Radical-Cation Vinylcyclopropane Rearrangements by TiO2Photocatalysis

Article abstract of DOI:10.1021/acs.joc.0c00544

Radical cation vinylcyclopropane rearrangements by TiO2 photocatalysis in lithium perchlorate/nitromethane solution are described. The reactions are triggered by oxidative single electron transfer, which is followed by immediate ring-opening of the cyclopropanes to generate distonic radical cations as unique reactive intermediates. This approach can also be applied to vinylcyclobutane, leading to the construction of six-membered rings. A stepwise mechanism via distonic radical cations is proposed based on preliminary mechanistic studies, which is supported by density functional theory calculations.

Full text of DOI:10.1021/acs.joc.0c00544

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Article
Radical-Cation Vinylcyclopropane Rearrangements by TiO2 Photocatalysis
Naoya Maeta, Hidehiro Kamiya, and Yohei Okada
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00544 • Publication Date (Web): 01 Apr 2020
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by TiO Photocatalysis
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Naoya Maeta, Hidehiro Kamiya, and Yohei Okada*
Department of Chemical Engineering, Tokyo University of Agriculture and Technology, 2-24-16
Naka-cho, Koganei, Tokyo 184-8588, Japan
*
yokada@cc.tuat.ac.jp
ABSTRACT
Radical cation vinylcyclopropane rearrangements by TiO photocatalysis in lithium
2
perchlorate/nitromethane solution are described. The reactions are triggered by oxidative single
electron transfer, which is followed by immediate ring-opening of the cyclopropanes to generate
distonic radical cations as unique reactive intermediates. This approach can also be applied to
vinylcyclobutane, leading to the construction of six-membered rings. A stepwise mechanism via
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distonic radical cations is proposed based on preliminary mechanistic studies, which is supported
by DFT calculations.
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INTRODUCTION
Synthetic organic chemistry has developed in tandem with the advancement of catalysis, where
non- or less-reactive small molecules are activated to undergo chemical transformations.
Catalytic activation of small molecules can be carried out by enzymes, transition metals, Lewis
acids/bases, and organocatalysts. Among the simplest approaches is the use of a proton and/or
1
electron as a catalyst. While the addition or removal of a proton is well-documented in
textbooks as acid/base catalysis, the corresponding mode of small molecule activation using an
electron, referred to as redox catalysis, is somewhat less widespread. However, explosive growth
2
3
in the use of photochemical and electrochemical reactions in this field has recently established
the concept of redox catalysis, where reductive and/or oxidative single electron transfer (SET) is
involved. SET primarily produces radical ions from neutral closed shell small molecules,
offering distinctive reactivities that are difficult to achieve by neutral radicals or ions.
Understanding radical ion reactivities should lead to the design of novel chemical
transformations.
Distonic radical ions are transient species with formally separated radical and charge sites. They
potentially exhibit independent radical and ion reactivities, which may differ from typical radical
ions. However, distonic radical ions are not commonly used as reactive intermediates in the field
of synthetic organic chemistry, likely due to the lack of simple generation methods. In this
context, Yoon recently reported reductive SET-triggered formal [3 + 2] cycloadditions between
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cyclopropyl phenyl ketone (1) and styrene (2) by photocatalysis (Scheme 1). The distonic
•-) is proposed as a reactive intermediate, which is generated from the radical anion
radical ion (1
d
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(1 ) via immediate ring-opening, known as a radical clock reaction. In addition, Zheng reported
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oxidative SET-triggered formal [3 + 2] cycloadditions between N-cyclopropylaniline (3) and
styrene (2) by photocatalysis, where the distonic radical cation (3
•+) is likely to be involved as a
d
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reactive intermediate (Scheme 2). SET in combination with cyclopropyl ring-opening would be
a versatile approach to generate distonic radical ions.6
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We have been developing oxidative SET-triggered cycloadditions by photocatalysis and
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electrocatalysis. The use of lithium perchlorate (LiClO
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NO ) solution has
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facilitated the generation of radical cations from electron-rich alkenes and styrenes, providing
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unique reactive intermediates for carbon−carbon bond formations. We questioned whether the
distonic radical cation (4
•+) could be generated to realize formal [5 + 2] cycloadditions with
d
styrene (2) (Scheme 3). Described herein is our serendipitous finding that vinylcyclopropane
rearrangements can be triggered by oxidative SET, in which distonic radical cations are likely to
be involved as reactive intermediates.
Scheme 1. Reductive SET-Triggered [3 + 2] Cycloaddition.
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Scheme 2. Oxidative SET-Triggered [3 + 2] Cycloaddition.
Scheme 3. Working Hypothesis.
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RESULTS AND DISCUSSION
The present work began with the reaction of the vinylcyclopropane (4) with styrene (2) under
TiO
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photocatalysis conditions. Unfortunately, the reaction gave the corresponding [2 + 2]
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cycloadduct (6) instead of [5 + 2] cycloadduct (5) (Scheme 4). This outcome clearly suggests
•+
that while the radical cation (4 ) was indeed generated by the oxidative SET, it was not followed
by immediate ring-opening. This hypothesis was further confirmed by the fact that the reaction
with 2,3-dimethyl-1,3-butadiene (7) gave [4 + 2] cycloadduct (8) (Scheme 5).11
Scheme 4. [2 + 2] Cycloaddition of the Vinylcyclopropane (4).
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Scheme 5. [4 + 2] Cycloaddition of the Vinylcyclopropane (4).
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In order to facilitate the ring-opening, vinylcyclopropanes (9−11) with additional substituents
were synthesized and used for the reaction with styrene (2) (Table 1). The radical cations of the
vinylcyclopropanes (9−11) were expected to generate secondary, tertiary, or benzyl radicals via
ring-opening, respectively, which are more stable than primary radicals. Unfortunately, the
reactions of the vinylcyclopropanes (9, 10) gave the corresponding [2 + 2] cycloadducts (12, 13),
suggesting that ring-opening did not take place, despite the generation of radical cations (9•+,
•+
1
0 ) by oxidative SET. The reaction of vinylcyclopropane (11) also failed to give the [5 + 2]
cycloadduct, however, cyclopentene (14) was obtained in 72% yield.
Table 1. Reactions of Vinylcyclopropanes (9−11).
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These observations were supported by DFT calculations (Figure 1). In the optimized structures
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of the radical cations (4 , 9 , 10 , 11 ), the bond length between C
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and C in the cyclopropyl
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indicates that the ring-opening was most favored in the radical cation (11 ), which was in good
accordance with the experimental results.
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Figure 1. Optimized Structures and Spin Density Distributions of the Radical Cations (4•+, 9•+,
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When the reaction of the vinylcyclopropane (11) was carried out in the absence of styrene (2),
the yield of the cyclopentene (14) was significantly improved to 94% (Table 2, Entry 1). Control
studies showed that both TiO
2
and light were necessary for efficient conversion to the
/CH NO solution was essential for the
cyclopentene (14) (Entries 2−4) and the use of LiClO
4
3
2
reaction (Entries 5−7). The vinylcyclopropane rearrangement remained high-yielding even on a 1
mmol scale (Entry 8).
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Table 2. Optimization of the Conditions for the Vinylcyclopropane Rearrangement.
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To gain further mechanistic insights, the vinylcyclopropanes (15−17) were synthesized and used
for the reaction (Scheme 6). The reaction of the vinylcyclopropane (15), which has a
nonsubstituted phenyl ring, did not give the cyclopentene (18) under TiO photocatalysis
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conditions. On the other hand, the vinylcyclopropanes (16, 17) were efficiently converted into
the cyclopentenes (19, 20), suggesting that either or both aryl rings must be electron-rich. On the
basis of these results, a stepwise mechanism via distonic radical cations can be proposed
(Scheme 7). The reaction is triggered by oxidative SET, which is followed by immediate ring-
•+
opening to generate a distonic radical cation (D ). Intramolecular radical addition then gives a
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transient cyclopentenyl radical cation (C ). When either or both aryl rings are electron-rich, the
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cyclopentenyl radical cation (C ) is efficiently converted into the aryl radical cation (A ), which
affords the corresponding cyclopentenes by reductive SET.
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Scheme 6. Preliminary Mechanistic Studies.
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Scheme 7. Plausible Reaction Mechanism.
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DFT calculations supported a formal expression of the reaction mechanism (Figure 2). In the
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optimized structures of the radical cations (14 , 19 , 20 ), spin densities were mainly localized
in the aryl rings, suggesting that the aryl radical cations were more stable than the cyclopentenyl
radical cations in these cases. On the other hand, the spin density in the optimized structure of
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the radical cation (18 ) was distributed over the entire molecule, including the cyclopentenyl
moiety. Furthermore, the bond length between C and C in the cyclopentenyl framework was
found to be 1.67 Å, which was in good accordance with the formal mechanistic understanding.
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Figure 2. Optimized Structures and Spin Density Distributions of the Radical Cations (14 , 18 ,
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The scope of the aryl rings in the reaction was investigated using variously substituted
vinylcyclopropanes (Scheme 8). The positioning effect of the methoxy group in either aryl ring
was found to be similar, namely, ortho-substitutions (21, 23) were less effective than para-
variants (14, 19) and meta-substitutions (22, 24) were not productive. Installation of additional
methoxy groups (25, 26) had a negligible impact on the reaction, while the yields were finely
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tuned by using weak electron-donating methyl groups (27−32). When both aryl rings were
electron-rich, the corresponding cyclopentenes (20, 33−37) were obtained in high yields. Several
heteroarenes, except pyridine (41), and aryl halides were also found to be compatible with the
reaction to give the corresponding cyclopentenes (38−40, 42−45) in moderate to excellent yields.
Strong electron-withdrawing cyano and trifluoromethyl groups had a negative effect on the
reaction (46, 47), likely because the nucleophilicity of the benzyl radical was decreased,
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inhibiting the intramolecular radical additions (from D to C in Scheme 7). Indeed, when the
positions of the methoxy and trifluoromethyl groups were switched, the corresponding
cyclopentene (48) was obtained in high yield. It should be noted that the rearrangement of donor-
acceptor cyclopropanes (49, 50) did not take place, suggesting that the method described herein
12
would be complementary to previously reported Lewis acid-triggered versions. Furthermore,
vinylcyclobutane (51) was found to be productive under TiO photocatalysis conditions, offering
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a unique approach to access six-membered rings.
Scheme 8. Scope of the Vinylcyclopropane Rearrangements.
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CONCLUSION
1
1
1
1
1
1
1
1
1
1
2
2
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2
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2
2
2
2
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0
In conclusion, we have demonstrated that radical cation vinylcyclopropane rearrangements are
enabled by TiO photocatalysis in LiClO /CH NO solution. The reactions are triggered by
2
4
3
2
oxidative single electron transfer, followed by immediate ring-opening to generate distonic
radical cations. SET in combination with cyclopropyl ring-opening would be a versatile
approach to generate distonic radical ions, which can be used as unique reactive intermediates in
the field of synthetic organic chemistry. Furthermore, we found that this method can be applied
to vinylcyclobutane for accessing six-membered rings. A stepwise mechanism via distonic
radical cations can be proposed based on preliminary mechanistic studies, which are supported
by DFT calculations. Further experimental and theoretical studies of reactions involving SET in
combination with cycloalkyl ring-opening are under investigation in our laboratory.
EXPERIMENTAL SECTION
General Remarks. All reagents and solvents were purchased from commercial sources and used
without further purification. Reactions were monitored using thin-layer chromatography (TLC)
with silica gel plates, and detection by UV absorption (254 nm) and by heating the plates after
dipping them in a solution of 12 M molybdo(VI) phosphoric acid n-hydrate in 95% ethanol.
1
Silica gel (particle size 40−50 μm) was used for column chromatography. H nuclear magnetic
resonance (NMR) spectra were collected on a 500 MHz NMR spectrometer using the deuterated
solvent as an internal deuterium reference. Chemical shift data are given in 훿 units calibrated
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
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6
with residual protic solvent. The multiplicity of a signal is indicated as follows: s, singlet; d,
13
1
doublet; t, triplet; q, quartet; quint, quintet; m, multiplet. C{ H} NMR spectra were collected at
125 MHz with proton decoupling using the deuterated solvent as an internal carbon reference.
High-resolution mass spectra (HRMS) were collected using electrospray ionization (ESI) or
direct analysis in real-time (DART) time-of-flight (TOF) spectrometers.
0
1
2
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8
9
0
1
2
3
4
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8
9
0
1
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0
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9
0
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9
0
1
-(2-Cyclopropylvinyl)-4-methoxybenzene (4, cis : trans = 1 : 4). White solid. To a solution of
(4-methoxyphenylmethyl)triphenylphosphonium chloride (S1, 8.38 g, 20.0 mmol) in
tetrahydrofuran (60 mL) stirred at 0 °C was added potassium tert-butoxide (2.24 g, 20.0 mmol).
After the color turned red, the cyclopropanecarboxaldehyde (S2, 753 μL ,10.0 mmol) was added,
stirred at 0 °C until the starting material was consumed (checked by thin layer chromatography),
diluted with water, and extracted with ethyl acetate. The combined organic layers were dried
over sodium sulfate, filtered, and concentrated in vacuo. Silica gel column chromatography
1
(hexane/ethyl acetate = 50/1) gave the titled compound (4, 1.31 g, 7.60 mmol) in 76% yield. H
NMR (CDCl
3
, 500 MHz) δ 7.23 (2H, d, J = 8.6 Hz), 6.81 (2H, d, J = 8.6 Hz), 6.41 (1H, d, J =
1
0
5
6.0 Hz), 5.59 (1H, dd, J = 16.0, 9.2 Hz), 3.78 (3H, s), 1.57-1.49 (1H, m), 0.84-0.77 (2H, m),
1
3
1
.49-0.44 (2H, m); C{ H} NMR (125 MHz, CDCl
3
) δ 158.4, 132.5, 130.6, 126.8, 126.6, 113.9,
+
5.1, 14.5, 7.1; HRMS m/z: [M + H] calcd for C12
H15O 175.1123; found 175.1110.
2
1
-Cyclopropyl-4'-methoxy-4,5-dimethyl-1,2,3,6-tetrahydro-1,1'-biphenyl (8, cis : trans = 1 :
2). Colorless oil (purified by silica gel column chromatography using hexane/ethyl acetate =
1
50/1). Product yield; 51% (determined by NMR), isolated in 46% (51 mg, 0.18 mmol). H NMR
(CDCl
3
, 500 MHz) δ 7.09 (2H, d, J = 8.6 Hz), 6.82 (2H, d, J = 8.6 Hz), 3.80 (3H, s), 2.65-2.59
(1H, m), 2.29-2.13 (2H, m), 2.07-1.99 (1H, m), 1.93-1.85 (1H, m), 1.64 (3H, s), 1.63 (3H, s),
1
.10-1.01 (1H, m), 0.45-0.37 (1H, m), 0.24-0.18 (1H, m), 0.07-0.01 (1H, m), -0.03- -0.09 (1H,
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1
m), -0.27- -0.32 (1H, m); C{ H} NMR (125 MHz, CDCl3) δ 157.7, 138.2, 128.8, 125.2, 125.2,
+
1
13.4, 55.3, 46.6, 44.4, 40.2, 37.9, 19.0, 18.8, 15.8, 5.0, 1.8 ; HRMS m/z: [M + H] calcd for
C
18
H
29
O 277.2168; found 277.2177.
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
3
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3
3
3
3
4
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0
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8
9
0
1-Methoxy-4-(2-(2-methylcyclopropyl)vinyl)benzene (9, cis : trans = 1 : 30 ). White solid. To
a solution of crotonic acid (S3, 2.58 g, 30 mmol) and N,O-dimethylhydroxylamine hydrochloride
(
4.39 g, 45.0 mmol) in dichloromethane (80 mL) stirred at room temperature were added N,N’-
diisopropylcarbodiimide (6.97 mL, 45.0 mmol), 4-dimethylaminopyridine (36.7 mg, 0.30 mmol),
and N,N-diisopropylethylamine (10.3 mL, 60.0 mmol). The resulting reaction mixture was stirred
at room temperature overnight, diluted with water, and extracted with dichloromethane. The
combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo.
Silica gel column chromatography (hexane/ethyl acetate = 1/1) gave the Weinreb amide (S4) in
6
0% yield (2.32 g, 18.0 mmol). To a solution of trimethylsulfoxonium iodide (7.92 g, 36.0
mmol) in dimethyl sulfoxide (80 mL) stirred with a water bath was added NaH (1.44 g, 36.0
mmol). The resulting reaction mixture was stirred with a water bath for 30 min, the Weinreb
amides (S4, 2.32 g, 18.0 mmol) was added. The resulting reaction mixture was stirred with a
water bath for 4 h, diluted with water, and extracted with ethyl acetate. The combined organic
layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel column
chromatography (hexane/ethyl acetate = 1/1) gave the cyclopropane (S5) in 78% yield (2.01 g,
1
4.0 mmol). To a solution of the cyclopropane (S5, 1.72 g, 12.0 mmol) in tetrahydrofuran (50
mL) stirred at 0 °C was added lithium aluminum hydride (683 mg, 18.0 mmol). The resulting
reaction mixture was stirred at 0 °C until the starting material was consumed (checked by thin
layer chromatography), diluted with water, and extracted with pentane. The combined organic
layers were dried over sodium sulfate, filtered, and used without further purification. To a
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solution of (4-methoxyphenylmethyl)triphenylphosphonium chloride (S1, 10.0 g, 24.0 mmol) in
tetrahydrofuran (60 mL) stirred at 0 °C was added potassium tert-butoxide (2.69 g, 24.0 mmol).
After the color turned red, the aldehyde (S6) was added, stirred at 0 °C until the starting material
was consumed (checked by thin layer chromatography), diluted with water, and extracted with
ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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8
9
0
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3
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9
0
concentrated in vacuo. Silica gel column chromatography (hexane/ethyl acetate = 50/1) gave the
1
titled compounds in 24% yield (542 mg, 2.90 mmol) over 2 steps. H NMR (CDCl
3
, 500 MHz) δ
7
1
.22 (2H, d, J = 8.6 Hz), 6.81 (2H, d, J = 8.6 Hz), 6.36 (1H, d, J = 16.0 Hz), 5.62 (1H, dd, J =
5.5, 8.6 Hz), 3.78 (3H, s), 1.25-1.19 (1H, m), 1.10 (3H, d, J = 5.7 Hz), 0.89-0.82 (1H, m), 0.68-
1
3
1
0.63 (1H, m), 0.57-0.52 (1H, m); C{ H} NMR (125 MHz, CDCl
3
) δ 158.4, 132.4, 130.7, 126.6,
17O 189.1279;
+
1
26.3, 113.9, 55.2, 23.4, 18.6, 15.6, 15.6; HRMS m/z: [M + H] calcd for C13
H
found 189.1258.
1
-Methoxy-4-(2-(2-methylcyclopropyl)vinyl)benzene (10, cis : trans = 1 : 7 ). White solid. To
a solution of the 2,2-dimethylcyclopropanecarboxylic acid (S7, 5.00 g, 43.8 mmol) and N,O-
dimethylhydroxylamine hydrochloride (5.85 g, 60.0 mmol) in dichloromethane (100 mL) stirred
at room temperature were added N,N’-diisopropylcarbodiimide (9.29 mL, 60.0 mmol), 4-
dimethylaminopyridine (48.9 mg, 0.40 mmol), and N,N-diisopropylethylamine (13.6 mL, 80
mmol). The resulting reaction mixture was stirred at room temperature overnight, diluted with
water, and extracted with dichloromethane. The combined organic layers were dried over sodium
sulfate, filtered, and concentrated in vacuo. Silica gel column chromatography (hexane/ethyl
acetate = 1/1) gave the Weinreb amide in 54 % yield (S8, 3.73 g, 23.7 mmol). To a solution of
the Weinreb amide (S8, 3.14 g, 20.0 mmol) in tetrahydrofuran (50 mL) stirred at 0 °C was added
lithium aluminum hydride (949 mg, 25.0 mmol). The resulting reaction mixture was stirred at
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°C until the starting material was consumed (checked by thin layer chromatography), diluted
with water, and extracted with pentane. The combined organic layers were dried over sodium
sulfate, filtered, and used without further purification. To a solution of (4-
1
1
1
1
1
1
1
1
1
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2
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0
methoxyphenylmethyl)triphenylphosphonium chloride (S1, 12.6 g, 30.0 mmol) in
tetrahydrofuran (80 mL) stirred at 0 °C was added potassium tert-butoxide (3.36 g, 30.0 mmol).
After the color turned red, the aldehyde (S9) was added, stirred at 0 °C until the starting material
was consumed (checked by thin layer chromatography), diluted with water, and extracted with
ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and
concentrated in vacuo. Silica gel column chromatography (hexane/ethyl acetate = 50/1) gave the
1
titled compound (10) in 12% yield (485 mg, 2.40 mmol) over 2 steps. H NMR (CDCl
3
, 500
MHz) δ 7.25 (2H, d, J = 8.6 Hz), 6.82 (2H, d, J = 8.6 Hz), 6.40 (1H, d, J = 16.0 Hz), 5.84 (1H,
dd, J = 16.0, 9.2 Hz), 3.79 (3H, s), 1.42-1.36 (1H, m), 1.12 (3H, s), 1.11 (3H, s), 0.74 (1H, dd, J
1
3
1
= 8.6, 4.6 Hz), 0.46 (1H, t, J = 5.2 Hz); C{ H} NMR (125 MHz, CDCl
3
) δ 158.5, 130.9, 129.4,
+
1
2
28.6, 126.7, 113.9, 55.3, 28.5, 27.2, 22.1, 20.8, 19.4; HRMS m/z: [M + H] calcd for C14
19
H O
03.1436; found 203.1428.
General Procedure for the Synthesis of the Vinylcyclopropanes (11, 15−17, S17−S44). To a
solution of malonic acid (S10, 6.25 g, 60.0 mmol) and the respective benzaldehyde (S11, 30.0
mmol) in pyridine (80 mL) stirred at 130 °C was added piperidine (3 mL). The resulting reaction
mixture was stirred at 130 °C for 5 h, acidified with 1 M HCl aq., diluted with water, and
extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate,
filtered, concentrated in vacuo, and used without further purification. To a solution of the
respective substituted cinnamic acids (S12) and N,O-dimethylhydroxylamine hydrochloride
(4.39 g, 45.0 mmol) in dichloromethane (80 mL) stirred at room temperature were added N,N’-
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diisopropylcarbodiimide (6.97 mL, 45.0 mmol), 4-dimethylaminopyridine (36.7 mg, 0.30 mmol),
and N,N-diisopropylethylamine (10.3 mL, 60.0 mmol). The resulting reaction mixture was stirred
at room temperature overnight, diluted with water, and extracted with dichloromethane. The
combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo.
Silica gel column chromatography (hexane/ethyl acetate = 2/1−1/2) gave the respective Weinreb
amides (S13) in 38−66% yield over 2 steps. To a solution of trimethylsulfoxonium iodide (4.84 g,
0
1
2
3
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5
6
7
8
9
0
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9
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2
2
2.0 mmol) in dimethyl sulfoxide (60 mL) stirred with a water bath was added NaH (880 mg,
2.0 mmol). The resulting reaction mixture was stirred with a water bath for 30 min, the
respective Weinreb amides (S13, 11.0 mmol) was added. The resulting reaction mixture was
stirred with a water bath for 4 h, diluted with water, and extracted with ethyl acetate. The
combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo.
Silica gel column chromatography (hexane/ethyl acetate = 2/1−1/2) gave the respective
cyclopropanes (S14) in 76−84% yield. To a solution of the respective cyclopropanes (S14, 8.00
mmol) in tetrahydrofuran (50 mL) stirred at 0 °C was added lithium aluminum hydride (380 mg,
1
0.0 mmol). The resulting reaction mixture was stirred at 0 °C until the starting material was
consumed (checked by thin layer chromatography), diluted with water, and extracted with ethyl
acetate. The combined organic layers were dried over sodium sulfate, filtered, and used without
further purification. To a solution of the respective (arylmethyl)triphenylphosphonium halides
(S16, 16.0 mmol) in tetrahydrofuran (60 mL) stirred at 0 °C was added potassium tert-butoxide
(1.80 g, 16.0 mmol). After the color turned red, the respective aldehydes (S15) was added, stirred
at 0 °C until the starting material was consumed (checked by thin layer chromatography), diluted
with water, and extracted with ethyl acetate. The combined organic layers were dried over
sodium sulfate, filtered, and concentrated in vacuo. Silica gel column chromatography
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(
hexane/ethyl acetate = 50/1−10/1) gave the titled compounds (11, 15−17, S17−S44) in 24−65%
yield over 2 steps.
1
-Methoxy-4-(2-(2-phenylcyclopropyl)vinyl)benzene (11, cis : trans = 1 : 3). White solid
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
3
3
3
3
4
4
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4
4
4
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5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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5
6
7
8
9
0
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4
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8
9
0
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2
3
4
5
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8
9
0
1
(purified by silica gel column chromatography using hexane/ethyl acetate = 50/1). H NMR
(CDCl
3
, 500 MHz) δ 7.31-7.23 (4H, m), 7.16 (1H, t, J = 7.5 Hz), 7.09 (2H, d, J = 8.6 Hz), 6.83
(2H, d, J = 8.6 Hz), 6.43 (1H, d, J = 16.0 Hz), 5.78 (1H, dd, J = 16.0, 8.6 Hz), 3.80 (3H, s), 2.04-
1
3
1
1.99 (1H, m), 1.84-1.78 (1H, m), 1.32-1.26 (1H, m), 1.23-1.18 (1H, m); C{ H} NMR (125
MHz, CDCl
3
) δ 158.6, 142.3, 130.6, 130.3, 128.4, 127.7, 126.8, 125.6, 125.6, 113.9, 55.2, 27.5,
+
2
5.6, 17.1; HRMS m/z: [M + H] calcd for C18
H19O 251.1436; found 251.1441.
2
-(2-Phenylcyclopropyl)vinylbenzene (15, cis : trans = 1 : 4). White solid (purified by silica
1
gel column chromatography using hexane/ethyl acetate = 50/1). H NMR (CDCl
3
, 500 MHz) δ
7
.38-7.22 (6H, m), 7.21-7.13 (2H, m), 7.12-7.04 (2H, m), 6.47 (1H, d, J = 15.5 Hz), 5.90 (1H, dd,
J = 15.5, 8.6 Hz), 2.06-2.00 (1H, m), 1.86-1.79 (1H, m), 1.34-1.26 (1H, m), 1.25-1.18 (1H, m);
1
3
1
C{ H} NMR (125 MHz, CDCl
3
) δ 142.1, 137.5, 132.8, 128.5, 128.4, 128.3, 128.3, 126.8, 125.7,
+
1
25.6, 27.5, 25.7, 17.2; HRMS m/z: [M + H] calcd for C17
H17 221.1330; found 221.1341.
1
-Methoxy-4-(2-styrylcyclopropyl)benzene (16, cis : trans = 1 : 4). White solid (purified by
1
silica gel column chromatography using hexane/ethyl acetate = 50/1). H NMR (CDCl
3
, 500
MHz) δ 7.34-7.25 (4H, m), 7.21-7.16 (1H, m), 7.03 (2H, d, J = 8.6 Hz), 6.83 (2H, d, J = 8.6 Hz),
6
1
1
.47 (1H, d, J = 16.0 Hz), 5.90 (1H, dd, J = 15.5, 8.6 Hz), 3.78 (3H, s), 2.03-1.97 (1H, m), 1.79-
1
3
1
.72 (1H, m), 1.28-1.21 (1H, m), 1.19-1.14 (1H, m); C{ H} NMR (125 MHz, CDCl ) δ 157.8,
3
37.6, 134.0, 133.1, 128.5, 128.0, 126.8, 126.7, 125.6, 113.8, 55.2, 27.0, 25.0, 16.7; HRMS m/z:
+
[
M + H] calcd for C18
H19O 251.1436; found 251.1435.
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1
-Methoxy-4-(2-(2-(4-methoxyphenyl)cyclopropyl)vinyl)benzene (17, cis : trans = 1 : 4).
White solid (purified by silica gel column chromatography using hexane/ethyl acetate = 20/1).
1H NMR (CDCl
3
, 500 MHz) δ 7.25 (2H, d, J = 8.6 Hz), 7.03 (2H, d, J = 8.6 Hz), 6.83 (4H, d, J =
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
8
2
.6 Hz), 6.42 (1H, d, J = 15.5 Hz), 5.76 (1H, dd, J = 15.5, 8.6 Hz), 3.80 (3H, s), 3.78 (3H, s),
1
3
1
.00-1.95 (1H, m), 1.76-1.69 (1H, m), 1.25-1.19 (1H, m), 1.17-1.12 (1H, m); C{ H} NMR (125
MHz, CDCl
3
) δ 158.6, 157.8, 134.3, 130.9, 130.5, 129.9, 128.8, 126.8, 114.0, 113.9, 55.4, 55.3,
+
2
7.0, 24.9, 16.6; HRMS m/z: [M + H] calcd for C19
H
21
2
O 281.1542; found 281.1541.
1
-Methoxy-2-(2-(2-phenylcyclopropyl)vinyl)benzene (S17, cis : trans = 1 : 15). White solid
(purified by silica gel column chromatography using hexane/ethyl acetate = 50/1).
1H NMR (CDCl
2H, m), 7.10 (2H, dd, J = 8.6, 1.7 Hz), 6.90 (1H, t, J = 7.5 Hz), 6.85 (1H, d, J = 8.0 Hz), 6.80
(1H, d, J = 15.5 Hz), 5.91 (1H, dd, J = 16.0, 8.6 Hz), 3.84 (3H, s), 2.06-2.01 (1H, m), 1.90-1.84
, 500 MHz) δ 7.38 (1H, dd, J = 7.5, 1.2 Hz), 7.27 (2H, t, J = 7.5 Hz), 7.20-7.14
3
(
13
1
(1H, m), 1.33-1.29 (1H, m), 1.25-1.20 (1H, m); C{ H} NMR (125 MHz, CDCl
3
) δ 156.1, 142.3,
1
33.6, 128.4, 127.8, 126.5, 126.2, 125.7, 125.6, 123.0, 120.6, 110.7, 55.4, 28.1, 25.8, 17.4;
+
HRMS m/z: [M + H] calcd for C18H19O 251.1436; found 251.1432.
1-Methoxy-3-(2-(2-phenylcyclopropyl)vinyl)benzene (S18, cis : trans = 1 : 10). White solid
(purified by silica gel column chromatography using hexane/ethyl acetate = 50/1).
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8
9
0
1H NMR (CDCl
, 500 MHz) δ 7.28 (2H, t, J = 7.5 Hz), 7.20 (1H, t, J = 8.0 Hz), 7.17 (1H, t, J =
3
7
.5 Hz), 7.10 (2H, d, J = 7.5 Hz), 6.92 (1H, d, J = 8.0 Hz), 6.85 (1H, m), 6.75 (1H, dd, J = 8.0,
2.3 Hz), 6.45 (1H, d, J = 16.0 Hz), 5.90 (1H, dd, J = 16.0, 8.6 Hz), 3.81 (3H, s), 2.05 (1H, m),
1
3
1
1
1
.83 (1H, m), 1.33 (1H, m), 1.23 (1H, m); C{ H} NMR (125 MHz, CDCl ) δ 159.8, 142.0,
3
38.9, 133.2, 129.5, 128.3, 128.1, 125.6, 125.6, 118.3, 112.3, 111.0, 55.0, 27.5, 25.7, 17.1;
+
HRMS m/z: [M + H] calcd for C18
H19O 251.1436; found 251.1424.
1-Methoxy-2-(2-styrylcyclopropyl)benzene (S19, cis : trans = 1 : 10). White solid (purified by
silica gel column chromatography using hexane/ethyl acetate = 50/1).
1H NMR (CDCl
m), 6.92-6.83 (3H, m), 6.49 (1H, d, J = 16.0 Hz), 5.96 (1H, dd, J = 15.5, 8.6 Hz), 3.85 (3H, s),
, 500 MHz) δ 7.33 (2H, d, J = 6.9 Hz), 7.29 (2H, t, J = 7.5 Hz), 7.20-7.13 (2H,
3
1
3
1
2
.39-2.34 (1H, m), 1.83-1.77 (1H, m), 1.31-1.24 (1H, m), 1.21-1.15 (1H, m); C{ H} NMR (125
MHz, CDCl
3
) δ 158.4, 138.1, 133.9, 130.7, 129.0 128.4, 127.1, 127.0, 126.2, 125.1, 121.0, 110.7,
+
5
5.8, 26.7, 20.2, 16.5; HRMS m/z: [M + H] calcd for C18
H19O 251.1436; found 251.1450.
1
-Methoxy-3-(2-styrylcyclopropyl)benzene (S20, cis : trans = 1 : 5). White solid (purified by
silica gel column chromatography using hexane/ethyl acetate = 50/1).
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The Journal of Organic Chemistry
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1H NMR (CDCl
, 500 MHz) δ 7.37-7.26 (4H, m), 7.22-7.16 (2H, m), 6.74-6.68 (2H, m), 6.65-
3
6
.64 (1H, m), 6.48 (1H, d, J = 16.0 Hz), 5.90 (1H, dd, J = 15.5, 8.6 Hz), 3.80 (3H, s), 2.05-1.99
1
3
1
(1H, m), 1.97-1.80 (1H, m), 1.35-1.29 (1H, m), 1.24-1.19 (1H, m); C{ H} NMR (125 MHz,
CDCl
3
) δ 159.6, 143.7, 137.3, 132.5, 129.2, 128.4, 128.2, 126.6, 125.6, 117.8, 111.6, 110.7, 54.7,
+
2
7.4, 25.6, 17.0; HRMS m/z: [M + H] calcd for C18
H19O 251.1436; found 251.1442.
2
,4-Dimethoxy-1-(2-(2-phenylcyclopropyl)vinyl)benzene (S21, cis : trans = 1 : 3). White solid
(purified by silica gel column chromatography using hexane/ethyl acetate = 20/1).
1H NMR (CDCl
, 500 MHz) δ 7.30-7.26 (2H, m), 7.26-7.22 (1H, m), 7.15 (1H, t, J = 7.5 Hz),
.09 (2H, dd, J = 8.0, 1.2 Hz), 6.70 (1H, d, J = 15.5 Hz), 6.47-6.42 (2H, m), 5.81 (1H, dd, J =
6.0, 8.6 Hz), 3.82 (3H, s), 3.80 (3H, s), 2.04-1.98 (1H, m), 1.87-1.80 (1H, m), 1.28 (1H, dt, J =
3
7
1
8
1
3
1
.6, 5.2 Hz), 1.21 (1H, dt, J = 8.6, 5.2); C{ H} NMR (125 MHz, CDCl ) δ 160.0, 157.4, 142.7,
3
131.6, 128.5, 127.0, 125.8, 125.6, 122.9, 119.8, 104.9, 98.6, 55.6, 55.5, 28.2, 25.9, 17.4; HRMS
+
m/z: [M + H] calcd for C19
H
20
2
O 281.1542; found 281.1512.
1
,3,5-Trimethoxy-2-(2-(2-phenylcyclopropyl)vinyl)benzene (S22, cis : trans = 1 : 10). White
solid (purified by silica gel column chromatography using hexane/ethyl acetate = 10/1).
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8
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0
1H NMR (CDCl
, 500 MHz) δ 7.29-7.22 (2H, m), 7.14 (1H, t, J = 7.5 Hz), 7.09 (2H, dd, J = 8.6,
3
1
3
=
.7 Hz), 6.71 (1H, d, J = 16.0 Hz), 6.20 (1H, dd, J = 16.0, 8.6 Hz), 6.13 (2H, s), 3.82 (6H, s),
.81 (3H, s), 2.04-1.98 (1H, m), 1.85-1.78 (1H, m), 1.27 (1H, dt, J = 8.0, 5.2 Hz), 1.20 (1H, dt, J
13
1
8.6, 5.2 Hz); C{ H} NMR (125 MHz, CDCl
3
) δ 159.2, 158.5, 142.5, 134.0, 128.0, 125.3,
+
1
25.1, 118.4, 107.6, 90.4, 55.3, 54.8, 29.2, 25.5, 17.2; HRMS m/z: [M + H] calcd for C20
H
22
O
3
310.1569; found 310.1572.
1
-Methyl-4-(2-(2-phenylcyclopropyl)vinyl)benzene (S23, cis : trans = 1 : 8). White solid
(purified by silica gel column chromatography using hexane/ethyl acetate = 50/1).
1H NMR (CDCl
, 500 MHz) δ 7.28 (2H, t, J = 7.7 Hz), 7.21 (2H, d, J = 8.0 Hz), 7.16 (1H, t, J =
3
6
.9 Hz), 7.11-7.07 (4H, m), 6.45 (1H, d, J = 16.0 Hz), 5.86 (1H, dd, J = 15.5, 8.6 Hz), 2.32 (3H,
1
3
1
s), 2.05-2.00 (1H, m),1.85-1.79 (1H, m), 1.33-1.28 (1H, m), 1.23-1.19 (1H, m); C{ H} NMR
(125 MHz, CDCl
3
) δ 142.2, 136.4, 134.7, 131.7, 129.2, 128.4, 128.2, 125.7, 125.6, 27.6, 25.7,
+
2
1.2, 17.2; HRMS m/z: [M + H] calcd for C18
H19 235.1487; found 235.1496.
2
,4-Dimethyl-1-(2-(2-phenylcyclopropyl)vinyl)benzene (S24, cis : trans = 1 : 6). White solid
(purified by silica gel column chromatography using hexane/ethyl acetate = 50/1).
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The Journal of Organic Chemistry
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1H NMR (CDCl
, 500 MHz) δ 7.31-7.26 (3H, m), 7.17 (1H, t, J = 8.6 Hz), 7.10 (2H, dd, J = 8.0,
3
1.2 Hz), 6.99-6.92 (2H, m), 6.65 (1H, d, J = 16.0 Hz), 5.72 (1H, dd, J = 15.5, 8.6 Hz), 2.30 (3H,
s), 2.29 (3H, s), 2.05-1.99 (1H, m), 1.89-1.83 (1H, m), 1.34-1.29 (1H, m), 1.24-1.19 (1H, m);
1
3
1
C{ H} NMR (125 MHz, CDCl
3
) δ 142.2, 136.2, 134.5, 133.6, 133.0, 131.0, 128.3, 126.8, 125.9,
+
125.6, 125.5, 124.9, 27.9, 25.7, 21.0, 19.8, 17.3; HRMS m/z: [M + H] calcd for C19
H
21
2
49.1643; found 249.1647.
1
,3,5-Trimethyl-2-(2-(2-phenylcyclopropyl)vinyl)benzene (S25, cis : trans = 1 : 9). White
solid (purified by silica gel column chromatography using hexane/ethyl acetate = 50/1).
1H NMR (CDCl
.5 Hz), 6.85 (2H, s), 6.40 (1H, d, J = 16.0 Hz), 5.36 (1H, dd, J = 16.6, 8.6 Hz), 2.27 (6H, s),
2.26 (3H, s), 2.01-1.95 (1H, m), 1.91-1.84 (1H, m), 1.27 (1H, dt, J = 8.6, 5.2 Hz), 1.18 (1H, dt, J
, 500 MHz) δ 7.29 (2H, t, J = 7.5 Hz), 7.18 (1H, t, J = 7.5 Hz), 7.11 (2H, d, J =
3
7
13
1
=
9.2, 5.2 Hz); C{ H} NMR (125 MHz, CDCl
3
) δ 142.5, 137.2, 135.8, 135.8, 135.6, 134.1,
+
1
28.6, 128.4, 125.6, 125.6, 27.5, 25.3, 21.1, 21.0, 17.1; HRMS m/z: [M + H] calcd for C20
H
23
263.1800; found 263.1784.
1-Methyl-4-(2-styrylcyclopropyl)benzene (S26, cis : trans = 1 : 4). White solid (purified by
silica gel column chromatography using hexane/ethyl acetate = 50/1).
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1H NMR (CDCl
, 500 MHz) δ 7.37-7.26 (4H, m), 7.18 (1H, t, J = 6.8 Hz), 7.09 (2H, d, J = 8.0
3
Hz), 7.00 (2H, d, J = 8.0 Hz), 6.47 (1H, d, J = 16.0 Hz), 5.90 (1H, dd, J = 16.0, 8.6 Hz), 2.32 (3H,
s), 2.04-1.98 (1H, m), 1.82-1.76 (1H, m), 1.29 (1H, dt, J = 8.6, 5.2 Hz), 1.19 (1H, dt, J = 8.6, 5.2
13
1
Hz); C{ H} NMR (125 MHz, CDCl
3
) δ 139.1, 137.6, 135.3, 133.1, 129.1, 128.6, 128.1, 126.8,
+
125.7, 125.7, 27.3, 25.5, 21.0, 17.0; HRMS m/z: [M + H] calcd for C18
H19 235.1487; found
2
35.1506.
2
,4-Dimethyl-1-(2-styrylcyclopropyl)benzene (S27, cis : trans = 1 : 8). White solid (purified
by silica gel column chromatography using hexane/ethyl acetate = 50/1).
1H NMR (CDCl
, 500 MHz) δ 7.36 (2H, m), 7.29 (2H, t, J = 7.5 Hz), 7.18 (1H, t, J = 7.5 Hz),
.99-6.98 (1H, m), 6.96-6.90 (1H, d, J = 15.5 Hz), 5.98 (1H, dd, J = 15.5, 8.6 Hz), 2.36 (3H, s),
.29 (3H, s), 2.04-1.98 (1H, m), 1.69-1.61 (1H, m), 1.34-1.29 (1H, m), 1.14 (1H, dt, J = 8.6, 5.2
3
6
2
13
1
Hz); C{ H} NMR (125 MHz, CDCl
3
) δ 137.8, 137.6, 136.8, 135.5, 133.6, 130.6, 128.6, 128.0,
+
1
26.7, 126.4, 125.8, 125.7, 25.3, 23.7, 21.0, 19.8, 14.9; HRMS m/z: [M + H] calcd for C19
H
21
249.1643; found 249.1664.
1
,3,5-Trimethyl-2-(2-styrylcyclopropyl)benzene (S28, cis : trans = 1 : 6). White solid
(purified by silica gel column chromatography using hexane/ethyl acetate = 50/1).
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1H NMR (CDCl
, 500 MHz) δ 7.41 (2H, m), 7.30 (2H, t, J = 7.5 Hz), 7.19 (1H, t, J = 7.5 Hz),
3
6
1
.84 (2H, s), 6.56 (1H, d, J = 16.0 Hz), 5.98 (1H, dd, J = 16.0, 9.2 Hz), 2.37 (6H, s), 2.26 (3H, s),
13
1
.87-1.81 (1H, m), 1.69-1.61 (1H, m), 1.27-1.22 (1H, m), 1.12-1.06 (1H, m); C{ H} NMR (125
MHz, CDCl
3
) δ 138.8, 137.7, 135.9, 135.0, 133.8, 128.8, 128.6, 128.3, 126.8, 125.8, 25.4, 22.4,
+
20.9, 20.9, 17.5; HRMS m/z: [M + H] calcd for C20
H23 263.1800; found 263.1790.
2
,4-Dimethoxy-1-(2-(4-methoxystyryl)cyclopropyl)benzene (S29, cis : trans = 1 : 3). White
solid (purified by silica gel column chromatography using hexane/ethyl acetate = 10/1).
1H NMR (CDCl
, 500 MHz) δ 7.26 (2H, d, J = 8.6 Hz), 6.83 (2H, d, J = 8.6 Hz), 6.81-6.77 (1H,
3
m), 6.47-6.42 (2H, m), 6.42 (1H, d, J = 16.0 Hz), 5.82 (1H, dd, J = 15.5, 8.6 Hz), 3.81 (3H, s),
3.79 (3H, s), 3.78 (3H, s), 2.23-2.15 (1H, m), 1.73-1.66 (1H, m), 1.19 (1H, dt, J = 8.6, 5.2 Hz),
13
1
1
1
.09 (1H, dt, J = 8.6, 5.2 Hz); C{ H} NMR (125 MHz, CDCl ) δ 159.0, 158.8, 158.5, 131.5,
3
29.9, 127.2, 126.7, 125.5, 122.9, 113.9, 104.0, 98.5, 55.5, 55.3, 55.2, 25.5, 19.4, 15.5; HRMS
+
m/z: [M + H] calcd for C20
H
23
3
O 311.1647; found 311.1667.
1,3,5-Trimethoxy-2-(2-(4-methoxystyryl)cyclopropyl)benzene (S30, cis : trans = 1 : 6). White
solid (purified by silica gel column chromatography using hexane/ethyl acetate = 10/1).
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0
1H NMR (CDCl
, 500 MHz) δ 7.27 (2H, d, J = 8.6 Hz), 6.83 (2H, d, J = 8.6 Hz), 6.45 (1H, d, J =
3
16.0 Hz), 6.12 (2H, s), 5.84 (1H, dd, J = 15.5, 8.6 Hz), 3.80 (12H, s), 2.02-1.95 (1H, m), 1.90-
1
3
1
1
1
.84 (1H, m), 1.43-1.38 (1H, m), 1.05-1.00 (1H, m); C{ H} NMR (125 MHz, CDCl ) δ 160.0,
3
59.2, 158.4, 132.8, 131.0, 129.8, 126.7, 113.9, 109.9, 91.0, 55.8, 55.3, 55.3, 23.4, 16.6, 15.2;
+
HRMS m/z: [M + H] calcd for C21
H
25
4
O 341.1753; found 341.1743.
1-Methoxy-4-(2-(2-(p-tolyl)cyclopropyl)vinyl)benzene (S31, cis : trans = 1 : 5). White solid
purified by silica gel column chromatography using hexane/ethyl acetate = 50/1).
(
1H NMR (CDCl
.0 Hz), 6.82 (2H, d, J = 8.6 Hz), 6.41 (1H, d, J = 16.0 Hz), 5.76 (1H, dd, J = 15.5, 8.6 Hz), 3.78
, 500 MHz) δ 7.24 (2H, d, J = 8.6 Hz), 7.08 (2H, d, J = 8.0 Hz), 6.98 (2H, d, J =
3
8
1
3
1
(
3H, s), 2.01-1.95 (1H, m), 1.79-1.72 (1H, m), 1.28-1.22 (1H, m), 1.18-1.13 (1H, m); C{ H}
NMR (125 MHz, CDCl
3
) δ 158.6, 139.2, 135.0, 130.7, 130.4, 129.0, 127.5, 126.8, 125.6, 113.9,
+
5
5.1, 27.3, 25.3, 21.0, 16.8; HRMS m/z: [M + H] calcd for C19
H21O 265.1592; found 265.1591.
1
-(2-(4-Methoxystyryl)cyclopropyl)-2,4-dimethylbenzene (S32, cis : trans = 1 : 4). White
solid (purified by silica gel column chromatography using hexane/ethyl acetate = 50/1).
ACS Paragon Plus Environment
2
9