ABCDs) in the presence of GaI3 +
Bu4N+GaI4 results in 5-iodo-5-arylpent-2-enylmalonates as
−
products of HI formal 1,6-addition to the bicyclopropyl system.
The use of GaCl3 or GaBr3 as a Lewis acid and terminal aryl or
alkyl acetylenes as 1,6-zwitterion interceptors allows the alkyl
substituent to be grown to give the corresponding acyclic 7-
chloro(bromo)-hepta-2,6-dienylmalonates. The reaction of ABCDs
with 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) catalyzed by
Yb(OTf)3 also results in the opening of both cyclopropane rings. The reaction products are tetrahydropyridazine derivatives 
(7,9-dioxo-1,6,8-triazabicyclo[4.3.0]non-3-en-2-ylmethyl)malonates  containing one more PTAD moiety in the malonyl group.
substituents. The only known process for 1a as a formal 1,6-
zwitterion is its reaction with EtAlCl2 that leads to formal 1,6-
addition of HCl to the bicyclopropyl system (Scheme 1D).
Later, Werz showed17 that only one cyclopropane ring is
opened in a bicyclopropyl 1,1-dicarboxylate containing no
donor group, which resulted in the classical 1,3-zwitterionic
reactivity of such compounds (Scheme 1C(d)).
INTRODUCTION
■
Donor−acceptor cyclopropanes (DACs)1,2 are widely used in
organic synthesis3,4 owing to their ability to react as synthetic
equivalents of 1,3-zwitterions (Scheme 1A). Recently,
reactions of DACs where they exhibit other reactivity types
have also been studied intensely.5−8 The use of 2-vinyl-
cyclopropane-1,1-dicarboxylates allows one to obtain not only
1,3-zwitterionic reactivity products but also conjugated 1,5-
addition products9,10 (Scheme 1B). Recently, using gallium
halides as Lewis acids, our team found11,12 yet another type of
DAC reactivity involving a three-membered ring opening
followed by a hydride shift to give rather stable 1,2-zwitterionic
gallium complexes (Scheme 1C(a)). In addition, isomeric
styrylmalonates13 and alkylidenemalonates14 can be used as
analogues of DACs and 1,2-zwitterionic intermediates.
RESULTS AND DISCUSSION
■
In this paper, we continued to study the activated
bicyclopropyl system that can trap the zwitterions formed in
situ. To this end, we expanded the range of the starting 2′-aryl-
1,1′-bicyclopropyl-2,2-dicarboxylates 1 (ABCDs) (Scheme
1C(b)) using some terminal acetylenes and PTAD (4-
phenyl-1,2,4-triazoline-3,5-dione) as unsaturated substrates,
as well as by the formal addition of HI via the GaI3/
Moreover, systems with a carbocationic center that is remote
from the acceptor moiety have almost not been studied.
Recently, we began a more detailed study of these systems, in
particular, with model substrates containing two cyclopropane
moieties in a molecule, such as 2′-phenyl-1,1′-bicyclopropyl-
2,2-dicarboxylate (1a)15 (Scheme 1C(b)) and 4-phenyl-
spiropentane-1,1-dicarboxylate (2)16 (Scheme 1C(c)). Using
these compounds as examples, it was shown that both
cyclopropane rings could be opened in tandem in the presence
of various Lewis acids.15,16 However, only processes of their
isomerization to the corresponding dienes and addition of
some nucleophiles were mainly studied without variation of
Bu4N+GaI4 system. We chose both of them as model
−
substrates because of their stability toward Lewis acids,
including GaCl3,18,19 and also because of their high reactivity.
Received: September 25, 2020
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© XXXX American Chemical Society
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Scheme 1. Main Types of D−A Cyclopropane-Based
Sources for the Generation of Various Formal 1,n-
Zwitterionic Synthons
Scheme 2. Synthesis of Starting 2′-Aryl-1,1′-bicyclopropyl-
a
2,2-dicarboxylates 1a−e (ABCDs)
a
Cu(I) = Cu(MeCN)4PF6; LAH = LiAlH4; PCC = PyrH+CrO3Cl−; E
= CO2Me. See the Experimental Section for detailed information.
most logical method for its preparation by cyclopropanation of
the corresponding 2-styrylcyclopropane-1,1-dicarboxylates
under any conditions.15 The double bond in the last
compounds proved to be surprisingly nonreactive and did
not undergo cyclopropanation, neither under conditions of
catalytic or thermal cyclopropanation with diazomethane, nor
under Simmons−Smith cyclopropanation conditions. An
alternative cyclopropanation approach of 2-vinylcyclopro-
pane-1,1-dicarboxylate using various aryldiazomethanes gives
very low yields of the target bicyclopropyls 1.
The target bicyclopropyls 1a−e were prepared in six steps
from commercially available aromatic aldehydes containing a
mixture of four diastereomers (Scheme 2). Previously,15 the
isomeric composition was studied in detail for bicyclopropyl
1a, and the isomer ratio was estimated to be 6.6:4.7:1.2:1.0.
The ratio of trans- and cis-isomers was the same as in the
previous vinylcyclopropane 3a (∼5:1). However, we did not
pay special attention to it for other substituted ABCDs,
because this isomerism should not play a significant role in
subsequent reactions that occur with the opening of both
cyclopropane rings. As a result, only the E- and Z-isomerism of
the resulting double bond is observed.
Moreover, the PTAD moiety (in case of its successful coupling
with DAC 1) is of interest in terms of potential biological
activity of the resulting compounds that are known for various
PTAD derivatives.20,21 For example, inflachromene, an
inhibitor with antineuroinflammatory effects (Figure 1), is
one of its famous derivatives.22
Nitrophenyl-substituted bicyclopropyl 1f has also been
synthesized (Scheme 3). However, the standard six-step
sequence gave very bad yields and a complex mixture and
could not be applied. In this case, ABCD 1f was obtained in a
Figure 1. Representative examples of PTAD derivatives and tetra-/
hexahydropyridazine skeletons in pharmaceuticals and its analogues.
Scheme 3. Synthesis of 2′-(Nitrophenyl)-1,1′-bicyclopropyl-
2,2-dicarboxylate 1f
To obtain substituted 1,1′-bicyclopropyl-2,2-dicarboxylates
1b−e, we successfully applied the scheme that we developed
earlier for synthesizing the simplest phenyl-substituted
bicyclopropyl 1a15 based on the traditional reaction sequence
well proven for D−A cyclopropanes: Knoevenagel condensa-
tion and Corey−Chaykovsky cyclopropanation (Scheme 2). At
the same time, attempts to use alternative synthetic schemes
failed. Therefore, we disregarded the use of the simplest and
B
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high yield by direct nitration of the simple Ph-analogue 1a.
Bicyclopropyl 1f is formed as a mixture of ortho-/para-isomers
with a dominant ortho-isomer. During nitration, the
bicyclopropyl system turns out to be unexpectedly stable
enough at least at low temperatures.
Scheme 5. Formal 1,6-Addition of HI to Bicyclopropyls 1 in
−
the Presence of the GaI3/Bu4N+GaI4 System and Scope of
a
the Reaction
The previously studied isomerization of bicyclopropyl 1a in
the presence of GaCl3 results in regioisomeric dienes 4 or 5
depending on the reaction conditions, but in each case only in
the form of the E-isomer (Scheme 4). The accompanying
Scheme 4. Isomerization of 2′-Phenyl-1,1′-bicyclopropyl-
2,2-dicarboxylate 1a in the Presence of GaCl3
minor process to give cyclohexene 6 occurs through generation
of a Z-1,6-zwitterionic intermediate or through a sigmatropic
rearrangement. The observed ratio of regioisomers 4 (or 5)/6
is >3:1.
We showed that approximately the same picture was
observed with GaBr3. However, on replacing these Lewis
acids with gallium(III) iodide, we found that the predominant
reaction pathway changed. In this case, the amount of dienes
sharply decreased and 5-iodopent-2-enylmalonate 7 became
the main product, while the amount of cyclohexene 6 remained
nearly unchanged (Scheme 5; Table 1). The regioselectivity of
iodide anion addition as a nucleophile (absence of the 1,3-
addition product) and the E-configuration of the C(3)−C(4)
double bond in the resulting compound 7 indicate that the E-
1,6-zwitterion generated upon opening of both cyclopropane
rings in ABCD 1a can be trapped. At the same time, the reason
for the change in the reaction pathway in the presence of GaI3
instead of GaCl3 or GaBr3 lies in a higher nucleophilicity of
iodide anions compared to those of chloride and bromide
anions (or tetrachlorogallate anions as its transporters14a).
Initially, if 1 equiv of gallium iodide was used as the Lewis
acid, the yield of iodide 7 was no higher than 40%. We have
shown previously in a study of DAC reactions with alkynes in
the presence of gallium halides that a halide anion is added not
a
b
Isolated yields. NMR yields.
Table 1. Variation of the Reaction Conditions for the
Formal 1,6-Addition of HI to Bicyclopropyl 1a
Bu4N+GaI4
(equiv)
yield of E-7,
yield of 6,
−
GaI3
(equiv)
a
a
entry
(%)
(%)
1
2
3
4
1.0
0.1
0.2
0.3
38
42
53
83 (72)a
15
∼15
∼15
b
1.0
1.0
1.0
b
16
a
b
NMR yields; isolated yields are given in parentheses. Accuracy:
2−3%.
gives the isomeric cyclohexene 6b mainly, while the
corresponding iodine product could not be isolated.
−
from GaX3 but from a GaX4 anion that is formed upon
It is also interesting to note selective formation in significant
quantities of the dimeric iodine adduct 8 for para-Br-
substituted bicyclopropyl 1d (Scheme 5). This compound is
assembled from two bicyclopropyl molecules with cleavage of
three cyclopropane rings and formal addition of HI, wherein
one bicyclopropyl molecule acts as a formal 1,6-zwitterion.
Moreover, this “acyclic” iodine product 8 contains four
stereocenters, and under the described conditions, it is formed
as a mixture of only two detected diastereomers of 16 possible
stereoisomers, and with high chemoselectivity to the
constructed skeleton. Also, this product can be apparently
optimized to higher yields under the deficiency of iodine
anions.
dismutation of intermediate gallium complexes.14a Assuming
−
that the presence of a high GaI4 concentration at the initial
instant of the reaction can improve the yield of iodide 7, we
decided to optimize the reaction conditions by replacing pure
−
GaI3 with its mixture with a compound containing the GaI4
anion. For this purpose, we used the air-stable tetrabutylam-
23
monium salt Bu4N+GaI4 . Indeed, using 0.3 equiv of GaI3
−
and 1.0 equiv of Bu4N+GaI4 , we succeeded in increasing the
−
isolated yield of iodide 7 to 83% (Scheme 4; Table 1, entry 4).
Under these conditions, we have studied other bicyclo-
propyls 1b,d,f for possibility of the formal 1,6-addition of HI
(Scheme 5). In general, bicyclopropyls 1d,f gave the
corresponding products 7f,d as single E-isomers without
problems, however, with lower yields because of the lower
stability of iodine derivatives. Methoxy bicyclopropyl 1b easily
Furthermore, we studied the possibility of extending the
alkyl chain by the reaction of the 1,6-zwitterion generated from
ABCD with phenylacetylene. We previously used this approach
C
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for the efficient addition of terminal acetylenes to 1,2-
zwitterions generated from DACs24 or to substituted
methylidenemalonates14a in the presence of gallium halides.
In this case, the intermediate highly reactive vinyl cations were
stabilized by the addition of a halide anion. Indeed, the
reaction of bicyclopropyl 1a with 1 equiv of gallium(III)
chloride or bromide in the presence of 4−5 equiv of
phenylacetylene gave substituted 2,6-heptadienyl malonates
9a and 9b in 65 and 45% yields, respectively (Scheme 6). At
C(8) bond was ∼10:1. The reaction involved the opening of
both cyclopropane rings (Figure 2A). Phenylacetylene was
Scheme 6. Three-Component Addition of Acetylenes to
ABCDs 1 in the Presence of GaCl3 or GaBr3 and Scope of
a
the Reaction
Figure 2. Some main mechanistic features: (A) initial generation of
the formal 1,6-zwitterion and (B) a step of trans-selective addition of
−
−
GaCl4 and GaBr4 anions to the resulting vinyl cation after
phenylacetylene addition.24
added regioselectively at the phenyl-substituted C(6) atom.
Ultimately, a halovinyl moiety was incorporated into the
molecule of the starting substrate 1a. In addition to the
formation of halides 9, we also detected the formation of
cyclopropylcyclopentene 10, a side product of the formal (3 +
2)-cycloaddition of phenylacetylene to the D−A cyclopropane
ring. This may imply that the consecutive opening of small
cycles in the 1,1′-bicyclopropyl ABCD system occurred.
The predominant formation of the E-C(7)−C(8) double
bond can be explained by a partial approach of the cationic
center in the intermediate vinyl cation to the C(3)−C(4)
double bond and its stabilization, which results in the shielding
of one of the sides for attack by the nucleophile (Figure 2B).
Furthermore, we have evaluated some different bicycloprop-
yls 1 and terminal acetylenes in this three-component process
using both GaCl3 and GaBr3 (Scheme 6). Apparently, this
process is general in nature. However, it is quite difficult to
study for each substrate. The reason lies in the complex
structures of products and multiple high reactivity of
bicyclopropyls in studied systems. The isolation of pure
compounds is also quite laborious in some cases due to its
partial decomposition during chromatography. Nevertheless,
this is compensated in full by interesting and unknown
chemistry of D−A bicyclopropyls and the complex nature of
constructed skeletons with multiple functional groups in one
synthetic step. Vinyl halide products such as 9 seem to be
interesting for further modification by cross-coupling reactions
in combination with the use of functional groups.14a,24
Therefore, we have successfully obtained the acyclic vinyl
halides 9a−f for bicyclopropyls 1a,c,d as starting compounds.
Phenylacetylene, para-tert-butyl phenylacetylene, and aliphatic
cyclopropylacetylene have been used as terminal acetylene
substrates (Scheme 6). The acyclic vinyl halides 9 were
prepared predominantly as 3E,7E-isomers with 7E/7Z ratios
from 3/1 to 10/1 depending on substituents. This ratio and
product yields are lower for more substituted compounds 9c−
f, apparently because of its higher reactivity and not fully
optimized reaction conditions.
a
b
Isolated yields. NMR yields.
the same time, iodination using GaI3 is not possible to perform
effectively under these reaction conditions and using this
halogenation system (similar to Cl and Br). Iodide anions are
attached directly to the bicyclopropyl skeleton much more
efficiently. Nevertheless, vinyl iodides such as 9 can be formed
in low yields, but further substantial developments of
iodination process should be performed.
In addition to the formation of vinyl chlorides 9e,f, we also
detected the formation of cyclopropyl cyclopentenes 11a,b as
side products of another formal (3 + 2)-cycloaddition process
In both cases (Cl and Br), the C(3)−C(4) bond had an E-
configuration, while the ratio of E and Z isomers for the C(7)−
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a
(Scheme 6). This type of product was detected only in the
cases of these combinations of substrates. Moreover, it is
similar to the formation of cyclopentene 10, but unlike the last,
this (3 + 2)-cycloaddition unexpectedly occurs at another 2nd
cyclopropane ring in ABCDs 1a,d. Moreover, for bicyclopropyl
1a and para-tert-butyl phenylacetylene, cyclopropylcyclopen-
tene 11b is the main product of the reaction. All these facts
could be explained through the course of the reaction via the
1,6-zwitterionic intermediate (Figure 2).
Scheme 7. Reaction of ABCD 1a with PTAD
Furthermore, it is important to explore other options for
trapping six-carbon synthons generated from ABCD. PTAD,
which is often used to solve problems of this kind, was applied
as a highly active interceptor.18,19,25−27 In fact, we performed
the reaction of bicyclopropyl 1a with a 2-fold excess of PTAD
under the conditions of soft catalysis with Yb(OTf)3 and
actually obtained one main product of their reaction (12a).
However, an unexpected structure was found that corre-
sponded to the reaction of 1a with two PTAD molecules, one
of which was involved in the formation of a tetrahydropyr-
idazine ring (Table 2; Scheme 7). Thus, one PTAD equivalent
formally acted as a dienophile, while the other one was added
to the malonyl moiety.
Table 2. Optimization of Conditions for the Reaction of 1a
a
with PTAD
a
Compound 16 is less stable under reaction conditions and on SiO2
and decomposes during isolation attempts; it was analyzed directly in
the reaction mixtures using the complex 1H/13C/15N NMR approach.
b
entry PTAD, equiv T, °C Lewis acid (10 mol %) yield of 12a (%)
1
2
3
4
5
6
7
8
9
2.3
2.3
2.3
2.3
2.3
2.3
1
20
40
84
60
60
60
60
0−20
0−20
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Sc(OTf)3
Ga(OTf)3
Yb(OTf)3
5
15
50 (45)
65 (60)
25
38
22
0 (c.m.)
0 (c.m.)
c
c
cause the isomerization of bicyclopropyl 1a to diene 12. This
fact indicates that the preceding carbocationic intermediates
rather than the diene are involved in the formation of
compound 12a. Moreover, this is confirmed by additional
mechanistic experiments (Scheme 7). It is interesting to note
that under optimized conditions using the equimolar 1a/
PTAD ratio, the reaction still gives only the double addition
product 12a but in a lower yield (Table 2, entry 7). In all the
cases, no products of addition of 1 equiv of PTAD to 1a (14,
15) were detected.
d
e
e
2.3
2.3
GaCl3
d
GaBr3
a
Solvent: DCM for entries 1 and 2; 1,2-DCE for entries 3−7; reaction
b
c
d
time = 2 h. NMR yields. Isolated yield, E/Z ∼ 3.5:1. 10−100 mol
e
% was used. c.m. = complex mixture.
Instead, a detailed analysis of reaction mixtures under
various conditions revealed that, along with 12a, an even more
exotic compound 16 was formed in 10−15% yield (Scheme 7).
Its most notable feature is that an eight-membered heterocycle
is formed with participation of as many as three PTAD
molecules. Formally, this process corresponds to [6 + 2]-
cycloaddition, which is the first example of such a reaction of a
bicyclopropyl system with any multiple bonds. The final
structure is formed upon addition of two more PTAD
molecules by an ene-reaction. However, as the resulting
compound 16 is not sufficiently stable, we failed to isolate it in
an individual state. Therefore, it was analyzed by NMR directly
in the reaction mixtures.
To optimize the conditions, we studied the effect of various
Lewis acids and the effect of temperature on the extent to
which this process occurs. Therefore, GaX3 (X = Cl, Br) is too
active and leads to complete polymerization/resinification of
the reaction mixture. Therefore, for this reason, it cannot be
used for catalysis. As a result of optimization, the reaction
using 10 mol % Yb(OTf)3 at a temperature of 60 °C gave
compound 12a in 65% yield (Table 2). It should be noted that
under the same conditions, but in the absence of PTAD,
bicyclopropyl 1a is converted to diene 12 by less than 20%
yield, that is, the presence of PTAD in the reaction mixture
significantly accelerates the opening of the bicyclopropyl
system.
The structures of the resulting compounds 12a and 16 were
1
The use of Ga(III) triflate also proved to be possible,
although by itself and in the absence of PTAD, it does not
analyzed in detail and confirmed using H/13C/15N NMR
spectroscopy (Figure 3). The configuration of the tetrahy-
E
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dropyridazine ring substituents was determined from the key
cross-peaks in the NOESY spectra, which showed their cis
arrangement (Figure 3).
a]pyridazine-1,3(2H)-diones 12b−e in moderate yields and
with even higher cis/trans isomer ratios up to 10:1 (Scheme
8). The best yields were achieved in the case of donor aryl
Scheme 8. Scope of the Reaction of ABCDs 1a−e with
a
PTAD
a
Isolated yields; cis/trans ratio is given in parentheses. bReaction time
for 12d,e is 5−5.5 h. cCompound 12e was isolated, but not in a pure
form, due to its partial decomposition during the isolation process.
dNMR yield, compound 12f was not isolated because of
e
decomposition. Reaction time for 12f is 11−12 h.
substituents, while the lowest yield of 22% was obtained in the
case of the naphthyl substituent. Apparently, in all the cases,
the yield decreases significantly due to partial decomposition of
the products during the reaction and isolation. For
bicyclopropyl 1f, we were unable to isolate the corresponding
nitrogen product 12f due to its complete decomposition
during chromatography by influence of the nitro group.
However, it is an important fact that the reaction proceeds for
both donor and acceptor substituents in bicyclopropyls 1.
However, we managed to describe one of the decomposition
processes of 12a in the reaction mixture during its synthesis
Figure 3. 15N-NMR-based structure determination for the diadduct
12a: (A) key 2J/3J 1H−15N interactions and 1H−1H NOE; (B)
reconstructed full 15N NMR spectrum with signal assignments; and
1
(C) superimposed 2D H−15N HMBC and HSQC NMR spectra.
Analysis of 15N spectra was used as the main method for
resolving the structure. They were recorded using inverse
1H−15N HMBC/HSQC 2D methods based on the natural
abundance of the 15N isotope. All the signals of nitrogen atoms
in the 15N spectrum were totally assigned, and the C/N
framework of the molecule was completely analyzed (Figure
3). The structure of compound 16 was determined in a similar
way (Figure 4).
In order to expand the scope of the objects of our study, we
used the series of 2′-aryl-1,1′-bicyclopropyl-2,2-dicarboxylates
(ABCDs) 1b−f that we obtained. A similar reaction of these
compounds with PTAD in the presence of 10 mol % Yb(OTf)3
resulted in a series of new 5,8-dihydro-1H-[1,2,4]triazolo[1,2-
using complex 2D H−13C and H−15N NMR techniques
applied to several reaction mixtures. One of the decomposition
pathways is associated with the cleavage of the triazolidinone
fragment and further cyclization involving NH-groups under
Lewis acid catalysis. Therefore, compound 17 was detected in
the reaction mixtures, which cannot be isolated due to its low
stability (Scheme 9A). Also, we have tried to deprotect
triazolidinone “protective” groups in the product 12a under
basic conditions, however, with poor success. We could only
detect a possible formation of a not very stable hydrazine
derivative 18 with low yields in the reaction mixtures without a
possibility of its isolation (Scheme 8B).
1
1
The assumed reaction mechanism taking the involvement of
PTAD in the opening of the bicyclopropyl system into
account25 is apparently related to the opening of the first
activated cyclopropane ring. In this case, the formation of the
first C−N bond and the subsequent opening of the second
cyclopropane ring, followed by the formation of yet another
C−N bond occur rather quickly via transition states I−IV
(Scheme 10). Furthermore, cyclization with formation of a
pyridazine ring, followed by proton transfer in intermediate V
occur to give the target product and recover M(OTf)3 for the
2
1
1
Figure 4. Registered key J/3J H−13C and H−15N interactions in
2D HMBC NMR spectra for the structure determination of the minor
[6 + 2]-triadduct 16.
F
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Scheme 9. (A) One of Further Decomposition Side-
Processes in the Reaction Mixture during Synthesis of 12a
Detected by Detailed NMR Analysis; (B) Attempts of
Deprotection of Compound 12a to Synthesize a
CONCLUSIONS
■
In summary, we have developed a strategy for utilizing
activated bicyclopropyl systems as possible sources of 1,6-
zwitterionic intermediates. In fact, opening of both cycles in 2′-
aryl-1,1′-bicyclopropyl-2,2-dicarboxylates formally corresponds
to the 1,6-addition of HI to give 5-iodo-5-arylpent-2-
enylmalonates. The use of gallium chloride or bromide in
the presence of terminal aryl or alkyl acetylenes allows the
alkenyl chain to be extended by incorporating an additional
halovinyl moiety to give the corresponding 7-halohepta-2,6-
dienyl malonates with the predominant E-configuration of the
double bonds. The reaction of 1,1′-bicyclopropyl-2,2-dicarbox-
ylates 1a−f with PTAD under catalysis of 10 mol % Yb(OTf)3,
regardless of the reagent ratio, occurs with the addition of 2
equiv of PTAD, one of which forms the 1,6,8-
triazabicyclo[4.3.0]non-3-ene system, while the second one is
added to the malonyl moiety.
a
Dihydrazine Derivative
EXPERIMENTAL SECTION
■
General Experimental Details. All reagents used were of
commercial grade. All operations were carried out under a dry
argon atmosphere. TLC analysis was performed on Silufol chromato-
graphic plates. For preparative chromatography, silica gel 60 (0.040−
a
Compounds 17 and 18 are less stable under reaction conditions and
1
0.063 mm) was used. H, 13C, and 15N NMR spectra were recorded
on SiO2, and decompose during isolation attempts; they were
analyzed directly in the reaction mixtures using complex 1H, 13C, and
15N NMR approaches.
on 400 MHz (400, 101, and 40 MHz, respectively) and 300 MHz
(300, 75, and 30 MHz, respectively) spectrometers in CDCl3
containing 0.05% Me4Si as the internal standard. Assignments of
1H, 13C, and 15N signals were made with the aid of 2D z-gradient-
selected COSY, TOCSY, NOESY, HSQC/edited-HSQC, HMBC/
Scheme 10. Proposed Mechanism for the Reaction of ABCD
with PTAD
1
constant-time HMBC, and H−15N HSQC/HMBC spectra, if it was
necessary.28 IR spectra were obtained on a FT-IR spectrometer in
CHCl3 solution (1%). Mass spectra were recorded using electron
impact ionization (70 eV, direct inlet probe). High-resolution mass
spectra were obtained using simultaneous electrospray ionization.29
The elemental compositions were determined on a CHN analyzer
instrument.
Synthesis of Starting Substituted Styrenes. Substituted
styrenes were synthesized from the corresponding aromatic aldehydes
according to the literature procedure.31 1H and 13C{1H} spectroscopic
data and physical data (bp or mp) are identical to those described in
the literature: 1-methoxy-4-vinylbenzene [ref 32], 1-bromo-4-vinyl-
benzene [ref 32], 1-fluoro-4-vinylbenzene [ref 32], and 2-vinyl-
naphthalene [ref 32].
Typical Experimental Procedure for the Preparation of
Methyl 2-Arylcyclopropane-1-carboxylates. Method A. To the
boiling mixture of Cu(acac)2 (1.3 g, 5 mmol) in 25 mL of CH2Cl2,
methyl diazoacetate (0.92 g, 9 mmol) was added in a single portion,
followed by the addition of styrene solution (104 g, 1 mol) in 75 mL
of CH2Cl2. After that, the remaining solution of methyl diazoacetate
(49.1 g, 0.49 mol) in 50 mL of CH2Cl2 was added (20 mL/h). The
resulting mixture was refluxed for 15 min, cooled to room
temperature, passed through a silica gel plug, and evaporated. The
crude product was fractionated to obtain the desired methyl-2-
phenylcyclopropane-1-carboxylate.
Methyl 2-Phenylcyclopropane-1-carboxylate.33 Colorless liquid
1
(55.2 g, 52%, bp: 55−57 °C/0.1 Torr, cis/trans ratio = 2:3). H and
13C{1H} spectroscopic data are identical to those described in the
literature [ref 33].
Typical Experimental Procedure for the Preparation of
Methyl 2-Arylcyclopropane-1-carboxylates. Method B. To the
stirred mixture of the corresponding styrene (26 mmol) and
Cu(MeCN)4PF6 (490 mg, 1.32 mmol) in 25 mL of CH2Cl2 under
an argon atmosphere, a solution of methyl diazoacetate (2.64 g, 26
mmol) in 16 mL of CH2Cl2 (5 mL/h) was added. The mixture was
stirred at room temperature overnight. The resulting solution was
passed through a silica gel plug and evaporated. The crude product
new catalytic cycle. This mechanism is partially confirmed by
several additional mechanistic experiments that we performed
(Scheme 10), as well as the detected formation of an eight-
membered ring in compound 16 as a side product.
G
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was separated by column chromatography on silica gel (eluent:
hexane−AcOEt) to afford the desired compound.
2-(Naphthalen-2-yl)cyclopropanecarbaldehyde.39 Yield: 76%
1
(1.83 g), yellow crystals, mp: 68−72 °C, cis/trans = 1:1.6. H and
Methyl 2-(4-Methoxyphenyl)cyclopropane-1-carboxylate.33 Col-
13C{1H} spectroscopic data are identical to those described in the
1
orless liquid (50%, 3.48 g). H and 13C{1H} spectroscopic data are
literature [ref 39].
identical to those described in the literature [ref 33].
Synthesis of Starting Cyclopropanes 1a−e. The starting 1,1′-
bicyclopropyl-2,2-dicarboxylates 1a−e (ABCD) were synthesized
from the corresponding dimethyl (2-arylcyclopropyl)-
methylenemalonates 3a−e through an adapted standard synthetic
procedure of Corey−Chaykovsky reactions.30 The compounds 3a−e
were prepared from 2-arylcyclopropanecarbaldehydes and dimethyl
malonate in the presence of piperidine and acetic acid.15
Typical Experimental Procedure for the Preparation of
Dimethyl 2′-Aryl-1,1′-bicyclopropane-2,2-dicarboxylates (1a−
e). To a stirred suspension of NaH (0.25 g, 10 mmol) in dry DMSO
(8 mL) under an argon atmosphere, trimethylsulfoxonium iodide
(1.55 g, 7.0 mmol) was added. The mixture was stirred until the gas
evolution ceased (30−50 min). Then, a solution of 3 (7.0 mmol) in
dry DMSO (4 mL) was added dropwise. The resulting mixture was
stirred at room temperature for 4−5 h, poured into H2O−ice, and
extracted with diethyl ether. The combined organic layers were
washed with water and brine, dried over MgSO4, and concentrated in
vacuo. The crude product was separated by column chromatography
on silica gel (eluent: petroleum ether−AcOEt, 5:1) to afford
compound 1 as a mixture of stereoisomers.
Methyl 2-(4-Fluorophenyl)cyclopropane-1-carboxylate.34 Yield:
55% (2.8 g), colorless liquid, cis/trans = 2:3. 1H and 13C{1H}
spectroscopic data are identical to those described in the literature
[ref 34].
Methyl 2-(4-Bromophenyl)cyclopropanecarboxylate.35 Yield:
57% (8.7 g), colorless liquid, cis/trans = 1:2. 1H and 13C{1H}
spectroscopic data are identical to those described in the literature
[ref 35].
Methyl 2-(Naphthalen-2-yl)cyclopropane-1-carboxylate.36 Yield:
52% (3.1 g), colorless oil, cis/trans = 1:3.5. 1H and 13C{1H}
spectroscopic data are identical to those described in the literature
[ref 36].
Typical Experimental Procedure for the Preparation of (2-
Arylcyclopropyl)methanols. A solution of 2-phenylcyclopropane-
1-carboxylate (6.53 g, 37.1 mmol) in 150 mL of dry Et2O was added
dropwise to the stirred suspension of LiAlH4 (2.11 g, 55.6 mmol) in
250 mL of dry Et2O. The reaction mixture was refluxed for 2 h,
followed by cooling in an ice-bath. Then, 2 mL of H2O, 2 mL of
NaOH (water solution, 15% w/w), and 6 mL of H2O were added in
sequence. The cooling bath was removed and the mixture was stirred
for 15 min. The precipitate was filtered and washed with Et2O. The
organic phase was washed with H2O and brine and dried over MgSO4.
The solvent was removed in vacuo to afford the desire product (4.40
g, 80%, cis/trans = 3:4) as a colorless liquid. The obtained product
was used without additional purification.
Dimethyl 2′-Phenyl-1,1′-bicyclopropane-2,2-dicarboxylate (1a).
Thick yellow oil, 69% (10.77 g), cis/trans = 1:5; for the trans-isomer,
the ratio of diastereomers A/B = 1.2:1; for the cis-isomer, the ratio of
diastereomers C/D = 1.4:1. The crude product was purified by silica
gel column chromatography (eluent: petroleum ether−AcOEt, 5:1).
IR (CHCl3) ν: 3063, 3027, 3005, 2953, 2906, 2847, 1727, 1605, 1582,
̅
1498, 1437, 1405, 1370, 1332, 1308, 1278, 1214, 1196, 1181, 1131
cm−1. HRMS: calcd for [M + Na]+ C16H18O4Na, 297.1097; found,
297.1108. Trans-1a, diastereomer-A: 1H NMR (300 MHz, CDCl3): δ
7.31−6.95 (m, 5H, Ph), 3.72 and 3.48 (both s, 2 × 3H, 2 OMe),
1.95−1.86 (m, 1H, H(1)), 1.88−1.77 (m, 1H, H(2′)), 1.61−1.52 (m,
2H, H2C(3)), 1.10−0.89 (m, 3H, H2C(3′,1′)). 13C{1H} NMR (75.5
MHz, CDCl3): δ 170.6 and 168.4 (2 COO), 142.2, 128.3, 125.8 and
125.7 (Ph), 52.6 and 52.5 (2 OMe), 34.2 (C(2)), 31.7 (C(1)), 22.7
(C(2′)), 21.3 (C(1′)), 20.3 (C(3)), 14.7 (C(3′)). Trans-1a,
(2-Phenylcyclopropyl)methanol.37 Yield: 80% (37.7 g), colorless
liquid, cis/trans = 3:4. 1H and 13C{1H} spectroscopic data are
identical to those described in the literature [ref 37].
(2-(4-Methoxyphenyl)cyclopropyl)methanol.37 Yield: 87% (5.76
1
g), light yellow oil, cis/trans = 2:3. H and 13C{1H} spectroscopic
data are identical to those described in the literature [ref 37].
(2-(4-Fluorophenyl)cyclopropyl)methanol.34 Yield: 89% (2.02 g),
1
light yellow oil, cis/trans = 4:5. H and 13C{1H} spectroscopic data
are identical to those described in the literature [ref 34].
1
diastereomer-B: H NMR (300 MHz, CDCl3): δ 7.31−6.95 (m, 5
(2-(4-Bromophenyl)cyclopropyl)methanol.36 Yield: 74% (5.72 g),
H, Ph), 3.71 and 3.52 (both s, 2 × 3H, 2 OMe), 2.03−1.93 (m, 1H,
H(1)), 1.82−1.73 (m, 1H, H(2′)), 1.59−1.52 and 1.45−1.38 (both
m, 2 × 1H, H2C(3)), 1.15−1.05 (m, 1H, H(1′)), 1.15−0.90 (m, 2H,
H2C(3′)). 13C{1H} NMR (75.5 MHz, CDCl3): δ 170.6 and 168.2 (2
COO), 142.1, 128.3, 125.8 and 125.7 (Ph), 52.6 and 52.5 (2 OMe),
34.4 (C(2)), 31.2 (C(1)), 21.6 (C(2′)), 20.9 (C(1′)), 19.7 (C(3)),
1
light yellow oil, cis/trans = 4:5. H and 13C{1H} spectroscopic data
are identical to those described in the literature [ref 36].
(2-(Naphthalen-2-yl)cyclopropyl)methanol.38 Yield: 89% (2.43
g), yellow oil, cis/trans = 4:5. 1H and 13C{1H} spectroscopic data are
identical to those described in the literature [ref 38].
Typical Experimental Procedure for the Preparation of 2-
Arylcyclopropane-1-carbaldehydes. A mixture of (2-
arylcyclopropyl)methanol (0.12 mol) and pyridinium chlorochromate
(PCC) (40.0 g, 0.186 mol) in dry dichloromethane (400 mL) was
stirred at room temperature for 4 h. The solution was decanted, and
the black solid was washed twice with ether. The mixture was passed
through a short silica gel column and solvent was evaporated under
reduced pressure to give the desired 2-arylcyclopropanecarbaldehyde
as a colorless oil. The product obtained was used without additional
purification.
1
15.1 (C(3′)). Cis-1a, diastereomer-C: H NMR (300 MHz, CDCl3):
δ 7.31−6.95 (m, 5H, Ph), 3.79 and 3.57 (both s, 2 × 3H, 2 OMe),
2.20−2.13 (m, 1H, H(2′)), 1.47−1.40 (m, 2H, H(1) and Ha(3)),
1.24−1.18 (m, 1H, Hb(3)), 1.13−1.08 (m, 1H, H(1′)), 0.87−0.81
(m, 2H, H2C(3′)). 13C{1H} NMR (75.5 MHz, CDCl3): δ 170.4 and
168.5 (2 COO), 138.4, 129.3, 128.0 and 126.1 (Ph), 52.6 and 52.4 (2
OMe), 33.6 (C(2)), 28.9 (C(1)), 20.9 (C(2′)), 20.6 (C(3)), 16.8
1
(C(1′)), 9.2 (C(3′)). Cis-1a, diastereomer-D: H NMR (300 MHz,
CDCl3): δ 7.31−6.95 (m, 5 H, Ph), 3.79 and 3.64 (both s, 2 × 3H, 2
OMe), 2.27−2.18 (m, 1H, H(2′)), 1.59−1.52 and 1.32−1.25 (both
m, 2 × 1H, H2C(3)), 1.29−1.23 (m, 1H, H(1)), 1.07−1.02 and
0.92−0.88 (m, 2H, H2C(3′)), 0.81−0.76 (m, 1H, H(1′)). 13C{1H}
NMR (75.5 MHz, CDCl3): δ 170.4 and 168.6 (2 COO), 138.5, 129.1,
128.3 and 126.2 (Ph), 52.6 and 52.5 (2 OMe), 33.6 (C(2)), 29.0
(C(1)), 21.9 (C(3)), 21.3 (C(2′)), 17.6 (C(1′)), 10.0 (C(3′)).
Dimethyl 2′-(4-Methoxyphenyl)-1,1′-bicyclopropane-2,2-dicar-
boxylate (1b). Yellow oil, 48% (1.077 g), cis/trans = 1:5; for the
trans-isomer, the ratio of diastereomers A/B ≈ 1.3:1. The crude
product was purified by silica gel column chromatography (eluent:
2-Phenylcyclopropane-1-carbaldehyde.39 Yield: 97% (25.3 g),
1
yellow oil, cis/trans = 3:4. H and 13C{1H} spectroscopic data are
identical to those described in the literature [ref 39].
2-(4-Methoxyphenyl)cyclopropane-1-carbaldehyde.39 Yield:
90% (5.15 g), yellow oil, cis/trans = 1:3.5. 1H and 13C{1H}
spectroscopic data are identical to those described in the literature
[ref 39].
2-(4-Fluorophenyl)cyclopropane-1-carbaldehyde.39 Yield: 76%
1
(1.51 g), orange oil, cis/trans = 1:1.6. H and 13C{1H} spectroscopic
data are identical to those described in the literature [ref 39].
2-(4-Bromophenyl)cyclopropane-1-carbaldehyde.39 Yield: 89%
(4.61 g), colorless oil, cis/trans = 1:1.4. 1H and 13C{1H}
spectroscopic data are identical to those described in the literature
[ref 39].
petroleum ether−AcOEt, 5:1). IR (CHCl3) ν: 3068, 3044, 3036,
̅
3010, 2955, 2911, 2838, 1723, 1613, 1581, 1516, 1459, 1439, 1368
cm−1. HRMS: calcd for [M + Na]+ C17H20O5Na, 327.1203; found,
327.1208. Trans-isomer-A: 1H NMR (300 MHz, CDCl3): δ 6.94
(br.d, J = 8.7 Hz, 2H, O-Ar), 6.77 (br.d, J = 8.7 Hz, 2H, m-Ar), 3.76
H
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(s, 3H, OMe), 3.72 and 3.52 (both s, 2 × 3H, 2 OMe), 2.01−1.95 (m,
1H, H(1)), 1.87−1.70 (m, 1H, H(2′)), 1.61−1.52 (m, 1H, Ha from
H2C(3)), 1.49−1.39 (m, 1H, Hb from H2C(3)), 0.95−0.83 (m, 2H,
H(3′)), 0.92−0.84 (m, 1H, H(1′)). 13C{1H} NMR (75 MHz,
CDCl3): δ 170.7 and 168.5 (2 COO), 157.8 (p-Ar), 134.2 (i-Ar),
126.9 (o-Ar), 113.8 (m-Ar), 55.3 (OMe), 52.6 and 52.5 (2 OMe),
34.2 (C(2)), 31.8 (C(1)), 21.9 (C(2′)), 20.7 (C(1′)), 20.3 (C(3)),
ether−AcOEt, 5:1). IR (CHCl3) ν: 3046, 3039, 3028, 3005, 2977,
̅
2893, 1723, 1605, 1514, 1458, 1438, 1336 cm−1. HRMS: calcd for [M
+ H]+ C20H21O4, 325.1438; found, 325.1434. Trans-isomer-A: 1H
NMR (300 MHz, CDCl3): δ 7.91−7.60, 7.47−7.34 and 7.17−7.08
(all m, 3 + 3 + 1H, Ar), 3.74 and 3.44 (both s, 2 × 3H, 2 OMe),
2.03−1.94 (m, 1H, H(1)), 2.09−2.02 (m, 1H, H(2′)), 1.70−1,59 (m,
1H, Ha from H2C(3)), 1.57−1.46 (m, 1H, Hb from H2C(3)), 1.19−
1.03 (m, 2H, H2C(3′)), 1.12−1.05 (m, 1H, H(1′)). 13C{1H} NMR
(75 MHz, CDCl3): δ 170.6 and 168.4 (2 COO), 139.6 (C(2″)),
133.4 and 131.9 (C(4a) and C(8a)), 127.9, 127.6, 127.3, 126.1, 125.0,
124.6 and 123.8 (all CH, Ar), 52.7 and 52.6 (2 OMe), 34.2 (C(2)),
31.8 (C(1)), 22.9 (C(2′)), 21.3 (C(1′)), 20.4 (C(3)), 14.7 (C(3′)).
1
14.2 (C(3′)). Trans-isomer-B: H NMR (300 MHz, CDCl3): δ 6.93
(br.d, J = 8.7 Hz 2H, o-Ar), 6.77 (br.d, J = 8.7 Hz, 2H, m-Ar), 3.76 (s,
3H, OMe), 3.72 and 3.55 (both s, 2 × 3H, 2 OMe), 1.92−1.88 (m,
1H, H(1)), 1.61−1.52 (m, 1H, Ha from H2C(3)), 1.49−1.39 (m, 1H,
Hb from H2C(3)), 1.06−0.96 (m, 1H, H(2′)), 0.95−0.83 (m, 2H,
H2C(3′)), 0.92−0.84 (m, 1H, H(1′)). 13C{1H} NMR (75 MHz,
CDCl3): δ 170.7 and 168.3 (2 COO), 157.9 (p-Ar), 134.1 (i-Ar),
126.9 (o-Ar), 113.8 (m-Ar), 55.3 (OMe), 52.64 and 52.55 (2 OMe),
34.4 (C(2)), 31.3 (C(1)), 20.9 (C(2′)), 20.3 (C(3)), 19.8 (C(1′))
14.7 (C(3′)).
1
Trans-isomer-B: H NMR (300 MHz, CDCl3): δ 7.91−7.60, 7.47−
7.34 and 7.17−7.08 (all m, 3 + 3 + 1H, Ar), 3.73 and 3.51 (both s, 2
× 3H, 2 OMe), 2.11−2.03 (H(1)), 2.02−1.97 (m, 2H, H(2′)), 1.70−
1.59 (m, 1H, Ha from H2C(3)), 1.57−1.46 (m, 1H, Hb from
H2C(3)), 1.28−1.22 (m, 1H, H(1′)), 1.19−1.03 (m, 2H, H2C(3′)).
13C{1H} NMR (75 MHz, CDCl3): δ 170.2 and 168.2 (2 COO), 139.5
Dimethyl 2′-(4-Fluorophenyl)-1,1′-bicyclopropane-2,2-dicarbox-
ylate (1c). Colorless oil, 53% (0.642 g), cis/trans = 1:6.5; for the
trans-isomer, the ratio of diastereomers A/B ≈ 1.2:1. The crude
product was purified by silica gel column chromatography (eluent:
(C(2″)), 133.4 and 132.0 (C(4a) and C(8a)), 127.9, 127.6, 127.3,
126.0, 125.1, 124.6 and 123.92 (all CH, Ar), 52.7 and 52.6 (2 OMe),
34.4 (C(2)) 31.2 (C(1)), 21.8 (C(2′)), 20.8 (C(1′)), 19.7 (C(3)),
15.1 (C(3′)).
petroleum ether−AcOEt, 5:1). IR (CHCl3) ν: 3075, 3046, 3028,
̅
3005, 2977, 2893, 1723, 1605, 1514, 1438, 1392, 1370 cm−1. HRMS:
calcd for [M + Na]+ C16H17FO4Na, 315.1003; found, 315.1003.
Trans-isomer-A: 1H NMR (300 MHz, CDCl3): δ 7.04−6.83 (m, 5H,
Ar), 3.73 and 3.51 (both s, 2 × 3H, 2 OMe), 1.91−1.83 (m, 1H,
H(1)), 1.87−1.79 (m, 1H, H(2′)), 1.61−1.51 (m, 1H, Ha from
H2C(3)), 1.50−1.39 (m, 1H, Hb from H2C(3)), 1.01−0.87 (m, 2H,
H(3′)), 0.92−0.85 (m, 1H, H(1′)). 13C{1H} NMR (75 MHz,
CDCl3): δ 170.6 and 168.4 (2 COO), 161.2 (d, J = 243 Hz, CF),
137.9 (i-Ar), 127.3 (d, J = 7.9 Hz, o-Ar), 115.1 (d, J = 21.3 Hz, m-Ar),
52.7 and 52.6 (2 OMe), 34.2 (C(2)), 31.7 (C(1)), 22.0 (C(2′)), 21.2
(C(1′)), 20.4 (C(3)), 14.6 (C(3′)). 19F NMR (282 MHz, CDCl3): δ
Typical Experimental Procedure for the Preparation of
Dimethyl (2-Arylcyclopropyl)methylenemalonates (3a−e). A
solution of 2-arylcyclopropanecarbaldehyde (1 equiv), dimethyl
malonate (1 equiv), piperidine (0.1 equiv), and acetic acid (0.1
equiv) in benzene was refluxed in an oil bath with a Dean−Stark
attachment for 3 h until water was not obtained. After that, the
reaction mixture was first washed with an aqueous solution of HCl
(10%) and then with a solution of NaHCO3 (5%). The organic layer
was dried over MgSO4 and evaporated. The residue was separated by
column chromatography on silica gel (eluent: benzene−AcOEt, 35:1)
to afford compound 3 as a colorless or thick orange oil.
1
−118.5 (ddd, J = 14.0, 8.5, 5.5 Hz). Trans-isomer-B: H NMR (300
Dimethyl (2-Phenylcyclopropyl)methylenemalonate (3a). The
crude product was purified by silica gel column chromatography
(eluent: eluent: benzene−AcOEt, 35:1). Thick orange oil (76%, 45.8
MHz, CDCl3): δ 7.08−6.80 (m, 5H, Ar), 3.72 and 3.54 (both s, 2 ×
3H, 2 OMe), 2.00−1.95 (m, 1H, H(1)), 1.79−1.72 (m, 1H H(2′)),
1.61−1.51 (m, 1H, Ha from H2C(3)), 1.50−1.39 (m, 1H, Hb from
H2C(3)), 1.08−1.00 (m, H(1′)), 1.01−0.87 (m, 2H, H(3′)).
13C{1H} NMR (75 MHz, CDCl3): δ 170.6 and 168.2 (2 COO),
161.2 (d, J = 244 Hz, CF), 137.7 (i-Ar), 127.2 (d, J = 7.9 Hz, o-Ar),
115.1 (d, J = 21.3 Hz, m-Ar), 52.7 and 52.6 (2 OMe), 34.4 (C(2)),
31.0 (C(1)), 20.9 (C(2′)), 20.7 (C(1′)), 19.6 (C(3)), 15.0 (C(3′)).
19F NMR (282 MHz, CDCl3): δ −118.4 (tt, J = 8.3 and 5.6 Hz).
g, cis/trans = 1:5). IR (CHCl3) ν: 3085, 3062, 3028, 2953, 2904,
̅
2847, 1725, 1630, 1606, 1498, 1458, 1368, 1318, 1305, 1194, 1177
cm−1. HRMS: calcd for [M + Na]+ C15H16O4Na, 283.0941; found,
1
283.0931. Trans-isomer: H NMR (300 MHz, CDCl3): δ 7.36−7.06
(m, 5H, Ph), 6.58 (d, 1H, J = 10.7 Hz, CH), 3.79 and 3.77 (both s,
2 × 3H, 2 OMe), 2.34−2.21 (m, 2H, HC−CH), 1.60−1.51 and
1.42−1.33 (both m, 2 × 1H, CH2). 13C{1H} NMR (75.5 MHz,
CDCl3): δ 165.8 and 164.8 (2 COO), 155.0 (CH), 139.8 (i-Ph),
128.6 and 126.3 (O- and m-Ph), 126.5 (p-Ph), 125.1 (C), 52.3 and
Dimethyl 2′-(4-Bromophenyl)-1,1′-bicyclopropane-2,2-dicarbox-
ylate (1d). Yellow oil, 59% (1.54 g), cis/trans = 1:5; for the trans-
isomer, the ratio of diastereomers A/B ≈ 1.5:1. The crude product
was purified by silica gel column chromatography (eluent: petroleum
1
52.2 (2 OMe), 28.0 (CH), 24.9 (CH), 18.7 (CH2). Cis-isomer: H
NMR (300 MHz, CDCl3): δ 7.31−7.05 (m, 5H, Ph), 6.30 (d, 1H, J =
11.5 Hz, CH), 3.85 and 3.64 (both s, 2 × 3H, 2 OMe), 2.73 (ddd,
1H, J = 8.4, 8.2 and 8.0 Hz, CHPh), 2.41−2.32 (m, 1H, CH), 1.62−
1.54 and 1.43−1.35 (both m, 2 × 1H, CH2). 13C{1H} NMR (75.5
MHz, CDCl3): δ 166.2 and 164.3 (2 COO), 152.9 (CH), 136.8 (i-
Ph), 129.2 and 128.5 (O- and m-Ph), 126.9 (p-Ph), 126.2 (C), 52.2
and 52.1 (2 OMe), 27.0 (C(2)), 20.5 (C(1)), 15.2 (CH2).
ether−AcOEt, 5:1). IR (CHCl3) ν: 3034, 1724, 1492, 1438, 1281
̅
cm−1. HRMS: calcd for [M + Na]+ C16H17BrO4Na, 375.0202 and
1
377.0183; found, 375.0198 and 377.0182. Trans-isomer-A: H NMR
(300 MHz, CDCl3): δ 7.34 (d, J = 8.4 Hz, 2H, m-Ar), 6.87 (d, J = 8.4
Hz, 1H, o-Ar), 3.73 and 3.50 (both s, 2 × 3H, 2 OMe), 1.84−1.76
and 1.92−1.83 (m, 2 × 1H, H(2′), H(1)), 1.63−1.55 (m, 1H, Ha
from H2C(3)), 1.49−1.42 (m, 1H, Hb from H2C(3)), 1.10−0.83 (m,
3H, H2C(3′) and H(1′)). 13C{1H} NMR (75 MHz, CDCl3): δ 170.5
(2 COO), 141.3 (i-Ar), 131.3 (m-Ar), 127.4 (o-Ar), 119.2 (C−Br),
52.7 and 52.6 (2 OMe), 34.1 (C(2)), 31.5 (C(1)), 22.2 (C(2′)), 21.5
Dimethyl (2-(4-Methoxyphenyl)cyclopropyl)methylenemalonate
(3b). The crude product was purified by silica gel column
chromatography (eluent: benzene−AcOEt, 35:1). Yield: 43% (3.12
g), yellow oil, cis/trans = 1:5. IR (CHCl3) ν: 3075, 3004, 2954, 2838,
̅
1731, 1628, 1614, 1582, 1437, 1397, 1368 cm−1. HRMS: calcd for [M
1
(C(1′)), 20.3 (C(3)), 14.9 (C(3′)). Trans-isomer-B: H NMR (300
1
+ Na]+ C16H18O5Na, 313.1046; found, 313.1049. Trans-isomer: H
MHz, CDCl3): δ 7.34 (br d, J = 8.4 Hz, 2H, m-Ar), 6.87 (br d, J = 8.4
Hz, 1H, o-Ar), 3.73 and 3.54 (both s, 2 × 3H, 2 OMe), 2.01−1.95 (m,
1H, H(2′)), 1.57−1.48 (m, 1H, Ha from H2C(3)), 1.47−1.38 (m, 1H,
Hb from H2C(3)), 1.13−0.81 (m, 3H, H2C(3′), H(1′)). 13C{1H}
NMR (75 MHz, CDCl3): δ 168.3 (2 COO), 141.1 (i-Ar), 131.3 (m-
Ar), 127.5 (o-Ar), 119.3 (C−Br), 52.7 and 52.6 (2 OMe), 34.3
(C(2)), 30.8 (C(1)), 21.08 and 20.98 (C(3′) and C(1′)), 19.5
(C(3)), 15.2 (C(3′)).
NMR (300 MHz, CDCl3): δ 7.03 (br.d, J = 8.7 Hz, 2H, o-C6H4), 6.81
(br.d, J = 8.7 Hz, 2H, m-C6H4), 6.57 (d, J = 11.1 Hz, 1H, CH),
3.81, 3.79 and 3.77 (all s, 3 × 3H, 3 OMe), 2.28 (ddd, J = 9.1, 6.3, 4.0
Hz, 1H, CH), 2.23−2.13 (m, 1H, CH), 1.52 (ddd, J = 8.3, 6.4, 5.1 Hz,
1H, Ha from CH2), 1.33 (dt, J = 8.8, 5.1 Hz, 1H, Hb from CH2).
13C{1H} NMR (75 MHz, CDCl3): δ 165.9 and 164.8 (2 COO), 158.4
(p-Ar), 155.3 (CH), 131.8 (i-Ar), 127.6 (o-Ar), 124.8 (C), 114.0
(m-Ar), 55.3 (OMe), 52.3 and 52.2 (2 OMe), 27.5 (C(1)), 24.8
Dimethyl 2′-Naphthalen-2-yl-1,1′-bicyclopropane-2,2-dicarbox-
ylate (1e). Colorless oil, 52% (0.632 g), cis/trans = 1:6; for the trans-
isomer, the ratio of diastereomers A/B ≈ 1.6:1. The crude product
was purified by silica gel column chromatography (eluent: petroleum
1
(C(2)), 18.5(C(3)). Cis-isomer: H NMR (300 MHz, CDCl3): δ
7.20 (br.d, J = 8.7 Hz, 2H, o-C6H4), 6.83 (br.d, J = 8.7 Hz, 2H, m-
C6H4), 6.30 (d, J = 11.4 Hz, 1H, CH), 3.86, 3.80 and 3.65 (all s, 3
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× 3H, 3 OMe), 2.67 (q, J = 7.9 Hz, 1H, CH). The remaining signals
overlap with the signals of the major isomer. 13C{1H} NMR (75
MHz, CDCl3): δ 153.4 (CH), 130.3 and 127.5 (o- and m-Ar),
125.9 (C), 26.3 (C(1)), 20.4(C(2)), 15.5 (C(3)); other signals are
not identified.
anhydride at −50 °C, fuming nitric acid (1.15 g, 18.2 mmol) was
added dropwise, followed by the slow addition of 1a (5 g, 18.2 mmol)
solution in acetic anhydride (3 mL). The mixture was stirred at −30
°C for 2 h, poured into hot water (about 60 °C), and extracted with
Et2O three times. The combined organic layers were washed with
water and saturated NaHCO3 solution, dried over MgSO4, and
concentrated in vacuo to give a mixture of ortho- and para-isomers of
1f (5.32 g, 91%, o/p 2.8:1, dr 1.85:1, trans/cis > 12:1) as a yellow oil.
The obtained product was used without additional purification.
HRMS: calcd for [M + Na]+ C16H17NO6Na, 342.0948; found,
Dimethyl (2-(4-Fluorophenyl)cyclopropyl)methylenemalonate
(3c). The crude product was purified by silica gel column
chromatography (eluent: benzene−AcOEt, 35:1). Yield: 50% (1.49
g), colorless oil, cis/trans = 1:5.5. IR (CHCl3) ν: 3053, 3036, 3029,
̅
2954, 2887, 1724, 1631, 1607, 1513, 1438, 1395, 1367, 1316 cm−1.
HRMS: calcd for [M + Na]+ C15H15FO4Na, 301.0847; found,
1
342.0956. Para-trans-isomer, both diastereomers (1.85/1): H NMR
1
301.0849. Trans-isomer: H NMR (300 MHz, CDCl3): δ 7.13−6.95
(300 MHz, CDCl3): δ 8.10 (d, J = 8.6 Hz, 2H, m-C6H4), 7.12 (d, J =
8.6 Hz, 2H, o-C6H4), 3.73, 3.68, 3.65, 3.48 (both s, 4 × 3H), 2.40
(ddd, J = 14.5, 9.6, 5.5 Hz, 1H, H(2′)), 1.87 (dt, J = 14.9, 6.1 Hz, 1H,
Ha from H(3)), 1.66−1.57 (m, 1H, Hb from H(3)), 1.27−0.81 (m, 3
× 1H, H(3′) and H(1′)). Ortho-trans-isomer, both diastereomers
(m, 4H, C6H4), 6.56 (d, J = 11.0 Hz, 1H, CH), 3.80 and 3.77 (both
s, 2 × 3H, 2 OMe), 2.43−2.09 (m, 2H, HC−CH), 1.70−1.45 (m, Ha
from CH2), 1.36 (dt, J = 9.1, 5.2 Hz, 1H, Hb from CH2). 13C{1H}
NMR (75 MHz, CDCl3): δ 165.9 and 164.8 (2 COO), 161.7 (d, J =
243 Hz, CF), 154.8 (CH), 135.5 (i-Ar), 128.0 (d, J = 8.0 Hz, o-Ar),
125.3 (C), 115.5 (d, J = 21.4 Hz, m-Ar), 52.4 and 52.3 (2 OMe),
27.3 (C(2)), 24.7 (C(1)), 18.6 (CH2). 19F NMR (282 MHz, CDCl3):
1
(1.85/1): H NMR (300 MHz, CDCl3): δ 7.85 (d, J = 8.1 Hz, 1H,
ma-C6H4), 7.47 (t, J = 7.2 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.13−
7.05 (m, 1H), 3.73, 3.68, 3.65, 3.48 (both s, 4 × 3H), 2.17−2.06 (m,
1H, H(2′)), 1.69−1.39 (m, 2H, H(3)), 1.27−0.81 (m, 3 × 1H, H(3′)
and H(1′)). 13C{1H} NMR (75 MHz, CDCl3): δ 170.3, 168.4, 150.6,
136.6, 132.8, 128.2, 127.9, 126.8, 126.2, 126.0, 124.3, 123.6, 52.8,
52.7, 52.5, 34.3, 34.1, 31.8, 31.2, 30.4, 23.3, 22.9, 22.6, 21.6, 21.0,
20.4, 20.2, 19.9, 19.6, 19.5, 19.3, 13.8, 13.1.
1
δ −117.03 (tt, J = 8.8, 5.2 Hz). Cis-isomer: H NMR (300 MHz,
CDCl3): δ 6.23 (d, J = 11.4 Hz, 1H, CH), 3.87 and 3.68 (both s, 2
× 3H, 2 OMe), 2.68 (q, J = 8.0 Hz, 1H, CH). The remaining signals
overlap with the signals of the major isomer. 13C{1H} NMR (75
MHz, CDCl3): δ 166.1 and 165.7 (2 COO), 161.7 (d, J = 243 Hz,
CF), 152.6 (CH), 137.8 (i-Ar), 130.8 (d, J = 8.0 Hz, o-Ar), 126.8
(C), 115.4 (d, J = 21.3 Hz, m-Ar), 52.41 and 52.37 (2 OMe), 26.1
(C(2)), 20.3 (C(1)), 15.5 (CH2). 19F NMR (282 MHz, CDCl3): δ
−116.4 (tt, J = 9.1, 5.3 Hz).
Dimethyl (E)-2-(5-Iodo-5-phenylpent-2-en-1-yl)malonate (7a).
GaI3 (40 mg, 0.09 mol) was added to the solution of 1a (80.3 mg,
0.29 mmol) and Bu4NGaI4 (239.8 mg, 0.29 mmol) in dry CH2Cl2 (3
mL) and the resulting mixture was stirred at room temperature for 2
h. After that, the reaction mixture was treated with 10% HCl and
extracted with CH2Cl2. The combined organic phases were dried over
MgSO4 and concentrated in vacuo. Silica gel column chromatography
(eluent: benzene−AcOEt, 35:1) gave the desired product as a yellow
Dimethyl (2-(4-Bromophenyl)cyclopropyl)methylenemalonate
(3d). The crude product was purified by silica gel column
chromatography (eluent: benzene−AcOEt, 35:1). Yield: 73% (4.87
g), yellow oil, cis/trans = 1:6. IR (CHCl3) ν: 3052, 3041, 3022, 1724,
̅
1632, 1492, 1438 cm−1. HRMS: calcd for [M + Na]+ C15H15BrO4Na,
361.0046 and 363.0026; found, 361.0041 and 363.0025. Trans-
isomer: 1H NMR (300 MHz, CDCl3): δ 7.45 (br.d, J = 8.4 Hz, 2H, o-
C6H4), 7.00 (br.d, J = 8.4 Hz, 2H, H m-C6H4), 6.55 (d, J = 10.5 Hz,
1H, (CH)), 3.80 and 3.78 (both s, 2 × 3H, 2 OMe), 2.42−2.12 (m,
2H, HC−CH), 1.63−1.47 and 1.44−1.31 (both m, 2 × 1H, CH2).
13C{1H} NMR (75 MHz, CDCl3): δ 165.8 and 164.7 (2 COO), 154.4
(CH), 138.9 (i-Ar), 131.6 (o-Ar), 128.1 (m-Ar), 125.4 (C),
120.2 (p-Ar), 52.3 and 52.3 (2 OMe), 27.4 (C(2)), 24.9 (C(1)), 18.6
oil (84 mg, 72%). IR (CHCl3) ν: 3084, 2956, 2877, 1733, 1461, 1437,
̅
1283, 1187 cm−1. HRMS: calcd for [M + Na]+ C16H19IO4Na,
1
425.0220; found, 425.0220. H NMR (300 MHz, CDCl3): δ 7.49−
7.07 (m, 5H, Ph), 5.64−5.37 (m, 2 H, H(2) and H(3)), 5.06 (t, J =
7.7 Hz, 1H, H(5)), 3.73 and 3.72 (both s, 2 × 3H, 2 OMe), 3.41 (t, J
= 7.5 Hz, 1H, CH), 3.02 (ddd, J = 14.1, 8.2 and 6.1 Hz, 1H, Ha from
H2C(4)), 2.83 (ddd, J = 14.1, 7.4 and 5.2 Hz, 1H, Hb from H2C(4)),
2.67−2.49 (m, 2H, H(1)). 13C{1H} NMR (75 MHz, CDCl3): δ 169.2
(2 COO), 143.5 (i-Ph), 131.1 and 129.1 (C(2) and C(3)), 128.7 and
127.2 (o- and m-Ph), 128.0 (p-Ph), 52.6 (2 OMe), 51.6 (CH), 44.0
(C(4)), 32.9 (C(5)), 31.7 (C(1)).
1
(C(3)). Cis-isomer: H NMR (300 MHz, CDCl3): δ 7.47 (br.d, J =
8.4 Hz, 2H, o-C6H4), 7.11 (d, J = 8.4 Hz, 2H, m-C6H4), 6.24 (d, J =
11.1 Hz, 1H, CH), 3.86 and 3.67 (both s, 2 × 3H, 2 OMe), 2.66
(q, J ≈ 8.0 Hz, 1H, HC), 2.42−2.31 (m, 1H, CH). The remaining
signals overlap with the signals of the major isomer.
Mixture of Dimethyl (E)-2-(5-Iodo-5-(4-nitrophenyl)pent-2-en-1-
yl)malonate (para-7f) and Dimethyl (E)-2-(5-Iodo-5-(2-
nitrophenyl)pent-2-en-1-yl)malonate (ortho-7f). This compound
was obtained analogously to compound 7a (o/p 1.6/1). HRMS: calcd
for [M + Na]+ C16H18INO6Na, 470.0071; found, 470.0067. Yellow
Dimethyl (2-(Naphthalen-2-yl)cyclopropyl)methylenemalonate
(3e). The crude product was purified by silica gel column
chromatography (eluent: benzene−AcOEt, 35:1). Yield: 56% (1.55
1
oil, 53% (210 mg), o-/p- = 1.7:1. Para-isomer: H NMR (300 MHz,
CDCl3): δ 8.16 (d, J = 8.8 Hz, 2H, m-C6H4), 7.52 (d, J = 8.8 Hz, 2H,
o-C6H4), 5.59−5.32 (m, 2H, H(2) and H(3)), 5.03 (t, J = 7.7 Hz, 1H,
H(5)), 3.72 and 3.71 (both s, 2 × 3H, 2 OMe), 3.43−3.33 (m, 1H,
CH), 3.11−2.92 (m, 1H, Ha from H2C(4)), 2.83 (dd, J = 14.2 and 6.7
Hz, 1H, Hb from H2C(4)), 2.77−2.43 (m, 2H, H(1)). 13C{1H} NMR
(75 MHz, CDCl3): δ 169.1 (2 COO), 150.6 (p-C6H4), 147.0 (i-
C6H4), 130.1 and 130.0 (C(2) and C(3)), 128.2 (o-C6H4), 124.0 (m-
C6H4), 52.6 (2 OMe), 51.4 (CH), 43.4 (C(4)), 31.6 (C(1)), 28.6
g), colorless crystals, mp 59−62 °C, cis/trans = 1:7. IR (CHCl3) ν:
̅
3050, 3035, 3016, 2954, 2887, 1724, 1631, 1603, 1510, 1438, 1374,
1348, 1309 cm−1. HRMS: calcd for [M + Na]+ C19H18O4Na,
333.1097; found, 333.1098. Trans-isomer: 1H NMR (300 MHz,
CDCl3): δ 7.87−7.73, 7.50−7.31, 7.25−7.20 (all m, 3 + 2 + 1H, Ar),
7.56 (br s, 1H, H(1′)), 6.63 (d, J = 11.1 Hz, CH), 3.79 and 3.78
(both s, 2 × 3H, 2 OMe), 2.47 (ddd, J = 9.0, 6.3, 4.0 Hz, 1H, CH),
2.35 (dddd, J = 11.1, 8.3, 5.2, 4.0 Hz, 1H, CH), 1.71 (ddd, J = 8.3, 6.3,
5.2 Hz, 1H, Ha from CH2), 1.44 (dt, J = 9.0, 5.2 Hz, 1H, Hb from
CH2). 13C{1H} NMR (75 MHz, CDCl3): δ 165.9 and 164.8 (2
COO), 154.9 (CH), 137.3 (C(2′)), 133.5 and 132.4 (C(4a) and
C(8a)), 128.3, 127.7, 127.5, 127.1, 126.3, 125.6 and 124.8 (all CH,
Ar), 124.9 (C), 52.4 and 52.2 (2 OMe), 28.3 (C(1)), 25.2 (C(2)),
18.7 (C(3)). Cis-isomer: 1H NMR (300 MHz, CDCl3): δ 6.30 (d, J =
11.3 Hz, 1H, CH), 2.88 (q, J ≈ 8.1 Hz, 1H, H(2)). The remaining
signals overlap with the signals of the major isomer. 13C{1H} NMR
(75 MHz, CDCl3): δ 152.8 (CH), 27.3 (C(1)), 20.7 (C(2)), 15.4
(C(3)); other signals are not identified.
1
(C(5)). Ortho-isomer: H NMR (300 MHz, CDCl3): δ 7.84−7.74
(m, 2 × 1H, o- and ma-C6H4), 7.64−7.55 (m, 1H, p-C6H4),7.44−7.34
(m, 1H, mb-C6H4),5.65 (dd, J = 8.2, 6.8 Hz, 1H, H(5)), 5.59−5.32
(m, 3H, H(2) and H(3)), 3.72 and 3.71 (both s, 2 × 3H, 2 OMe),
3.43−3.33 (m, 1H, CH), 3.11−2.92 (m, 1H, Ha from H2C(4)), 2.83
(dd, J = 14.2 and 6.8 Hz, 1H, Hb from H2C(4)), 2.77−2.43 (m, 2H,
H(1)). 13C{1H} NMR (75 MHz, CDCl3): δ 169.1 (2 COO), 147.0
(i-C6H4) 133.3 (p-C6H4), 130.9 (ma-C6H4),130.1 and 130.0 (C(2)
and C(3)), 128.5 (mb-C6H4), 124.6 (o-C6H4), 52.6 (2 OMe), 51.4
(CH), 43.7 (C(4)), 31.6 (C(1)), 22.9 (C(5)).
Dimethyl (E)-2-(5-(4-Bromophenyl)-5-iodopent-2-en-1-yl)-
malonate (7d). This compound was obtained analogously to
compound 7a. Yellow oil, 41% (79 mg). HRMS: calcd for [M +
Mixture of Dimethyl 2’-(4-Nitrophenyl)-[1,1′-bi(cyclopropane)]-
2,2-dicarboxylate (ortho-1f) and Dimethyl 2’-(2-Nitrophenyl)-[1,1′-
bi(cyclopropane)]-2,2-dicarboxylate (para-1f). To 8.5 mL of acetic
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Na]+ C17H20O5Na, 327.1203; found, 327.1197. 1H NMR (300 MHz,
CDCl3): δ 7.44 (d, J = 8.4 Hz, 2H, m-C6H4), 7.31−7.20 (m, 2H, o-
C6H4), 5.48 (dt, J = 12.6, 6.3 Hz, 2H, H(2) and H(3)), 4.99 (t, J =
7.6 Hz, 1H, H(5)), 3.73 and 3.72 (both s, 2 × 3H, 2 OMe), 3.40 (t, J
= 7.6 Hz, 1H, CH), 2.97 (dd, J = 14.4, 7.6 Hz, 1H, Ha from H2C(4)),
2.80 (dt, J = 14.0, 6.7 Hz, 1H, Hb from H2C(4)), 2.57 (t, J = 6.8 Hz,
2H, H(1)). 13C{1H} NMR (75 MHz, CDCl3): δ 169.1 (2 COO),
142.6 (i-C6H4), 131.8 (m-C6H4), 130.7 and 129.4 (C(2) and C(3)),
128.9 (o-C6H4), 121.6 (p-C6H4), 52.6 (2 OMe), 51.5 (CH), 43.9
(C(4)), 31.7 (C(1)), 31.0 (C(5)).
Tetramethyl (E)-9-(4-Bromophenyl)-3-(2-(4-bromophenyl)-
cyclopropyl)-9-iodonon-6-ene-1,1,4,4-tetracarboxylate (8). Silica
gel column chromatography (eluent: benzene−AcOEt, 35:1) gave
the desired product as a yellow oil (33 mg, 20%, dr = 1/1). HRMS:
calcd for [M + Na]+ C32H35Br2IO8Na, 854.9636; found, 854.9626. 1H
NMR (400 MHz, CDCl3): δ 7.46−7.37 (m, 2 × 2H, 2 m-C6H4),
7.25−7.21 (m, 2H, o-C6H4), 6.99−6.79 (m, 2H, o-C6H4), 5.72−5.55
(m, 1H, H(6)), 5.47−5.37 (m, 1H, H(7)), 5.08−4.85 (m, 1H, H(9)),
3.80, 3.72, 3.70 and 3.64 (all s, 4 × 3H, 4 OMe), 3.67−3.62 (m, 1H,
H(1)), 3.04−2.91 (m, 1H, Ha from CH2(8)), 2.81 (dd, J = 13.9, 6.6
Hz, 1H, Hb from CH2(8)), 2.67 (dd, J = 12.3, 7.1 Hz, 2H, H(5)),
2.36−2.14 (m, 1H, Ha from CH2(2)), 2.02−1.90 (m, 1H, Hb from
CH2(2)), 1.80−1.68 (m, 1H, H(3)), 1.74−1.64 (m, 1H, CH), 1.06−
0.95 (m, 1H, CH), 0.97−0.88 (m, 2H, CH2). 13C{1H} NMR (101
MHz, CDCl3): δ170.6, 170.5, 169.6 and 169.5 (4 COO), 142.5 (i-
C6H4), 141.3 (i-C6H4), 131.9 (m-C6H4), 131.5 (m-C6H4), 131.5
(C(7)), 128.8 (o-C6H4), 128.3 (C(6)), 127.2 (o-C6H4), 121.6 (p-
C6H4), 119.3 (p-C6H4), 62.5 (C(4)), 52.7 and 52.6 (4 OMe), 49.7
(C(1)), 45.4 (C(3)), 43.9 (C(8)), 37.5 (C(5)), 31.7 (C(2)), 30.9
(C(9)), 25.5 (CH), 22.1 (CH), 15.2 (CH2).
Ph), 6.37 (d, J = 10.9 Hz, 1H, CH(6)), 5.45−5.30 (m, 2H, H(2) and
H(3)), 3.72 (s, 6H, 2 OMe), 3.44−3.38 (m, 1H, H(5)), 3.37−3.32
(m, 1H, CH), 2.57 (dd, J = 7.3 and 3.9 Hz, 2H, H2C(1)), 2.39 (t, J =
5.9 Hz, 2H, H2C(4)). 13C{1H} NMR (75 MHz, CDCl3): δ 169.3 (2
COO), 142.9 and 138.8 (2 i-Ph), 136.6 (C(6)), 130.4 and 128.6
(C(2) and C(3)), 128.7, 128.6, 128.3 and 127.3 (o- and m-C from 2
Ph), 127.9 and 126.6 (2 p-Ph), 120.7 (C(7)), 52.5 (2 OMe), 51.8
(CH), 46.7 (C(5)), 39.6 (C(4)), 31.8 (C(1)).
Dimethyl 2-(5-(4-Bromophenyl)-7-chloro-7-cyclopropylhepta-
2,6-dien-1-yl)malonate (9c). This compound was obtained analo-
gously to compound 9a. Yield: 37% (37 mg), yellow oil, 6E/6Z ≈ 3:1.
HRMS: calcd for [M + NH4]+ C21H28Br2NO4, 516.0380; found,
1
516.0366. H NMR (400 MHz, chloroform-d): δ 7.44−7.33 (m, 2H,
m-Ar), 7.09−6.99 (m, 2H, o-Ar), 5.98 (d, J = 9.7 Hz, 1H, CH(6)),
5.43−5.31 (m, 2H, CH(1) + CH(3)), 3.70 and 3.70 (both s, 2 × 3H,
2 OMe), 3.74−3.68 (m, 1H, CH(5)), 3.39−3.30 (m, 1H, CH), 2.58−
2.48 (m, 2H, CH(1)), 2.38−2.29 (m, 2H, CH(4)), 1.73−1.55 (m,
1H, CH(1′)), 0.91−0.61 (m, 4H, 2 CH2(2′)). 13C{1H} NMR (101
MHz, chloroform-d): δ 169.3 (2 COO), 155.6 (i-Ar), 142.3 (C(7)),
134.0 (CH(6)), 131.6 (m-Ar), 129.3 (CH(2) and CH(3)), 129.1 (o-
Ar), 120.1 (p-Ar), 52.5 (2 OMe), 51.7 (CH), 45.1 (CH(5)), 39.6
(CH2(4)), 31.8 (CH2(1)), 15.0 (CH(1′)), 7.4 (CH2(2′)).
Dimethyl 2-(7-Bromo-5-(4-fluorophenyl)-7-phenylhepta-2,6-
dien-1-yl)malonate (9d). This compound was obtained analogously
to compound 9a. Yield: 43% (29 mg), yellow oil, 6E/6Z ≈ 5:1. IR
(CHCl3) ν: 3054, 3049, 3032, 3022, 3016, 2399, 1733, 1603, 1510,
̅
1438, 1341, 1280, 1183, 1158 cm−. HRMS: calcd for [M + H]+
C24H25BrFO4, 475.0915; found, 475.0929. 1H NMR (300 MHz,
chloroform-d): δ 7.54−6.91 (m, 9H, Ph and C6H4), 6.30 (d, J = 10.7
Hz, 1H, CH(6)), 5.37−5.29 (m, 2H, H(2) and H(3)), 3.70 and 3.69
(both s, 2 × 3H, 2 OMe), 3.40−3.25 (m, 2H, CH(5) and CH), 2.60−
2.44 (m, 2H, CH(1)), 2.37−2.29 (m, 2H, CH(4)). 13C{1H} NMR
(75 MHz, chloroform-d): δ 169.3 (2 COO), 161.56 (d, J = 244.8 Hz,
p-Ar), 138.7 (i-Ar), 136.4 (C(6)), 134.0 (i-Ph), 130.2 and 128.3
(C(2) and C(3)), 128.8, 128.7 and 128.4 (o-Ph, m-Ph, p-Ph and o-
Ar), 121.1 (C(7)), 115.5 (d, J = 21.2 Hz, m-Ar), 52.6 (2 OMe), 51.8
(CH), 45.9 (C(5)), 39.7 (C(4)), 31.9 (C(1)). 19F NMR (282 MHz,
chloroform-d): δ −117.1 (tt, J = 8.6, 5.5 Hz).
Dimethyl 4′-Methoxy-3,6-dihydro-[1,1′-biphenyl]-2,2(1H)-dicar-
boxylate (6b). This compound was obtained analogously to
compound 7a. Yield: 56% (80 mg), yellow oil. IR (CHCl3) ν:
̅
3054, 3046, 2954, 2839, 2401, 1731, 1611, 1554, 1513, 1461, 1436,
1341, 1299, 1283, 1258, 1116 cm−1. HRMS: calcd for [M + Na]+
C17H20O5Na, 327.1203; found, 327.1197. 1H NMR (400 MHz,
chloroform-d): δ 7.16 (d, J = 8.7 Hz, 2H, o-C6H4), 6.80 (d, J = 8.7 Hz,
2H, m-C6H4), 5.92−5.72 (m, 2H, H(5) and H(4)), 3.79 (s, 3H,
OMe), 3.83−3.70 (m, 1H, H(1)), 3.70 and 3.62 (both s, 2 × 3H, 2
CO2Me), 3.03−2.90 (m, 1H, Ha from CH2(6)), 2.78−2.56 (m, 2H,
CH2(3)), 2.42−2.30 (m, 1H, Hb from CH2(6)). 13C{1H} NMR (101
MHz, chloroform-d): δ 171.5 and 170.6 (2 COO), 158.6 (C(Ar) at
OMe), 134.3 (i-Ar), 129.3 (o-Ar), 127.4 (C(5)), 123.8 (C(4)), 113.6
(m-Ar), 57.4 (C(2)), 55.1 (OMe), 52.7 and 52.2 (2 CO2Me), 41.5
(C(1)), 30.3 (C(6)), 27.0 (C(3)).
Dimethyl 2-(5-(4-Bromophenyl)-7-chloro-7-phenylhepta-2,6-
dien-1-yl)malonate (9e). This compound was obtained analogously
to compound 9a. Yield: 48% (64 mg), yellow oil, 6E/6Z ≈ 4.2:1. IR
(CHCl3) ν: 3065, 3051, 3046, 3014, 2409, 2393, 1733, 1489, 1438,
̅
1342, 1280, 1183 cm−1. HRMS: calcd for [M + H]+ C24H26Br2O4,
1
535.0114; found, 535.0127. H NMR (400 MHz, chloroform-d): δ
7.56−6.95 (m, 9H, Ph and C6H4), 6.32 (d, J = 10.7 Hz, 1H, CH(6)),
5.40−5.31 (m, 2H, H(2) and H(3)), 3.73 and 3.72 (both s, 2 × 3H, 2
OMe), 3.42−3.28 (m, 3H, CH2(5) and CH), 2.63−2.49 (m, 2H,
CH2(1)), 2.39−2.33 (m, 2H, CH2(4)). 13C{1H} NMR (101 MHz,
chloroform-d): δ 169.3 (2 COO), 142.0 (i-Ar), 138.6 (C(7)), 135.9
(C(6)), 131.8 (o-Ar), 129.9 C(3), 129.4 (p-Ph), 129.0 (m-Ar), 128.8
and 128.4 (o-Ph and m-Ph), 128.3 (C(2)), 121.3 (i-Ph), 120.3 (CBr),
52.7 and 52.5 (2 OMe), 51.7 (CH), 46.1 C(5), 39.5 C(4), 31.8
(C(1).
Mixture of Dimethyl 2-(4-(4-Bromophenyl)-2-phenylcyclopent-2-
en-1-yl)cyclopropane-1,1-dicarboxylate (11a) and Dimethyl (2SR)-
2-((1SR,2SR)-4-(4-Bromophenyl)-2-phenylcyclopentyl)-
cyclopropane-1,1-dicarboxylate (Hydrogenated Analogue of 11a
via Ionic Hydrogenation). Minor products during the synthesis of 9e.
Ratio: 2/1. Compound 11a. Yield 10%, yellow oil, dr 1.75/1. 1H
NMR (400 MHz, chloroform-d): δ 7.82−6.86 (m, 9H, Ar), 4.07−
3.89 (m, 1H, H(4)), 3.80 (s, 3H, OMe), 3.75 (s, 3H, OMe), 3.08−
2.87 (m, 1H, H(1)), 2.71 (dt, J = 13.4, 8.7 Hz, 1H, H(5)), 1.99−1.81
(m, 1H, CH), 1.82−1.74 (m, 1H, CH, H(5′)), 1.74−1.68 (m, 1H, Ha
from CH2), 1.40−1.33 (m, 1H, Hb from CH2). 13C{1H} NMR (101
MHz, CDCl3): δ 131.6, 131.5, 129.2, 129.0, 128.8, 128.7, 128.5,
128.5, 128.3, 127.5, 127.2, 126.8 (Ar), 49.4 (C(4)), 45.9 (C(1)), 40.7
(C(5)), 35.2 (CH), 23.6 (CH2). Other signals are very small or
overlap with the signals of the minor compound and cannot be exactly
identified. Hydrogenated analogue of 11a. Yield 5%, dr 3/1. 1H NMR
(400 MHz, CDCl3): δ 7.82−6.86 (m, 9H, Ar), 4.19 (t, J = 8.1 Hz, 1H,
Dimethyl 2-(7-Chloro-5,7-diphenylhepta-2,6-dien-1-yl)malonate
(9a). GaCl3 (142.3 mg, 0.8 mmol) was added to the ice-cooled
solution of 1a (221.5 mg, 0.8 mmol) and phenylacetylene (412.6 mg,
4 mmol) in dry CH2Cl2 (8 mL). The resulting mixture was stirred at 0
°C for 1 h, followed by treatment with 10% HCl. Then, the mixture
was extracted with CH2Cl2, the combined organic phases were dried
over MgSO4, and concentrated in vacuo. The residue was separated
by column chromatography on silica gel (eluent: petroleum ether−
AcOEt, 10:1) yielding 215 mg (65%, 6E/6Z ≈ 10:1) of compound 9a
as a yellow oil. HRMS: calcd for [M + Na]+ C24H25ClO4Na,
1
435.1334; found, 435.1325. H NMR (300 MHz, CDCl3): δ 7.89−
6.88 (m, 10H, 2 Ph), 6.17 (d, J = 10.9 Hz, 1H, H(6)), 5.43−5.36 (m,
2H, H(2) and H(3)), 3.73 (s, 6H, 2 OMe), 3.47 (dt, J = 10.9 and 7.1
Hz, 1H, H(5)), 3.38 (t, J = 7.5 Hz, 1H, CH), 2.63−2.53 (m, 2H,
H2C(1)), 2.49−2.34 (m, 2H, H2C(4)). 13C{1H} NMR (75 MHz,
CDCl3): δ 169.3 (2 COO), 143.3 (C(7)), 132.2 (C(6)), 130.4 and
128.5 (C(2) and C(3)), 128.8, 128.7, 128.6, 128.3, 127.6 and 127.3
(2 Ph, C(2) and C(3)), 52.5 (2 OMe), 51.8 (CH), 45.6 C(5), 40.0
C(4), 31.8 C(1).
Dimethyl 2-(7-Bromo-5,7-diphenylhepta-2,6-dien-1-yl)-malo-
nate (9b). This compound was obtained analogously to compound
9a. Yield: 45% (147 mg), yellow oil, 6E/6Z ≈ 10:1. IR (CHCl3) ν:
̅
3069, 2847, 1732, 1520, 1494, 1286, 1188 cm−1. HRMS: calcd for [M
+ Na]+ C24H25BrO4Na, 479.0828 and 481.0809; found, 479.0840 and
1
481.0818. H NMR (300 MHz, CDCl3): δ 7.47−7.20 (m, 10H, 2
K
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H(4)), 3.83 (s, 3H, OMe), 3.66 (s, 3H, OMe), 2.57−2.42 (m, 1H,
H(5)), 2.12−1.97 (m, 1H, CH), 2.03−1.99 (m, 1H, H(5′)), 1.81−
1.63 (m, 1H, Ha from CH2), 1.38−1.33 (m, 1H, Hb from CH2).
13C{1H} NMR (101 MHz, CDCl3): δ 131.6, 131.5, 129.2, 129.0,
128.8, 128.7, 128.5, 128.5, 128.3, 127.5, 127.2, 126.8 (Ar), 52.6
(C(4)), 45.3 (C(1)), 41.9 (C(5)), 33.5 (CH), 22.7 (CH2). Other
signals are very small or overlap with the signals of major compound
and cannot be exactly identified.
Mixture of Dimethyl 2-(2-(4-(tert-Butyl)phenyl)-4-phenylcyclo-
pent-2-en-1-yl)cyclopropane-1,1-dicarboxylate (9f) and Dimethyl
2-(7-(4-(tert-Butyl)phenyl)-7-chloro-5-phenylhepta-2,6-dien-1-yl)-
malonate (11b). This mixture was obtained analogously to
compound 9a. Yield: 36% (for 11b, 56 mg, dr 1.6/1) and 20% (for
9f, 34 mg, 6E/6Z 4.4/1), yellow oil. HRMS: calcd for [M + Na]+
C28H32O4Na, 455.2193; found, 455.2200. Compound 11b, major
reaction mixture, key signals only): δ 6.43 (dd, 1H, CH(9), 3J = 9.9
3
4
and 4.9 Hz), 6.03 (ddd, 1H, CH(8), J = 9.9 Hz, J = 2.5 and 1.7
Hz), 5.80 (dd, 1H, CH(10)Ph, 3J = 4.9 Hz, 4J = 1.7 Hz), 4.70 (d, 1H,
CH2(6)-a, 2J = 14.8 Hz), 3.60 (dd, 1H, CH2(6)-b, 2J = 14.8 Hz, 4J =
2.5 Hz), other signals are overlapped. 13C{1H} NMR (75.5 MHz,
CDCl3, from the reaction mixture, key signals only): δ 130.3 (
CH(9)), 122.3 (CH(8)), 76.0 (C(7)), 69.5 (C(5)), 56.2
(CH(10)Ph), 49.9 (CH2(6)), other signals are overlapped. 15N{1H}
1
diastereomer. H NMR (400 MHz, chloroform-d): δ 7.60−7.08 (m,
9H, Ar), 6.04 (t, J = 2.1 Hz, 1H, CH(3′)), 4.01 (ddt, J = 9.3, 7.1, 2.3
Hz, 1H, CH(4′)), 3.84 and 3.66 (both s, 2 × 3H, 2 OMe), 3.06−2.95
(m, 1H, CH(1′)), 2.72 (dt, J = 13.4, 8.6 Hz, 1H, CHa from 5′), 1.95
(ddd, J = 10.6, 9.0, 8.0 Hz, 1H, CH(4)), 1.88−1.74 (m, 2H, Hb from
CH2(5′) and Ha from CH(3)), 1.47−1.40 (m, 1H, CHb from
CH2(3)), 1.38 (s, 9H, t-Bu). Compound 11b, minor diastereomer. 1H
NMR (400 MHz, chloroform-d): δ 7.60−7.08 (m, 9H, Ar), 6.18−
6.14 (m, 1H, CH(3′)), 4.24 (tt, J = 8.2, 2.1 Hz, 1H, CH(4′)), 3.81
and 3.77 (both s, 2 × 3H, 2 OMe), 3.58−3.49 (m, 1H, CH(1′)), 2.52
(ddd, J = 13.1, 7.8, 2.1 Hz, 1H, Ha from CH(5′)), 2.14−2.03 (m, 2H,
Hb from 5′ and CH(4)), 1.88−1.79 (m, 1H, Ha from CH(3)), 1.47−
1.40 (m, 1H, CHb from CH2(3)), 1.38 (s, 9H, t-Bu). Compound 9f.
1H NMR (400 MHz, chloroform-d): δ 6.14 (d, J = 11.0 Hz, 1H), 5.39
1
NMR (30.4 MHz, CDCl3, reconstructed from 2D H−15N HMBC
spectra, accuracy: 0.2−0.3 ppm, from the reaction mixture, key
signals only): δ 138.0 and 137.5 (N(1′) and N(1″)), 134.0 (N(11)),
104.0 (N(4)), other signals are overlapped.
Dimethyl 2-(3,5-Dioxo-4-phenyl-1,2,4-triazolidin-1-yl)-2-(8-(4-
methoxyphenyl)-1,3-dioxo-2-phenyl-2,3,5,8-tetrahydro-1H-[1,2,4]-
triazolo[1,2-a]pyridazin-5-yl)methylmalonate (12b). Reaction time:
2 h, yield: 54% (108 mg), yellow oil, cis/trans ≈ 8:1. The crude
product was purified by silica gel column chromatography (eluent:
CHCl3−MeOH, 35:1). IR (CHCl3) ν: 3046, 3036, 3012, 2956, 2841,
̅
1741, 1611, 1504, 1458, 1412, 1216 cm−1. HRMS: calcd for [M +
Na]+ C33H30N6O9Na, 677.1966; found, 677.1955. 1H NMR (300
MHz, CDCl3): δ 9.58 (s, 1H, NH), 7.68−7.31 (m, 14H, 2 Ph and
C6H4), 6.06 (ddd, J = 10.4, 3.4, 1.7 Hz, 1H, H(6)), 5.91−6.06 (m,
1H, H(7)), 5.47 (dd, J = 4.0, 2.0 Hz, 1H, H(8)), 5.22−5.13 (m, 1H,
H(5)), 3.91 and 3.87 (both s, 2 × 3H, 2 OMe), 3.80 (s, 3H, OMe),
3.11−2.96 (m, 2H, CH2). 13C{1H} NMR (75 MHz, CDCl3): δ 166.5
and 166.1 (2 COO), 160.1 (i-Ar), 156.8, 153.9, 153.0 and 151.0 (4
CO), 131.0, 130.5, 130.0 (3 i-Ar), 129.6, 129.3, 129.1, 128.9 and
128.7 (o- and m-C from 2 Ph and o-Ar), 128.4 and 128.0 (2 p-Ph),
125.3 and 125.1 (C(6) and C(7)), 114.3 (m-Ar), 72.4 (C), 57.2
(C(8)), 55.3 (OMe), 54.2 and 54.0 (2 OMe), 50.1 (C(5)), 37.7
(CH2).
(qd, J = 3.7, 1.8 Hz, 2H), 3.73 (d, J = 3.6 Hz, 5H). Other signals are
very small or overlap with the signals of major compound and cannot
be exactly identified.
Typical Procedure for the Reaction of Cyclopropanes 1a−e
with PTAD. Yb(OTf)3 (41 mg, 0.07 mmol) was added to the
solution of 1 (0.65 mmol) and PTAD (265 mg, 1.51 mmol) in 5−6
mL of dry DCE. The resulting mixture was stirred at 60 °C (in an oil
bath) for 2−5.5 h, followed by treatment with 10% HCl. The mixture
was extracted with CH2Cl2 and the combined organic phases were
dried over MgSO4 and concentrated in vacuo. Silica gel column
chromatography (eluent: CHCl3−MeOH, 25:1) gave the desired
product 12.
Dimethyl 2-((1,3-Dioxo-2,8-diphenyl-2,3,5,8-tetrahydro-1H-
[1,2,4]triazolo[1,2-a]pyridazin-5-yl)methyl)-2-(3,5-dioxo-4-phenyl-
1,2,4-triazolidin-1-yl)malonate (12a). Reaction time: 2 h, yield: 60%
(250 mg), yellow oil, cis/trans ≈ 3.5:1. The crude product was
purified by silica gel column chromatography (eluent: CHCl3−
Dimethyl 2-(3,5-Dioxo-4-phenyl-1,2,4-triazolidin-1-yl)-2-(8-(4-
fluorophenyl)-1,3-dioxo-2-phenyl-2,3,5,8-tetrahydro-1H-[1,2,4]-
triazolo[1,2-a]pyridazin-5-yl)methylmalonate (12c). Reaction time:
2 h, yield: 45% (95 mg), yellow oil, cis/trans ≈ 8:1. The crude
product was purified by silica gel column chromatography (eluent:
MeOH, 25:1). IR (CHCl3) ν: 3068, 3036, 3012, 2958, 2849, 1727,
̅
CHCl3−MeOH, 25:1). IR (CHCl3) ν: 3043, 3029, 3023, 3011, 1726,
̅
1599, 1503, 1421, 1235 cm−1. HRMS: calcd for [M + H]+
C32H29N6O8, 625.2041; found, 625.2037. Cis-isomer: 1H NMR
(300 MHz, CDCl3): δ 9.55 (s, 1H, NH), 7.54−7.32 (m, 15H, 3
Ph), 6.08 (ddd, J = 10.7, 3.4, 1.7 Hz, 1H, H(6)), 5.97 (ddd, J = 10.7,
3.7, 1.4 Hz, 1H, H(7)), 5.55−5.46 (m, 1H, H(8)), 5.23−5.08 (m, 1H,
H(5)), 3.91 and 3.87 (both s, 2 × 3H, 2 OMe), 3.06 (s, 2H, CH2).
13C{1H} NMR (101 MHz, CDCl3): δ 166.4 and 166.1 (2 COO),
156.8, 153.9, 152.9 and 151.0 (4 CO), 136.2, 131.0 and 130.5 (3 i-
Ph), 129.3, 129.1, 129.0, 128.8, 128.5 and 128.0 (o- and m-C from 3
Ph), 128.6, 128.4 and 125.9 (3 p-Ph), 125.3 and 125.2 (C(6) and
C(7)), 72.5 (C), 57.8 (C(8)), 54.1 and 54.0 (2 OMe), 49.9 (C(5)),
37.8 (CH2). 15N{1H} NMR (30.4 MHz, CDCl3, reconstructed from
1606, 1504, 1458, 1427, 1288, 1243 cm−1. HRMS: calcd for [M +
1
Na]+ C32H27FN6O8Na, 665.1767; found, 665.1758. H NMR (300
MHz, CDCl3): δ 9.48 (s, 1H, NH), 7.61−7.33 (m, 14H, 2 Ph and
C6H4), 6.13 (ddd, J = 10.4, 3.6 and 1.9 Hz, 1H, H(6)), 5.96 (ddd, J =
10.4, 3.9, 1.8 Hz, 1H, H(7)), 5.50 (dd, J = 3.9, 1.9 Hz, 1H, H(8)),
5.24−5.09 (m, 1H, H(5)), 3.93 and 3.89 (both s, 2 × 3H, 2 OMe),
3.12−3.07 (m, 2H, CH2). 13C{1H} NMR (75 MHz, CDCl3): δ 166.4
and 166.1 (2 COO), 163.0 (d, 1J = 248 Hz, C−F), 156.8, 153.8, 152.9
and 151.2 (4 CO), 131.0, 130.4, 130.1 (3 i-Ar), 130.0, 129.3, 129.2,
128.7 and 128.5 (o- and m-C from 2 Ph and o-Ar), 126.0 and 125.3
2
(C(6) and C(7)), 116.0 (d, J = 21.7 Hz, m-Ar), 72.4 (C), 57.2
(C(8)), 54.2 and 54.0 (2 OMe), 50.0 (C(5)), 37.8 (CH2). 19F NMR
(282 MHz, CDCl3): δ −113.00 (tt, J = 8.5, 5.1 Hz).
1
2D H−15N HSQC and HMBC spectra): δ 150.4 and 148.2 (N(2)
and N(4′)), 133.8 (N(9), 131.9 (N(4)), 127.2 (N(1′)), 124.3
(N(2′)).
Dimethyl 2-(8-(4-Bromophenyl)-1,3-dioxo-2-phenyl-2,3,5,8-tet-
rahydro-1H-[1,2,4]triazolo-[1,2-a]pyridazin-5-yl)methyl-2-(3,5-
dioxo-4-phenyl-1,2,4-triazolidin-1-yl)malonate (12d). Reaction
time: 5.5 h, yield: 48% (170 mg), yellow oil, cis/trans ≈ 4.5:1. The
crude product was purified by silica gel column chromatography
Dimethyl (Z)-7,7-Bis(3,5-dioxo-4-Phenyl-1,2,4-triazolidin-1-yl)-
1,3-dioxo-2,10-diphenyl-2,3,7,10-tetrahydro-1H-[1,2,4]triazolo[1,2-
a][1,2]diazocine-5,5(6H)-dicarboxylate (16). Compound 16 is a
minor product, less stable under reaction conditions and on SiO2, and
decomposes during isolation attempts; it was analyzed directly in the
reaction mixtures using complex 1H/13C/15N NMR spectral data.
HRMS (from the reaction mixture) calcd for [M + K]+ C40H33N9O10,
(eluent: CH2Cl2−MeOH, 10:1). IR (CHCl3) ν: 3053, 1948, 1728,
̅
1599, 1503, 1485, 1427, 1277 cm−1. HRMS: calcd for [M + Na]+
C32H27BrN6O8Na, 725.0966 and 727.0948; found, 725.0949 and
1
727.0969. H NMR (300 MHz, CDCl3): δ 9.43 (s, 1H, NH), 7.60−
1
838.1982; found, 838.1947. H NMR (300.1 MHz, CDCl3, from the
7.28 (m, 14H, 2 Ph and C6H4), 6.11 (ddd, J = 10.5, 3.7, 1.9 Hz, 1H,
L
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H(6)), 5.90 (ddd, J = 10.5, 3.8, 1.8 Hz, 1H, H(7)), 5.45−5.39 (m,
1H, H(8)), 5.22−5.08 (m, 1H, H(5)), 3.90 and 3.86 (both s, 2 × 3H,
2 OMe), 3.08−3.00 (m, 2H, CH2). 13C{1H} NMR (75 MHz,
CDCl3): δ 166.4 and 166.1 (2 COO), 156.7, 153.9, 152.7 and 151.4
(4 CO), 135.3, 132.2 and 130.9 (3 i-Ar), 130.4, 130.2, 129.8, 129.3,
129.2 and 129.0 (3 o- and m-Ar), 129.1 and 128.5 (2 p-Ph), 126.0 and
125.3 (C(6) and C(7)), 122.2 (C−Br), 72.5 (C(6)), 57.4 (C(1)),
54.2 and 54.1 (2 OMe), 49.8 (C(5)), 37.7 (CH2).
Dimethyl 2-(3,5-Dioxo-4-phenyl-1,2,4-triazolidin-1-yl)-2-(8-
(naphthalen-2-yl)-1,3-dioxo-2-phenyl-2,3,5,8-tetrahydro-1H-
[1,2,4]triazolo[1,2-a]pyridazin-5-yl)methylmalonate (12e). Reac-
tion time: 5.5 h, yield: 22% (81 mg), yellow oil, cis/trans ≈ 10:1.
The crude product was purified using silica gel column chromatog-
mass spectra were recorded in the Department of Structural
Studies of N. D. Zelinsky Institute of Organic Chemistry RAS,
Moscow.
REFERENCES
■
(1) Reissig, H.-U.; Zimmer, R. Donor−Acceptor-Substituted
Cyclopropane Derivatives and Their Application in Organic Syn-
thesis. Chem. Rev. 2003, 103, 1151.
(2) Tomilov, Y. V.; Menchikov, L. G.; Novikov, R. A.; Ivanova, O.
A.; Trushkov, I. V. Methods for the synthesis of donor-acceptor
cyclopropanes. Russ. Chem. Rev. 2018, 87, 201.
(3) (a) Carson, C. A.; Kerr, M. A. Heterocycles from cyclopropanes:
applications in natural product synthesis. Chem. Soc. Rev. 2009, 38,
3051. (b) Schneider, T. F.; Kaschel, J.; Werz, D. B. A new golden age
for donor−acceptor cyclopropanes. Angew. Chem., Int. Ed. 2014, 53,
5504. (c) De Nanteuil, F.; De Simone, F.; Frei, R.; Benfatti, F.;
Serrano, E.; Waser, J. Cyclization and annulation reactions of
nitrogen-substituted cyclopropanes and cyclobutanes. Chem. Com-
mun. 2014, 50, 10912. (d) Cavitt, M. A.; Phun, L. H.; France, S.
Intramolecular donor−acceptor cyclopropane ring-opening cycliza-
tions. Chem. Soc. Rev. 2014, 43, 804. (e) Grover, H. K.; Emmett, M.
R.; Kerr, M. A. Carbocycles from donor−acceptor cyclopropanes. Org.
Biomol. Chem. 2015, 13, 655.
raphy (eluent: CHCl3−MeOH, 25: 1). IR (CHCl3) ν: 3064, 2847,
̅
1949, 1726, 1600, 1503, 1458, 1425, 1280 cm−1. HRMS: calcd for [M
1
+ Na]+ C36H30N6O8Na, 697.2017; found, 697.2004. H NMR (300
MHz, CDCl3): δ 9.65 (s, 1H, NH), 8.06−7.12 (m, 17H, 2 Ph and
naphthyl), 6.26−6.08 (m, 1H, H(6)), 6.10−6.01 (m, 1H, H(7)),
5.74−5.64 (m, 1H, H(8)), 5.27−5.17 (m, 1H, H(5)), 3.95 and 3.91
(both s, 2 × 3H, 2 OMe), 3.20−3.11 (m, 2H, CH2). 13C{1H} NMR
(75 MHz, CDCl3): δ 166.8 and 166.1 (2 COO), 156.0, 153.1, 152.4
and 151.3 (4 CO), 133.6, 133.0, 131.5, 129.3, 129.1, 128.4, 128.2,
126.1, 126.0, 125.7, 125.6, 125.3 and 125.1 (3 Ar and CC), 72.5
(C), 58.1 (C(8)), 54.2 and 54.0 (2 OMe), 50.0 (C(5)), 37.8 (CH2).
(4) (a) Budynina, E.; Ivanov, K.; Sorokin, I.; Melnikov, M. Ring
opening of donor−acceptor cyclopropanes with N-nucleophiles.
Synthesis 2017, 49, 3035. (b) Pagenkopf, B. L.; Vemula, N.
Cycloadditions of Donor−Acceptor Cyclopropanes and Nitriles.
Eur. J. Org. Chem. 2017, 2561. (c) Meazza, M.; Guo, H.; Rios, R.
Synthetic applications of vinyl cyclopropane opening. Org. Biomol.
Chem. 2017, 15, 2479−2490. (d) Ivanova, O. A.; Trushkov, I. V.
Donor-Acceptor Cyclopropanes in the Synthesis of Carbocycles.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02293.
■
sı
Copies of 1H, 13C, 15N, and 2D NMR spectra for
isolated products (PDF)
Chem. Rec. 2019, 19, 2189. (e) Kreft, A.; Lucht, A.; Grunenberg, J.;
̈
Jones, P. G.; Werz, D. B. Kinetic Studies of Donor−Acceptor
Cyclopropanes: The Influence of Structural and Electronic Properties
on the Reactivity. Angew. Chem., Int. Ed. 2019, 58, 1955−1959.
(f) Werz, D. B.; Biju, A. T. Uncovering the Neglected Similarities of
Arynes and Donor−Acceptor Cyclopropanes. Angew. Chem., Int. Ed.
2020, 59, 3385−3398.
AUTHOR INFORMATION
Corresponding Authors
■
Roman A. Novikov − N. D. Zelinsky Institute of Organic
Chemistry, Russian Academy of Sciences, 119991 Moscow,
Russian Federation; orcid.org/0000-0002-3740-7424;
Email: novikovfff@bk.ru
Yury V. Tomilov − N. D. Zelinsky Institute of Organic
Chemistry, Russian Academy of Sciences, 119991 Moscow,
Russian Federation; orcid.org/0000-0002-3433-7571;
Email: tom@ioc.ac.ru
(5) (a) Guin, A.; Rathod, T.; Gaykar, R. N.; Roy, T.; Biju, A. T.
Lewis Acid Catalyzed Ring-Opening 1,3-Aminothiolation of Donor−
Acceptor Cyclopropanes Using Sulfenamides. Org. Lett. 2020, 22,
2276−2280. (b) Li, B. Q.; Qiu, Z.-W.; Ma, A.-J.; Peng, J.-B.; Feng, N.;
Du, J.-Y.; Pan, H.-P.; Zhang, X.-Z.; Xu, X.-T. Diastereoselective
Synthesis of Cycloheptannelated Indoles via Lewis-Acid-Catalyzed (4
+ 3)-Cyclization of Donor−Acceptor Cyclopropanes. Org. Lett. 2020,
22, 1903−1907. (c) Chen, D.-F.; Chrisman, C. H.; Miyake, G. M.
Bromine Radical Catalysis by Energy Transfer Photosensitization.
ACS Catal. 2020, 10, 2609−2614. (d) Zhang, X.; Feng, M.; Yang, G.;
Chai, Z. Sc(OTf) 3 -Catalyzed Chemodivergent Annulations of γ-
Butyrolactone-Fused Cyclopropanes with Anthranils. J. Org. Chem.
2020, 85, 430−440. (e) Boichenko, M. A.; Andreev, I. A.;
Chagarovskiy, A. O.; Levina, I. I.; Zhokhov, S. S.; Trushkov, I. V.;
Ivanova, O. A. Ring Opening of Donor−Acceptor Cyclopropanes
with Cyanide Ion and Its Surrogates. J. Org. Chem. 2020, 85, 1146−
1157. (f) Tamilarasan, V. J.; Srinivasan, K. AlCl 3 -Promoted Ritter-
Type Ring-Opening Reactions of γ-Butyrolactone Fused Donor-
Acceptor Cyclopropanes with Wet Aliphatic Nitriles. Eur. J. Org.
Chem. 2020, 593−598.
Authors
Konstantin V. Potapov − N. D. Zelinsky Institute of Organic
Chemistry, Russian Academy of Sciences, 119991 Moscow,
Russian Federation
Dmitry A. Denisov − N. D. Zelinsky Institute of Organic
Chemistry, Russian Academy of Sciences, 119991 Moscow,
Russian Federation
Valeriia V. Glushkova − N. D. Zelinsky Institute of Organic
Chemistry, Russian Academy of Sciences, 119991 Moscow,
Russian Federation
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02293
́
(6) (a) Augustin, A. U.; Merz, J. L.; Jones, P. G.; Mloston, G.; Werz,
Author Contributions
D. B. (4 + 3)-Cycloaddition of Donor−Acceptor Cyclopropanes with
Thiochalcones: A Diastereoselective Access to Tetrahydrothiepines.
Org. Lett. 2019, 21, 9405−9409. (b) Singh, K.; Bera, T.; Jaiswal, V.;
Biswas, S.; Mondal, B.; Das, D.; Saha, J. Lewis Acid Catalyzed
Nucleophilic Ring Opening and 1,3-Bisfunctionalization of Donor−
Acceptor Cyclopropanes with Hydroperoxides: Access to Highly
Functionalized Peroxy/(α-Heteroatom Substituted)Peroxy Com-
pounds. J. Org. Chem. 2019, 84, 710−725. (c) Luo, W.; Sun, Z.;
Fernando, E. H. N.; Nesterov, V. N.; Cundari, T. R.; Wang, H.
†K.V.P., D.A.D., and R.A.N. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the grant of the Russian Science
Foundation (RSF grant no. 19-73-10210). High-resolution
■
M
https://dx.doi.org/10.1021/acs.joc.0c02293
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Asymmetric Ring-Opening of Donor−Acceptor Cyclopropanes with
Primary Arylamines Catalyzed by a Chiral Heterobimetallic Catalyst.
ACS Catal. 2019, 9, 8285−8293. (d) Augustin, A. U.; Jones, P. G.;
Werz, D. B. Ring-Opening 1, 3-Aminochalcogenation of Donor-
Acceptor Cyclopropanes: A Three-Component Approach. Chem.
Eur. J. 2019, 25, 11620−11624. (e) Singh, K.; Pramanik, S.; Hamlin,
T. A.; Mondal, B.; Das, D.; Saha, J. Lewis acid catalyzed annulation of
spirocyclic donor−acceptor cyclopropanes with exo-heterocyclic
olefins: access to highly functionalized bis-spirocyclopentane oxindole
frameworks. Chem. Commun. 2019, 55, 7069−7072. (f) Akaev, A. A.;
Melnikov, M. Y.; Budynina, E. M. Chameleon-Like Activating Nature
of the Spirooxindole Group in Donor−Acceptor Cyclopropanes. Org.
Lett. 2019, 21, 9795−9799.
Directing Group for the Cobalt-Catalyzed C−H Allylation. J. Org.
Chem. 2019, 84, 13203−13210. (c) Hu, Z.; Hu, X.-Q.; Zhang, G.;
Gooßen, L. J. Ring-Opening Ortho -C−H Allylation of Benzoic Acids
with Vinylcyclopropanes: Merging Catalytic C−H and C−C
Activation Concepts. Org. Lett. 2019, 21, 6770−6773. (d) Ivanova,
O. A.; Chagarovskiy, A. O.; Shumsky, A. N.; Krasnobrov, V. D.;
Levina, I. I.; Trushkov, I. V. Lewis Acid Triggered Vinyl-
cyclopropane−Cyclopentene Rearrangement. J. Org. Chem. 2018,
83, 543−560.
(11) Novikov, R. A.; Tarasova, A. V.; Korolev, V. A.; Timofeev, V.
P.; Tomilov, Y. V. A New Type of Donor−Acceptor Cyclopropane
Reactivity: The Generation of Formal 1,2-and 1,4-Dipoles. Angew.
Chem., Int. Ed. 2014, 53, 3187.
(12) (a) Zotova, M. A.; Novikov, R. A.; Shulishov, E. V.; Tomilov, Y.
V. GaCl3-Mediated “Inverted” Formal [3 + 2]-Cycloaddition of
Donor−Acceptor Cyclopropanes to Allylic Systems. J. Org. Chem.
2018, 83, 8193. (b) Zotova, M. A.; Novikov, R. A.; Volodin, A. D.;
Korlyukov, A. A.; Tkachev, Y. V.; Korolev, V. A.; Tomilov, Y. V. Four-
Membered Cycle Formation Challenge: GaCl3-Promoted Formal
[2+2]-Cycloaddition of Donor−Acceptor Cyclopropanes to Bicyclo-
butylidene. Eur. J. Org. Chem. 2019, 4207−4214.
(13) (a) Borisov, D. D.; Novikov, R. A.; Tomilov, Y. V. GaCl3-
Mediated Reactions of Donor−Acceptor Cyclopropanes with
Aromatic Aldehydes. Angew. Chem., Int. Ed. 2016, 55, 12233.
(b) Borisov, D. D.; Novikov, R. A.; Eltysheva, A. S.; Tkachev, Y.
V.; Tomilov, Y. V. Styrylmalonates as an Alternative to Donor−
Acceptor Cyclopropanes in the Reactions with Aldehydes: A Route to
5, 6-Dihydropyran-2-ones. Org. Lett. 2017, 19, 3731.
(14) (a) Novikov, R. A.; Denisov, D. A.; Potapov, K. V.; Tkachev, Y.
V.; Shulishov, E. V.; Tomilov, Y. V. Ionic Ga-Complexes of
Alkylidene- and Arylmethylidenemalonates and Their Reactions
with Acetylenes: An In-Depth Look into the Mechanism of the
Occurring Gallium Chemistry. J. Am. Chem. Soc. 2018, 140, 14381−
14390. (b) Denisov, D. A.; Borisov, D. D.; Korolev, V. A.; Novikov, R.
A.; Tomilov, Y. V. Three-Component GaHal3-Promoted Reactions of
Substituted Methylidenemalonates and Donor−Acceptor Cyclo-
propanes with Propargyl Halides: Cascade Diastereoselective
Construction of Five-Membered Lactones. J. Org. Chem. 2019, 84,
6174−6182.
(15) Denisov, D. A.; Novikov, R. A.; Potapov, K. V.; Korolev, V. A.;
Shulishov, E. V.; Tomilov, Y. V. 1,1’-Bicyclopropyl-2,2-Dicarboxylate
and Cyclopropylmethylidenemalonate as Homovinylogs and Vinylogs
of Donor-Acceptor Cyclopropanes. ChemistrySelect 2016, 1, 6374−
6381.
(16) Denisov, D. A.; Borisov, D. D.; Potapov, K. V.; Novikov, R. A.;
Tomilov, Y. V. 4-Phenylspiro[2.2]Pentane-1,1-Dicarboxylate: Syn-
thesis and Reactions with EtAlCl2 and 4,5-Diazaspiro[2.4]Hept-4-Ene
Derivative. Mendeleev Commun. 2019, 29, 417−418.
(17) Kreft, A.; Jones, P. G.; Werz, D. B. The Cyclopropyl Group as a
Neglected Donor in Donor−Acceptor Cyclopropane Chemistry. Org.
Lett. 2018, 20, 2059−2062.
(7) (a) Augustin, A. U.; Busse, M.; Jones, P. G.; Werz, D. B. Formal
Insertion of Thioketenes into Donor−Acceptor Cyclopropanes by
Lewis Acid Catalysis. Org. Lett. 2018, 20, 820. (b) Richmond, E.;
́
Vukovic, V. D.; Moran, J. Nucleophilic ring opening of Donor−
Acceptor cyclopropanes catalyzed by a Brønsted Acid in hexafluor-
oisopropanol. Org. Lett. 2018, 20, 574. (c) Dey, R.; Kumar, P.;
Banerjee, P. Lewis Acid Catalyzed Annulation of Cyclopropane
Carbaldehydes and Aryl Hydrazines: Construction of Tetrahydropyr-
idazines and Application Toward a One-Pot Synthesis of
Hexahydropyrrolo[1,2-b]pyridazines. J. Org. Chem. 2018, 83, 5438−
5449. (d) Irwin, L. C.; Renwick, C. R.; Kerr, M. A. Nucleophilic
Opening of Donor−Acceptor Cyclopropanes with Indoles via
Hydrogen Bond Activation with 1,1,1,3,3,3-Hexafluoroisopropanol.
J. Org. Chem. 2018, 83, 6235−6242. (e) Matsumoto, Y.; Nakatake, D.;
Yazaki, R.; Ohshima, T. An Expeditious Route to trans-Configured
Tetrahydrothiophenes Enabled by Fe(OTf)3-Catalyzed [3+2] Cyclo-
addition of Donor−Acceptor Cyclopropanes with Thionoesters.
Chem.Eur. J. 2018, 24, 6062−6066. (f) Chagarovskiy, A. O.;
Vasin, V. S.; Kuznetsov, V. V.; Ivanova, O. A.; Rybakov, V. B.;
Shumsky, A. N.; Makhova, N. N.; Trushkov, I. V. (3 + 3)-Annulation
of Donor−Acceptor Cyclopropanes with Diaziridines. Angew. Chem.,
Int. Ed. 2018, 57, 10338−10342.
(8) (a) Das, S.; Daniliuc, C. G.; Studer, A. Stereospecific 1, 3-
Aminobromination of Donor−Acceptor Cyclopropanes. Angew.
Chem., Int. Ed. 2017, 56, 11554. (b) Dey, R.; Banerjee, P. Lewis
Acid Catalyzed Diastereoselective Cycloaddition Reactions of
Donor−Acceptor Cyclopropanes and Vinyl Azides: Synthesis of
Functionalized Azidocyclopentane and Tetrahydropyridine Deriva-
tives. Org. Lett. 2017, 19, 304. (c) Preindl, J.; Chakrabarty, S.; Waser,
J. Dearomatization of electron poor six-membered N-heterocycles
through [3 + 2] annulation with aminocyclopropanes. Chem. Sci.
2017, 8, 7112−7118. (d) Augustin, A. U.; Sensse, M.; Jones, P. G.;
Werz, D. B. Stereospecific Reactions of Donor−Acceptor Cyclo-
propanes with Thioketones: Access to Highly Substituted Tetrahy-
drothiophenes. Angew. Chem., Int. Ed. 2017, 56, 14293−14296.
(e) Garve, L. K. B.; Jones, P. G.; Werz, D. B. Ring-Opening 1-Amino-
3-aminomethylation of Donor−Acceptor Cyclopropanes via 1, 3-
Diazepanes. Angew. Chem., Int. Ed. 2017, 56, 9226.
(9) (a) Sherry, B. D.; Fu
̈
rstner, A. Iron-Catalyzed Addition of
(18) Korotkov, V. S.; Larionov, O. V.; Hofmeister, A.; Magull, J.; De
Meijere, A. GaCl3-Catalyzed Insertion of Diazene Derivatives into the
Cyclopropane Ring. J. Org. Chem. 2007, 72, 7504−7510.
(19) Wu, J.; Winiarz, P.; Patel, D.; de Jong, J.; Tong, D.; Chidley, T.;
Vemula, N.; Pagenkopf, B. L. Synthesis of Hexahydropyridazines by
[4 + 2] Cycloaddition of Donor−Acceptor Cyclobutanes and cis-
Diazenes. Org. Lett. 2020, 22, 3140−3144.
Grignard Reagents to Activated Vinyl Cyclopropanes. Chem.
Commun. 2009, 7116−7118. (b) Dieskau, A. P.; Holzwarth, M. S.;
Plietker, B. Fe-Catalyzed Allylic C-C-Bond Activation: Vinyl-
cyclopropanes as Versatile A1,A3,D5-Synthons in Traceless Allylic
Substitutions and [3 + 2]-Cycloadditions. J. Am. Chem. Soc. 2012,
134, 5048−5051. (c) Niu, H.-Y.; Du, C.; Xie, M.-S.; Wang, Y.; Zhang,
Q.; Qu, G.-R.; Guo, H.-M. Diversity-Oriented Synthesis of Acyclic
Nucleosides via Ring-Opening of Vinyl Cyclopropanes with Purines.
Chem. Commun. 2015, 51, 3328−3331. (d) Trost, B. M.; Bai, W.-J.;
Hohn, C.; Bai, Y.; Cregg, J. J. Palladium-Catalyzed Asymmetric Allylic
Alkylation of 3-Substituted 1 H -Indoles and Tryptophan Derivatives
with Vinylcyclopropanes. J. Am. Chem. Soc. 2018, 140, 6710−6717.
(10) (a) Wang, J.; Dai, Z.; Xiong, C.; Zhu, J.; Lu, J.; Zhou, Q.
Palladium-Catalyzed Allylic Alkylation of Aldimine Esters with Vinyl-
Cyclopropanes to Yield α,Α-Disubstituted Α-Amino Acid Derivatives.
Adv. Synth. Catal. 2019, 361, 5105−5111. (b) Tanaka, R.; Tanimoto,
I.; Kojima, M.; Yoshino, T.; Matsunaga, S. Imidate as the Intact
̈
̈
̈
̈
(20) (a) Maki-Opas, I.; Hamalainen, M.; Moilanen, L. J.; Haavikko,
R.; Ahonen, T. J.; Alakurtti, S.; Moreira, V. M.; Muraki, K.; Yli-
Kauhaluoma, J.; Moilanen, E. Pyrazine-Fused Triterpenoids Block the
TRPA1 Ion Channel in Vitro and Inhibit TRPA1-Mediated Acute
Inflammation in Vivo. ACS Chem. Neurosci. 2019, 10, 2848−2857.
(b) Xin, X.; Zimmermann, S.; Flegel, J.; Otte, F.; Knauer, L.;
Strohmann, C.; Ziegler, S.; Kumar, K. Unravelling the Synthesis and
Chemistry of Stable, Acyclic, and Double-Deficient 1,3-Butadienes:
An Endo-Selective Diels−Alder Route to Hedgehog Pathway
Inhibitors. Chem.Eur. J. 2019, 25, 2717−2722. (c) Cho, W.; Koo,
J. Y.; Park, Y.; Oh, K.; Lee, S.; Song, J.-S.; Bae, M. A.; Lim, D.; Lee,
N
https://dx.doi.org/10.1021/acs.joc.0c02293
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
D.-S.; Park, S. B. Treatment of Sepsis Pathogenesis with High
Mobility Group Box Protein 1-Regulating Anti-Inflammatory Agents.
J. Med. Chem. 2017, 60, 170−179. (d) Laavola, M.; Haavikko, R.;
Hamalainen, M.; Leppanen, T.; Nieminen, R.; Alakurtti, S.; Moreira,
V. M.; Yli-Kauhaluoma, J.; Moilanen, E. Betulin Derivatives
Effectively Suppress Inflammation in Vitro and in Vivo. J. Nat.
Prod. 2016, 79, 274−280.
(21) (a) Lee, S.; Nam, Y.; Koo, J. Y.; Lim, D.; Park, J.; Ock, J.; Kim,
J.; Suk, K.; Park, S. B. A Small Molecule Binding HMGB1 and
HMGB2 Inhibits Microglia-Mediated Neuroinflammation. Nat. Chem.
Acceptor Cyclopropanes: Evidence for a Stereospecific Intimate Ion
Pair Pathway. J. Am. Chem. Soc. 2008, 130, 8642−8650.
(31) Perkowski, A. J.; You, W.; Nicewicz, D. A. Visible Light
Photoinitiated Metal-Free Living Cationic Polymerization of 4-
Methoxystyrene. J. Am. Chem. Soc. 2015, 137, 7580−7583.
(32) Wang, C.; Gong, S.; Liang, Z.; Sun, Y.; Cheng, R.; Yang, B.;
Liu, Y.; Yang, J.; Sun, F. Ligand-Promoted Iridium-Catalyzed Transfer
Hydrogenation of Terminal Alkynes with Ethanol and Its Application.
ACS Omega 2019, 4, 16045−16051.
(33) Anciaux, A. J.; Hubert, A. J.; Noels, A. F.; Petiniot, N.; Teyssie,
P. Transition-Metal-Catalyzed Reactions of Diazo Compounds. 1.
Cyclopropanation of Double Bonds. J. Org. Chem. 1980, 45, 695−
702.
(34) Higgins, M. A.; Marcin, L. R.; Christopher Zusi, F.; Gentles, R.;
Ding, M.; Pearce, B. C.; Easton, A.; Kostich, W. A.; Seager, M. A.;
Bourin, C.; et al. Triazolopyridine Ethers as Potent, Orally Active
MGlu2 Positive Allosteric Modulators for Treating Schizophrenia.
Bioorg. Med. Chem. 2017, 25, 496−513.
(35) Kallemeyn, J.; Mulhern, M.; Ku, Y.-Y. Asymmetric Synthesis of
Di- and Trisubstituted Cyclopropanes through an Intramolecular
Ring Closure. Synlett 2011, 535−538.
(36) Melancon, B. J.; Perl, N. R.; Taylor, R. E. Competitive Cationic
Pathways and the Asymmetric Synthesis of Aryl-Substituted Cyclo-
propanes. Org. Lett. 2007, 9, 1425−1428.
(37) Chanthamath, S.; Phomkeona, K.; Shibatomi, K.; Iwasa, S.
Highly Stereoselective Ru(II)−Pheox Catalyzed Asymmetric Cyclo-
propanation of Terminal Olefins with Succinimidyl Diazoacetate.
Chem. Commun. 2012, 48, 7750.
(38) Bobileva, O.; Bokaldere, R.; Gailite, V.; Kaula, I.; Ikaunieks, M.;
Duburs, G.; Petrovska, R.; Mandrika, I.; Klovins, J.; Loza, E. Synthesis
and Evaluation of (E)-2-(Acrylamido)Cyclohex-1-Enecarboxylic Acid
Derivatives as HCA1, HCA2, and HCA3 Receptor Agonists. Bioorg.
Med. Chem. 2014, 22, 3654−3669.
(39) Singh, P.; Kaur, N.; Banerjee, P. Regioselective Brønsted Acid-
Catalyzed Annulation of Cyclopropane Aldehydes with N′-Aryl
Anthranil Hydrazides: Domino Construction of Tetrahydropyrrolo-
[1,2-a]Quinazolin-5(1H)Ones. J. Org. Chem. 2020, 85, 3393−3406.
̈
̈
̈
̈
́
́
Biol. 2014, 10, 1055−1060. (b) Fejes, Z.; Mandi, A.; Komaromi, I.;
Majoros, L.; Batta, G.; Herczegh, P. A Synthetic and in Silico Study
on the Highly Regioselective Diels-Alder Reaction of the Polyenic
Antifungal Antibiotics Natamycin and Flavofungin. Tetrahedron Lett.
2010, 51, 4968−4971. (c) Grange, R. L.; Gallen, M. J.; Schill, H.;
Johns, J. P.; Dong, L.; Parsons, P. G.; Reddell, P. W.; Gordon, V. A.;
Bernhardt, P. V.; Williams, C. M. [4+2] Cycloaddition Reactions
between 1,8-Disubstituted Cyclooctatetraenes and Diazo Dienophiles:
Stereoelectronic Effects, Anticancer Properties and Application to the
Synthesis of 7,8-Substituted Bicyclo [4.2.0] Octa-2,4-Dienes. Chem.
Eur. J. 2010, 16, 8894−8903. (d) Brummond, K. M.; Mao, S.; Shinde,
S. N.; Johnston, P. J.; Day, B. W. Design and Synthesis of a Library of
Tetracyclic Hydroazulenoisoindoles. J. Comb. Chem. 2009, 11, 486−
494. (e) Li, J. J.; Chao, H.-G.; Wang, H.; Tino, J. A.; Lawrence, R. M.;
Ewing, W. R.; Ma, Z.; Yan, M.; Slusarchyk, D.; Seethala, R.; et al.
Discovery of a Potent and Novel Motilin Agonist. J. Med. Chem. 2004,
47, 1704−1708.
(22) Cornelis, S.; Kersse, K.; Festjens, N.; Lamkanfi, M.;
Vandenabeele, P. Inflammatory Caspases: Targets for Novel
Therapies. Curr. Pharm. Des. 2007, 13, 367−385.
(23) Rudawska, K.; Ptasiewicz-Bąk, H. The Crystal Structures of
Tetra-n-Butylammonium Salts of GaCl− , GaBr−4 and GaI− . J. Coord.
4
4
Chem. 2003, 56, 1567−1574.
(24) Novikov, R. A.; Borisov, D. D.; Tarasova, A. V.; Tkachev, Y. V.;
Tomilov, Y. V. Three-Component Gallium(III)-Promoted Addition
of Halide Anions and Acetylenes to Donor−Acceptor Cyclopropanes.
Angew. Chem., Int. Ed. 2018, 57, 10293−10298.
(25) Alberti, M. N.; Orfanopoulos, M. Concerning the Reactivity of
PTAD with Isomeric Dienes: The Mechanism of the Diels−Alder
Cycloaddition. Org. Lett. 2009, 11, 1659−1662.
(26) Chidley, T.; Vemula, N.; Carson, C. A.; Kerr, M. A.; Pagenkopf,
B. L. Cascade Reaction of Donor−Acceptor Cyclopropanes:
Mechanistic Studies on Cycloadditions with Nitrosoarenes and cis-
Diazenes. Org. Lett. 2016, 18, 2922−2925.
(27) (a) Narangoda, C. J.; Lex, T. R.; Moore, M. A.; McMillen, C.
D.; Kitaygorodskiy, A.; Jackson, J. E.; Whitehead, D. C. Accessing the
Rare Diazacyclobutene Motif. Org. Lett. 2018, 20, 8009−8013.
(b) Scott, L. T.; Erden, I.; Brunsvold, W. R.; Schultz, T. H.; Houk, K.
N.; Paddon-Row, M. N. Competitive [6 + 2], [4 + 2], and [2 + 2]
Cycloadditions. Experimental Classification of Two-Electron Cyclo-
addends. J. Am. Chem. Soc. 1982, 104, 3659−3664.
(28) Goncharova, I. K.; Silaeva, K. P.; Arzumanyan, A. V.; Anisimov,
A. A.; Milenin, S. A.; Novikov, R. A.; Solyev, P. N.; Tkachev, Y. V.;
Volodin, A. D.; Korlyukov, A. A.; Muzafarov, A. M. Aerobic Co-/N-
Hydroxysuccinimide-Catalyzed Oxidation of p-Tolylsiloxanes to p-
Carboxyphenylsiloxanes: Synthesis of Functionalized Siloxanes as
Promising Building Blocks for Siloxane-Based Materials. J. Am. Chem.
Soc. 2019, 141, 2143−2151.
(29) Tsedilin, A. M.; Fakhrutdinov, A. N.; Eremin, D. B.; Zalesskiy,
S. S.; Chizhov, A. O.; Kolotyrkina, N. G.; Ananikov, V. P. How
sensitive and accurate are routine NMR and MS measurements?
Mendeleev Commun. 2015, 25, 454−456.
(30) (a) Corey, E. J.; Chaykovsky, M. Dimethyloxosulfonium
Methylide ((CH3)2SOCH2) and Dimethylsulfonium Methylide
((CH3)2SCH2). Formation and Application to Organic Synthesis. J.
Am. Chem. Soc. 1965, 87, 1353−1364. (b) Pohlhaus, P. D.; Sanders, S.
D.; Parsons, A. T.; Li, W.; Johnson, J. S. Scope and Mechanism for
Lewis Acid-Catalyzed Cycloadditions of Aldehydes and Donor−
O
https://dx.doi.org/10.1021/acs.joc.0c02293
J. Org. Chem. XXXX, XXX, XXX−XXX