Intermolecular [2+2] photocycloaddition of chalcones with 2,3-dimethyl-1,3-butadiene under neat reaction conditions

Article abstract of DOI:10.1016/j.tet.2018.09.060

The intermolecular [2 + 2] photocycloaddition of chalcones with 2,3-dimethyl-1,3-butadiene under visible-light irradiation for the synthesis of cyclobutane derivatives has been developed. Without using any photosensitizer, metallic catalyst and solvent, the reaction proceeded with high regioselectivity and moderate to high stereoselectivity. Mild reaction conditions and no additives make the reaction easy to operate. Control experiments and density functional theory (DFT) computations demonstrated that the reaction takes place via visible-light activation of chalcones, which is different from the previously reported [2 + 2] cycloaddition of chalcones.

Full text of DOI:10.1016/j.tet.2018.09.060

Accepted Manuscript
Intermolecular [2+2] photocycloaddition of chalcones with 2,3-dimethyl-1,3-butadiene
under neat reaction conditions
Fang Tang, Li Tang, Zhi Guan, Yan-Hong He
PII:
S0040-4020(18)31169-4
10.1016/j.tet.2018.09.060
TET 29833
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 6 August 2018
Revised Date: 25 September 2018
Accepted Date: 30 September 2018
Please cite this article as: Tang F, Tang L, Guan Z, He Y-H, Intermolecular [2+2] photocycloaddition
of chalcones with 2,3-dimethyl-1,3-butadiene under neat reaction conditions, Tetrahedron (2018), doi:
https://doi.org/10.1016/j.tet.2018.09.060.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
The visible-light-promoted intermolecular [2+2] cycloaddition of chalcones with
2,3-dimethyl-1,3-butadiene for the synthesis of cyclobutane derivatives is described.

ACCEPTED MANUSCRIPT
Intermolecular [2+2] photocycloaddition of chalcones with
2,3-dimethyl-1,3-butadiene under neat reaction conditions
Fang Tang, Li Tang, Zhi Guan*, Yan-Hong He*
Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and
Chemical Engineering, Southwest University, Chongqing 400715, China
E-mails: guanzhi@swu.edu.cn (for Z. Guan); heyh@swu.edu.cn (for Y.-H. He)
Abstract:
The
intermolecular
[2+2]
photocycloaddition
of
chalcones
with
2,3-dimethyl-1,3-butadiene under visible-light irradiation for the synthesis of cyclobutane
derivatives has been developed. Without using any photosensitizer, metallic catalyst and solvent,
the reaction proceeded with high regioselectivity and moderate to high stereoselectivity. Mild
reaction conditions and no additives make the reaction easy to operate. Control experiments and
density functional theory (DFT) computations demonstrated that the reaction takes place via
visible-light activation of chalcones, which is different from the previously reported [2+2]
cycloaddition of chalcones.
Key words: visible-light, [2+2] cycloaddition, solvent- and catalyst-free, cyclobutane derivatives,
chalcone, 2,3-dimethyl-1,3-butadiene
1. Introduction
As fossil-fuel energy resources are shrinking rapidly and air pollution is getting worse, it is
urgent to seek and utilize energy sources that are sustainable and environmentally friendly.1
Visible-light as a clean, cheap, and endlessly renewable energy source has drawn significant
attention from chemists.2 Photochemical reactions can enable the formation of special molecular
structures that are usually difficult to accomplish by traditional means.3 Photochemical substrates
can be activated by light without additional reagents, which reduces the generation of byproducts,
making it attractive in green synthetic chemistry.2a Cyclobutane subunits occur in a large amount
1

ACCEPTED MANUSCRIPT
of complex natural products,4 and cyclobutanes are important intermediates for the synthesis of
many organic compounds.5 The ring strain of a four-membered ring makes it easy to be opened or
expanded to a larger ring system.6 Thus, the research on the construction of cyclobutane
backbones is an indispensable part of organic synthesis.7 One of the most synthetically direct and
common methods is a photochemical [2+2] cycloaddition reaction. In addition to ultraviolet (UV)
which is traditionally used to promote [2+2] cycloaddition, visible-light is also an effective means
for the construction of four-membered ring compounds.6, 8 Visible-light is more easily available
than UV and it has advantages when used for the synthesis of compounds that are sensitive to
photodegradation under UV irradiation. Because of these features, visible-light has a broader
range of applications than UV in organic synthesis.9
Chalcones are naturally occurring α,β-unsaturated carbonyl compounds10 widely distributed in
plants. Due to the convenience of synthesis, a large number of chalcone derivatives have been
prepared. Many natural and synthetic chalcones have been demonstrated to exhibit various
biological activities.11 For example, methyl chalcone has been sold as an essential oil, and
sofalcone has been used as a mucosal protective drug.12 Therapeutic application of chalcones can
be traced back thousands of years by using herbs to treat different diseases.11b, 13
The cycloaddition of α,β-unsaturated carbonyl compounds with olefins is an important type of
reaction for the construction of cyclobutanes. However, relatively few works have been reported
on the intermolecular [2+2] cycloaddition of chalcones with olefins. In 2016, Yoon and coworkers
reported a chiral Lewis acid complex-catalyzed triplet energy transfer from an electronically
excited photosensitizer, and they applied this strategy to enantioselective [2 + 2]
photocycloadditions of 2'-hydroxychalcones by using Ru(bpy)3(PF6)2 as a sensitizer, in which
Lewis acid coordination lowers the triplet energy of the chalcone substrate.14 In 1998, Toda and
coworkers reported the intermolecular [2+2] cycloaddition of chalcones in the molten state
irradiated by a 400 W high-pressure Hg lamp.15a In 2017, Wu and coworkers reported the
intermolecular [2+2] cycloaddition of chalcones and cinnamic acid derivatives in dichloroethane,
using fac-tris(2-phenylpyridinato-C2,N) iridium as a photosensitizer, in which triplet chalcones
and cinnamic acid derivatives were produced by energy transfer.15b
2

ACCEPTED MANUSCRIPT
Herein, we report the intermolecular [2+2] cycloaddition of chalcones with
2,3-dimethyl-1,3-butadiene for the synthesis of functionalized cyclobutanes under the irradiation
of visible-light at room temperature under neat reaction conditions. The corresponding products
were obtained in yields of up to 72% with high regioselectivity and moderate to high
stereoselectivity. Mild reaction conditions and no additives make the reaction easy to operate.
Control experiments and density functional theory (DFT) computations demonstrated that the
reaction takes place via visible-light activation of chalcones.
2. Results and discussion
Initially, the model reaction of chalcone (1a, 0.3 mmol) with 2,3-dimethyl-1,3-butadiene (2, 1.0
mmol) was performed at room temperature under irradiation of a 32 W compact fluorescent light
(CFL) bulb. Several commonly used solvents were screened, and the results are shown in Table 1.
The data indicated that the model [2+2] cycloaddition reaction was remarkably influenced by
solvent. Product 3a was obtained in the best yield of 33% when using methanol as a solvent
(Table 1, entry 1). Only a trace amount of product was obtained in THF or CH2Cl2 (Table 1,
entries 6 and 7). Using acetonitrile/methanol (1:3) as a mixed solvent gave the product in a 30%
yield (Table 1, entry 8). Since 2,3-dimethyl-1,3-butadiene (2) is a liquid, we postulated that if 2
can dissolve chalcone (1a), the solvent may not be necessary. In order to test our hypothesis, an
experiment was implemented without any solvent under neat reaction conditions. Much to our
delight, the desired product 3a was obtained in 72% yield. The yield is better, compared to the
reaction with CH3OH as a solvent at the same reaction time (Table 1, entries 10 and 11). Hence,
all the reactions were performed under neat reaction conditions.
We speculate that the photocycloaddition reaction was significantly affected by solvent
probably due to the following possible causes: Solvent affects the triplet lifetime of chalcone (it
has been reported that solvent has effect on the triplet lifetime of some rhodamine dyes16). Solvent
may also affect the rates of 1,4-diradical intermediates (Scheme 4) reversing back to the starting
materials and converting forward to the products.18d Moreover, it is believed that photochemical
reactions of α,β-unsaturated carbonyl compounds occur from the lowest-lying triplet state T1
3

ACCEPTED MANUSCRIPT
(Scheme 4), which is often of ππ* character. However, the energy difference between the nπ* and
the ππ* triplet state in these compounds is relatively small. Thus, the character of the T1 state is
variable and can be affected by solvent polarity7a.
Table 1. Solvent screening a
entry
1
solvent
methanol
i-PrOH
yield (%)b
dre
4.7:1
4.0:1
4.2:1
4.9:1
5.2:1
-
33
22
2
3
acetone
13
4
MeCN
10
5
DMSO
7
6
THF
trace
trace
30
7
CH2Cl2
-
8
MeCN/MeOH (1:3)
MeCN/i-PrOH (1:3)
CH3OH
5.0:1
5.0:1
4.7:1
4.0:1
9
22
10c
11d
64
none
72
a Unless otherwise noted, reaction conditions: 1a (0.3 mmol), 2 (1.0 mmol), solvent (2.0 mL), under irradiation of
a 32 W CFL at rt for 36 h. b Isolated yield. c 1a (0.3 mmol), 2 (1.36 mL), CH3OH (2.0 mL).d 1a (0.3 mmol), 2 (1.36
mL). e dr was determined by 1H NMR analysis.
After optimizing the reaction conditions with chalcone (1a, 0.3 mmol) and commercially
available 2,3-dimethyl-1,3-butadiene (2) as a model system, the best yield of 72% was obtained
when using 1.36 mL of 2 under the irradiation of a 32 W CFL (For details, please see the
Supporting Information (SI) Table S1).
With the optimal conditions in hand, we investigated the substrate scope of the intermolecular
[2+2] photocycloaddition reaction. A variety of chalcones were synthesized and subjected to the
reaction conditions, as shown in Scheme 1. The reactions led to the desired products in 27% to 72%
4

ACCEPTED MANUSCRIPT
yields. It can be seen that substituent groups had significant effects on the reaction. For example,
chalcones with an alkenyl benzene ring bearing either an electron-donating (-Me, -OMe) or an
electron-withdrawing (-Cl, -Br) group gave good yields (3b, 3c, 3e and 3f). However, the yield
was obviously decreased for the chalcone bearing two -Cl on alkenyl benzene ring (3d), probably
due to the influence of both steric and electronic effects. The chalcones with an electron-donating
group (-Me or -OMe) on carbonyl aromatic ring gave higher yields (3h-3k) than those with an
electron-withdrawing group (-NO2) (3g). The chalcone substituted by -OMe at the ortho position
of the carbonyl aromatic ring (3i) provided a better yield than those substituted by -OMe at the
meta position (3j) and para position (3k). Additionally, the benzalacetone was investigated as a
substrate, and a moderate yield (3l) was obtained under the same reaction conditions. Isoprene can
also participate in the reaction, and the desired product (3m) was obtained in 54% yield (Scheme
2). However, pent-1-en-3-one, butyl acrylate, ethyl cinnamate etc resisted participating in the
reaction (for details, please see SI, Scheme S1). It is worth mentioning that all the products are
new compounds. Among the investigated reactions, four of them showed excellent
1
diastereoselectivity (Only single diastereomer was observed by H NMR, dr >20:1). The others
gave the products as a mixture of diastereomers. We have tried to isolate them by flash column
1
chromatography, prep-TLC and HPLC (with InertSustain C18 column), but failed. H NMR
indicated that there are two major diastereomers with dr ranged from 2:1 to 6:1; the major
diastereomers (3a – 3h and 3m) can be isolated by recrystallization after column chromatography.
The relative configuration of product 3a was unambiguously determined by single-crystal X-ray
diffraction analysis (Figure 1). The relative configurations of other products 3 (3b – 3m, the
major diastereomers) were assigned by analogy.
Figure 1 Single-crystal X-ray diffraction analysis of 3a
5

ACCEPTED MANUSCRIPT
Scheme 1. Substrate scope a
O
O
O
Br
Cl
3c
3b
3a
63% 4:1 dr
63% 2:1 drb
72% 4:1 dr
O
O
O
O
Cl
Cl
3f
3e
3d
49% 6:1 dr
61% 2:1 drb
31% 3:1 drb
O
O
O
O
H3C
O2N
3i
3h
3g
60% >20:1 dr
58% 4:1 drb
27% 3:1 dr
O
O
O
O
O
3j
3l
3k
54% >20:1 dr
41% >20:1 dr
45% >20:1 dr
6

ACCEPTED MANUSCRIPT
a Reaction conditions: 1 (0.3 mmol) and 2 (1.36 mL) under irradiation of a 32 W CFL at rt for 36 h. Yield of the
isolated product (the average of two repetitions).
b The ratio of two major diastereoisomers.
Scheme 2. The photocycloaddition between chalcone 1c and isoprene a
a Reaction conditions: 1c (0.3 mmol) and isoprene 4 (0.9 mL) under irradiation of a 32 W CFL at rt for 36 h. Yield
of the isolated product.
To understand the reaction mechanism, a control experiment was conducted (Scheme 3). No
reaction was observed for the experiment run in the dark at room temperature, indicating that light
is indispensable. We then measured the UV-visible absorption of chalcone (1a),
2,3-dimethyl-1,3-butadiene (2) and the mixture of 1a and 2. It was found that 1a had a strong
absorption between 400-430 nm at 2.2×10-2 mol/L while 2 did not show any absorption in the
visible range, and addition of 2 had no obvious effect on the absorption of 1a (For the absorption
spectra, please see the SI, Figure S1-S3). These results demonstrated that chalcone can absorb
energy from visible-light (The emission spectra range of CFL has been reported as 400-720 nm17)
to promote the reaction.
Scheme 3 The control experiment
7

ACCEPTED MANUSCRIPT
On the basis of the control experiment, and previously researched works18, a possible reaction
mechanism was proposed (Scheme 4). Under visible-light irradiation, chalcone molecules (1a)
absorb photons to be excited from ground state (S0) to the first excited singlet state (S1), and then,
S1 undergoes a rapid intersystem crossing (ISC) to form the excited triplet state (T1).19 It has been
demonstrated that the π* of the enone triplet state is occupied by an electron, making the
α-position electrophilic and the β-position nucleophilic18d, 20, meaning that the excitation induces
the umpolung of the enone. Thus, when it reacts with olefins bearing electron-donating groups,
head-to-tail (HT) products are generated. On the contrary, when it reacts with olefins containing
electron-withdrawing groups, head-to-head (HH) products are produced.11b In this reaction, the
excited triplet state (T1) of chalcone goes through the HT intermolecular cycloaddition with
2,3-dimethyl-1,3-butadiene (2) to generate 1,4-diradical intermediates21 (DR1 and DR2), which
undergo ring closure to generate the cyclobutane 3.21
To further verify the mechanism, we conducted density function theory (DFT) calculations. The
energy barrier between the substrates and transition state for DR1 is 6.267 Kcal/mol, and for DR2
is 88.386 Kcal/mol. Obviously, DR1 is easier to generate than DR2, suggesting that DR1 is the
main 1,4-diradical intermediate. According to this mechanism, the product can be formed with
four relative configurations (3a – 3a-3). The DFT calculations indicated that 3a has the lowest
energy (-187.45 Kcal/mol relative to substrates) among the four possible diastereomers,
suggesting that 3a is the main product (For details about the DFT calculations, please see the SI).
This is completely consistent with the experimental results.
Scheme 4 Proposed reaction mechanism
8

ACCEPTED MANUSCRIPT
3. Conclusion
In summary, we have developed a visible-light promoted intermolecular [2+2] cycloaddition
reaction of chalcones with 2,3-dimethyl-1,3-butadiene under neat reaction conditions at room
temperature. The corresponding cyclobutane derivatives were synthesized with yields of up to
72%. Mild reaction conditions and no additives make the reaction easy to operate. Control
experiments and DFT computations demonstrated that the reaction takes place by visible-light
activing chalcones. This work provides a convenient and gentle method for the preparation of
cyclobutanes.
4. Experimental section
4.1. General
trans-Chalcone (1a) was purchased from Alfa Aesar, A Johnson Matthey Company.
2,3-Dimethyl-1,3-butadiene was purchased from Energy Chemical. Unless otherwise noted, all
reagents were purchased from commercial suppliers and used without further purification.
α,β-Unsaturated ketones (1b-1k) were prepared according to literatures22 (for details, please see
SI). Reactions were monitored by thin-layer chromatography (TLC) with GF254 silica gel plates
using UV light and vanillic aldehyde as visualizing agents. Flash column chromatography was
1
performed using 200-300 mesh silica gel. H NMR and 13C NMR spectra were recorded on
9

ACCEPTED MANUSCRIPT
Bruker-AM 600 (600 MHz). Chemical shifts were reported in ppm from TMS with the solvent
resonance as the internal standard. Data were reported as follows: chemical shifts (δ) in ppm,
coupling constants (J) in Hz, and solvent (CDCl3 and DMSO-d6). High-resolution mass spectra
were obtained by using ESI ionization sources (Varian 7.0 T FTICR-MS). Melting points were
taken on a WPX-4 apparatus and were uncorrected. Emission spectra were taken on HITACHI
F-7000 fluorescence spectrophotometer.
4.2. General procedure for the intermolecular [2+2] photocycloaddition
A
round-bottom flask was charged with trans-chalcone (1) (0.3 mmol),
2,3-dimethyl-1,3-butadiene (2) (1.36 mL). The resultant mixture was stirred at rt under irradiation
of a 32 W CFL, and the reaction was monitored by TLC. The reaction mixture was concentrated in
vacuo. The residue was purified by silica gel column chromatography with petroleum ether/ethyl
acetate (400:1-50:1) as an eluent to give the products 3. The single diastereomers of 3a-3e and 3m
were obtained by further recrystallization from products 3 using the mixed solvents of
dichloromethane and petroleum ether at rt. The single diastereomer of 3h was obtained from
recrystallization at 4 oC.
4.2.1. (3-methyl-2-phenyl-3-(prop-1-en-2-yl)cyclobutyl)(phenyl)methanone (3a)
3a (major) and diastereomers as a mixture: Yield (62.5 mg, 72%); 1H NMR (600 MHz, CDCl3) δ 7.93
(d, J = 7.4 Hz, 1.41H), 7.59 (d, J = 7.3 Hz, 0.36H), 7.53 (t, J = 7.4 Hz, 0.78H), 7.43 (t, J = 7.7 Hz,
1.43H), 7.28 (t, J = 7.6 Hz, 1.61H), 7.24 – 7.17 (m, .33H), 6.98 – 6.92 (m, 0.78H), 4.89 (s, 0.72H), 4.83
(s, 0.17H), 4.82 (s, 0.67H), 4.75 (s, 0.16H), 4.43 (dd, J = 18.2, 10.0 Hz, 0.18H), 4.21 (dd, J = 18.6, 9.3
Hz, 0.82H), 4.16 (d, J = 9.7 Hz, 0.68H), 3.71 (dd, J = 9.8, 2.5 Hz, 0.18H), 3.33 (t, J = 11.1 Hz, 0.21H),
2.36 (t, J = 10.0 Hz, 0.82H), 2.22 – 2.16 (m, 0.76H), 2.11 – 2.05 (m, 0.20H), 1.74 (s, 2.23H), 1.62 (s,
0.58H), 1.16 (s, 2.08H), 1.14 (s, 0.59H). 13C NMR (150 MHz, CDCl3) δ 200.3, 152.4, 149.7, 140.0,
10

ACCEPTED MANUSCRIPT
136.2, 133.0, 132.3, 128.8, 128.6, 128.4, 128.1, 128.1, 128.0, 127.8, 127.4, 126.3, 126.1, 110.7, 108.9,
57.5, 47.9, 46.2, 45.0, 42.2, 41.0, 36.4, 32.1, 29.7, 21.9, 18.8, 18.4.
O
3a
White solid, mp 103–105 oC; 1H NMR (600 MHz, DMSO-d6) δ 7.99 (d, J = 7.7 Hz, 2H), 7.62 (t,
J = 7.3 Hz, 1H), 7.50 (t, J = 7.5 Hz, 2H), 7.31 (q, J = 7.7 Hz, 4H), 7.21 (t, J = 6.6 Hz, 1H), 4.80 (d,
J = 29.2 Hz, 2H), 4.57 (q, J = 9.4 Hz, 1H), 3.91 (d, J = 9.8 Hz, 1H), 2.21 – 2.10 (m, 2H), 1.69 (s,
3H), 1.09 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 200.3, 152.4, 140.0, 136.2, 133.0, 128.6, 128.4,
128.1, 128.1, 126.3, 108.9, 47.9, 45.0, 41.0, 36.4, 21.9, 18.8.
HRMS (ESI) calc. for C21H22O (M+Na)+: 313.1563, found: 313.1568.
4.2.2. (2-(4-chlorophenyl)-3-methyl-3-(prop-1-en-2-yl)cyclobutyl)(phenyl)methanone (3b)
3b (major) and diastereomers as a mixture: Yield (61.4 mg, 63%); 1H NMR (600 MHz, CDCl3) δ 7.92
(d, J = 7.4 Hz, 1.59H), 7.83 (d, J = 7.5 Hz, 0.41H), 7.55 (t, J = 7.4 Hz, 0.81H), 7.52 – 7.49 (m, 0.21H),
7.44 (t, J = 7.7 Hz, 1.59H), 7.42 – 7.37 (m, 0.53H), 7.25 – 7.22 (m, 2.10H), 7.19 (d, J = 8.5 Hz, 0.32H),
7.17 – 7.10 (m, 2.00H), 5.00 (s, 0.13H), 4.94 (s, 0.17H), 4.86 (s, 0.83H), 4.82 (s, 0.83H), 4.18 – 4.12
(m, 1.65H), 3.98 – 4.02 (m, 0.17H), 3.65 (d, J = 8.4 Hz, 0.14H), 2.82 – 2.75 (m, 0.19H), 2.34 – 2.32 (m,
0.85H), 2.25 – 2.23 (m, 0.29H), 2.23 – 2.18 (m, 0.84H), 1.73 (s, 2.44H), 1.67 (s, 0.44H), 1.39 (s,
0.39H), 1.14 (s, 2.76H). 13C NMR (150 MHz, CDCl3) δ 200.0, 152.1, 147.9, 139.2, 138.6, 136.0, 135.8,
133.1, 133.1, 132.2, 130.4, 129.4, 129.2, 128.8, 128.6, 128.6, 128.4, 128.2, 128.0, 111.2, 109.1, 52.2,
47.1, 45.0, 42.4, 41.1, 37.0, 36.6, 33.9, 28.6, 21.8, 20.2, 18.8.
11

ACCEPTED MANUSCRIPT
o
White solid, mp 118–120 C; 1H NMR (600 MHz, DMSO-d6) δ 7.98 (d, J = 7.4 Hz, 2H), 7.63
(t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.7 Hz, 2H), 7.36 (s, 4H), 4.81 (s, 1H), 4.78 (s, 1H), 4.57 (q, J = 9.5 Hz,
1H), 3.90 (d, J = 9.8 Hz, 1H), 2.20-2.17 (m, 1H), 2.14 – 2.10 (m, 1H), 1.67 (s, 3H), 1.08 (s, 3H). 13C
NMR (150 MHz, DMSO-d6) δ 200.6, 152.8, 139.1, 133.8, 131.5, 130.7, 129.2, 128.8, 128.4, 109.1,
47.5, 45.0, 40.3, 36.1, 21.7, 19.0. HRMS (ESI) calc. for C21H21ClO (M+Na)+: 347.1173, found:
347.1172.
4.2.3. (2-(4-bromophenyl)-3-methyl-3-(prop-1-en-2-yl)cyclobutyl)(phenyl)methanone (3c)
3c (major) and diastereomers as a mixture: Yield (69.8 mg, 63%); 1H NMR (600 MHz, DMSO-d6) δ
7.98 (d, J = 7.4 Hz, 0.97H), 7.92 – 7.87 (m, 0.81H), 7.78 (d, J = 7.5 Hz, 0.22H), 7.65 – 7.56 (m, 1.06H),
7.53 – 7.44 (m, 3.47H), 7.40 (d, J = 8.3 Hz, 0.24H), 7.32 (d, J = 8.4 Hz, 0.33H), 7.29 (d, J = 8.4 Hz,
0.97H), 7.24 – 7.20 (m, 0.81H), 7.17 (d, J = 8.3 Hz, 0.23H), 5.05 (s, 0.25H), 5.01 (s, 0.12H), 4.89 (s,
0.23H), 4.86 (s, 0.13H), 4.81 (s, 0.48H), 4.78 (s, 0.49H), 4.56 (q, J = 9.5 Hz, 0.51H), 4.22 – 4.17 (m,
0.35H), 3.89 (d, J = 9.8 Hz, 0.48H), 3.62 (d, J = 8.6 Hz, 0.26H), 2.19 (t, J = 9.9 Hz, 0.63H), 2.12 (t, J =
10.0 Hz, 0.68H), 2.05 – 2.01 (m, 0.3H), 1.69 (s, 0.3H), 1.68 (s, 1.46H), 1.64 (s, 0.42H), 1.63 (s, 0.44H),
1.32 (s, 0.70H), 1.11 (s, 0.8H), 1.08 (s, 1.4H). 13C NMR (150 MHz, DMSO-d6) δ 203.2, 200.6, 200.4,
152.8, 147.3,144.8, 140.2, 139.5, 139.2, 135.9, 135.7, 133.8, 133.7, 131.7, 131.5, 131.4, 131.3, 131.2,
131.0, 130.5, 130.2, 129.2, 129.2, 128.8, 128.8, 128.5, 128.3, 125.6, 124.2, 120.1, 120.0, 119.3, 115.1,
113.9, 112.2, 109.1, 51.8, 47.6, 46.6, 46.4, 45.0, 42.6, 41.5, 40.3, 37.9, 37.0, 36.6, 36.1, 34.2, 28.8, 21.7,
21.2, 20.5, 19.0, 18.8
12

ACCEPTED MANUSCRIPT
White solid, mp123–125 oC; 1H NMR (600 MHz, DMSO-d6) δ 7.98 (d, J = 7.2 Hz, 2H), 7.62 (t, J =
7.4 Hz, 1H), 7.51 – 7.48 (m, 4H), 7.29 (d, J = 8.4 Hz, 2H), 4.80 (s, 1H), 4.77 (s, 1H), 4.56 (q, J = 9.5
Hz, 1H), 3.88 (d, J = 9.8 Hz, 1H), 2.16-2.19 (m, 1H), 2.12-1.09 (m, 1H), 1.67 (s, 3H), 1.08 (s, 3H). 13C
NMR (150 MHz, DMSO-d6) δ 205.4, 157.5, 144.3, 140.6, 138.6, 136.1, 135.8, 134.0, 133.6, 124.7,
113.8, 52.3, 49.7, 45.0, 40.9, 26.4, 23.8.
HRMS (ESI) calc. for C21H21BrO (M+H)+: 391.0668, found: 391.0665.
4.2.4. (2-(2,3-dichlorophenyl)-3-methyl-3-(prop-1-en-2-yl)cyclobutyl)(phenyl)methanone (3d)
3d (major) and diastereomers as a mixture: Yield (33.4 mg, 31%); Yellow liquid ; 1H NMR (600
MHz, CDCl3) δ 7.91 (d, J = 7.7 Hz, 0.59H), 7.86 (d, J = 7.7 Hz, 0.75H), 7.73 (d, J = 7.8 Hz, 0.36H),
7.60 (d, J = 7.7 Hz, 0.3H), 7.54 (t, J = 7.4 Hz, 0.72H), 7.44 – 7.42 (m, 1.36H), 7.38 – 7.35 (m, 0.48H),
7.33 – 7.31 (m, 0.47H), 7.27 (d, J = 7.6 Hz, 0.26H), 7.24 – 7.18 (m, 0.89H), 7.13 (t, J = 7.9 Hz, 0.43H),
7.10 (d, J = 8.0 Hz, 0.19H), 7.05 (t, J = 7.4 Hz, 0.33H), 7.00 – 6.99 (m, 0.34H), 6.98 – 6.94 (m, 0.43H),
6.90 (t, J = 8.0 Hz, 0.16H), 5.04 (s, 0.35H), 5.01 (s, 0.39H), 4.97 (s, 0.18H), 4.94 (s, 0.54H), 4.83 (s,
0.14H), 4.76 (s, 0.15H), 4.59 (d, J = 10.1 Hz, 0.14H), 4.46 – 4.42 (m, 0.53H), 4.22 – 4.19 (m, 0.16H),
4.09 – 4.05 (m, 0.56H), 3.33 – 3.28 (m, 0.15H), 3.15 – 3.12 (m, 0.18H), 3.08 – 3.05 (m, 0.18H), 2.82 –
2.74 (m, 0.60H), 2.56 – 2.52 (m, 0.23H), 2.22 – 2.19 (m, 0.44H), 2.11 – 2.07 (m, 0.39H), 1.91 (s,
0.14H), 1.78 (s, 0.54H), 1.67 (s, 1.64H), 1.66 (s, 0.43H), 1.50 (s, 1.16H), 1.13 (s, 0.34H), 1.12 (s,
1.06H).13C NMR (150 MHz, CDCl3) δ 199.6, 148.7, 147.4, 142.2, 140.5, 139.6, 136.9, 135.8, 133.4,
133.1, 133.0, 132.9, 132.7, 120.0, 128.7, 128.6, 128.6, 128.4, 128.3, 128.2, 128.2, 128.1, 128.1, 127.7,
13

ACCEPTED MANUSCRIPT
127.2, 127.2, 127.0, 126.7, 126.6, 126.3, 125.6, 124.2, 115.2, 113.1, 111.3, 110.9, 51.7, 48.3, 48.2, 46.7,
46.4, 44.1, 41.6, 41.6, 37.6, 37.4, 37.0, 34.2, 32.4, 29.8, 28.8, 21.0, 20.0, 18.7, 18.6, 18.1.
1H NMR (600 MHz, DMSO-d6) δ 7.98 (d, J = 7.4 Hz, 2H), 7.75 (d, J = 7.8 Hz, 1H), 7.64 (t, J = 7.4 Hz,
1H), 7.53 – 7.50 (m, 3H), 7.37 (t, J = 7.9 Hz, 1H), 4.75 – 4.69 (m, 3H), 4.40 (d, J = 9.9 Hz, 1H), 2.33 (t,
J = 10.0 Hz, 1H), 2.12 (t, J = 10.1 Hz, 1H), 1.76 (s, 3H), 1.16 (s, 3H). 13C NMR (150 MHz, DMSO-d6
)
δ 200.2, 151.2, 140.0, 135.7, 133.9, 132.4, 131.8, 129.5, 129.2, 129.2, 128.8, 128.0, 110.0, 45.6, 45.3,
41.1, 34.8, 21.5, 19.6. HRMS (ESI) calc. for C21H20Cl2O (M+Na)+: 381.0783, found: 381.0782.
4.2.5. (3-methyl-3-(prop-1-en-2-yl)-2-(p-tolyl)cyclobutyl)(phenyl)methanone (3e)
3e (major) and diastereomers as a mixture: Yield (55.1 mg, 61%); Yellow liquid; 1H NMR (600 MHz,
CDCl3) δ 7.92 (d, J = 7.3 Hz, 1.19H), 7.84 (d, J = 7.3 Hz, 0.54H), 7.79(d, J = 7.3 Hz,0.20H)7.53 (t, J =
7.4 Hz, 0.63H), 7.50 (d, J = 7.3 Hz, 0.45H), 7.42 (t, J = 7.7 Hz, 1.17H), 7.38 (t, J = 7.7 Hz, 0.72H),
7.11 – 7.14 (m, 1.73H), 7.06 – 7.09 (m, 1.70H), 7.04(d, J = 7.2 Hz,0.23H), 4.99(s, 0.07),4.98 (s, 0.24H),
4.91 (s, 0.34H), 4.89(s, 0.08),4.87 (s, 0.59H), 4.80 (s, 0.59H), 4.19 (q, J = 9.4 Hz, 0.63H), 4.09 (d, J =
9.7 Hz, 0.58H), 4.03 (q, J = 9.4Hz, 0.30H), 3.61 (d, J = 8.3 Hz, 0.30H), 2.76(t, J = 10.1 Hz, 0.44H),
2.36 (t, J = 10.1 Hz, 0.55H), 2.31 (s, 2.39H), 2.24 – 2.27 (m, 0.63H), 2.15 – 2.20 (m, 0.84H),1.76 (s,
0.28H), 1.73 (s, 1.87H), 1.38 (s, 0.91H), 1.15 (s, 1.83H), 1.12 (s, 0.99H).13C NMR (150 MHz, CDCl3)
δ 200.4, 152.6, 148.5, 137.6, 136.9, 136.2, 135.8, 132.9, 132.9, 129.0, 129.0, 128.9, 128.8, 128.5, 128.5,
14

ACCEPTED MANUSCRIPT
128.4, 128.4, 128.1, 127.9, 127.2, 110.6, 108.8, 52.9, 47.9, 46.8, 45.0, 42.5, 41.0, 36.2, 33.6, 28.7, 22.0,
21.0, 21.0, 20.1, 18.8.
White solid, mp 107–109 oC; 1H NMR (600 MHz, DMSO-d6) δ 7.98 (d, J = 7.4 Hz, 2H), 7.62 (t, J =
7.4 Hz, 1H), 7.50 (t, J = 7.7 Hz, 2H), 7.21 (d, J = 7.9 Hz, 2H), 7.10 (d, J = 7.8 Hz, 2H), 4.80 (s, 1H),
4.76 (s, 1H), 4.54 (q, J = 9.5 Hz, 1H), 3.83 (d, J = 9.8 Hz, 1H), 2.26 (s, 3H), 2.14 (d, J = 9.3 Hz, 2H),
1.67 (s, 3H), 1.08 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ 200.8, 153.2, 136.9, 136.1, 135.8, 133.7,
129.2, 129.1, 128.8, 128.8, 108.8, 48.2, 45.0, 40.2, 35.8, 21.8, 21.1, 19.0. HRMS (ESI) calc. for
C22H24O (M+Na)+: 327.1719, found: 327.1716.
4.2.6. (2-(2-methoxyphenyl)-3-methyl-3-(prop-1-en-2-yl)cyclobutyl)(phenyl)methanone (3f)
O
+ diastereomers
O
3f (major)
3f (major) and diastereomers as a mixture: Yield (47.1 mg, 49%); 1H NMR (600 MHz, CDCl3) δ 7.91
(d, J = 7.1 Hz, 1.63H), 7.89 (d, J = 7.2 Hz, 0.27H), 7.51 (t, J = 7.4 Hz, 1.06H), 7.40 (t, J = 7.8 Hz,
2.01H), 7.26 (d, J = 7.5 Hz, 0.90H), 7.18 (d, J = 1.5Hz, 0.19H),7.17 (d, 7.9Hz, 0.80H), 6.91 (t, J = 7.4
Hz, 0.87H), 6.87 (t, J = 7.4 Hz, 0.17H), 6.79 (d, J = 8.2 Hz, 0.99H), 4.93 (s, 0.16H), 4.90 (s, 0.14H),
4.84 (s, 1.06H), 4.76 (s, 0.86H), 4.46 (d, J = 9.9 Hz, 0.83H), 4.28 (q, J = 9.4 Hz, 0.91H), 4.22 (d, J =
9.2 Hz, 0.14H), 4.15 (q, J =9.4 Hz, 0.18H), 3.77 (s, 0.39H), 3.62 (s, 2.66H), 2.73 (m, 0.17H), 2.44 (t, J
= 10.0 Hz, 0.89H), 2.19 (m, 0.19H), 2.08 (m, 0.93H), 1.79 (s, 2.57H), 1.59(s, 0.38H),1.45 (s, 0.36H),
1.18 (s, 2.99H). 13C NMR (150 MHz, CDCl3) δ 200.8, 200.6, 157.8, 157.7, 152.3, 148.6, 136.5, 136.3,
132.8, 132.8, 128.7, 128.5, 128.4, 128.4, 128.3, 128.3, 128.2, 127.6, 127.4, 127.4, 120.4, 120.2, 120.0,
110.6, 109.9, 108.3, 55.2, 54.9, 47.0, 45.5, 45.0, 42.5, 40.8, 40.6, 35.9, 34.4, 28.8, 21.9, 19.9, 18.9.
15

ACCEPTED MANUSCRIPT
Yellow liquid ; 1H NMR (600 MHz, CDCl3) δ 7.94 – 7.90 (m, 2H), 7.51 (t, J = 7.4 Hz, 1H), 7.40 (t, J
= 7.8 Hz, 2H), 7.28 – 7.24 (m, 1H), 7.18 – 7.16 (m, 1H), 6.91 (t, J = 7.2 Hz, 1H), 6.79 (d, J = 8.2 Hz,
1H), 4.84 (s, 1H), 4.76 (s, 1H), 4.46 (d, J = 9.9 Hz, 1H), 4.28 (q, J = 9.4 Hz, 1H), 3.62 (s, 3H), 2.44 (t,
J = 10.0 Hz, 1H), 2.09 – 2.07 (m, 1H), 1.79 (s, 3H), 1.18 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 200.6,
157.8, 152.3, 136.6, 132.7, 128.7, 128.5, 128.4, 128.3, 128.3, 127.4, 120.0, 110.6, 108.3, 54.9, 45.0,
42.6, 40.8, 35.9, 21.9, 18.9.
HRMS (ESI) calc. for C22H24O2 (M+Na)+: 343.1669, found: 343.1671
4.2.7. (3-methyl-2-phenyl-3-(prop-1-en-2-yl)cyclobutyl)(4-nitrophenyl)methanone (3g)
3g (major) and diastereomers as a mixture: Yield (26.7 mg, 27%); Yellow liquid ; 1H NMR (600 MHz,
CDCl3) δ 8.25 (d, J = 8.8 Hz, 1.46H), 8.20 (d, J = 8.8 Hz, 0.53H), 8.03 (d, J = 8.8 Hz, 1.50H), 7.94 (d,
J = 8.8 Hz, 0.52H), 7.34 – 7.27 (m, 2.07H), 7.25 – 7.22 (m, 2.62H), 5.01 (s, 0.25H), 4.95 (s, 0.26H),
4.88 (s, 0.73H), 4.83 (s, 0.74H), 4.20 (q, J = 9.4 Hz, 0.81H), 4.07 (d, J = 9.7 Hz, 0.77H), 4.06 – 4.02
(m, 0.31H), 3.57 (d, J = 8.4 Hz, 0.28H), 2.79 (dd, J = 11.9, 9.6 Hz, 0.31H), 2.45 – 2.42 (m, 0.77H),
2.33 (m, 0.34H), 2.22 – 2.16 (m, 0.82H), 1.73 (s, 2.25H), 1.40 (s, 0.77H), 1.18 (s, 2.26H), 1.10 (s,
0.78H). 13C NMR (150 MHz, CDCl3) δ 199.0, 152.2, 150.3, 147.9, 140.6, 139.2, 129.4, 129.3, 128.3,
128.3, 128.2, 127.9, 127.1, 126.8, 123.8, 123.7, 111.1, 109.0, 53.8, 48.9, 47.0, 45.2, 43.0, 41.6, 35.6,
32.9, 28.7, 22.0, 20.0, 18.7.
16

ACCEPTED MANUSCRIPT
1H NMR (600 MHz, CDCl3) δ 8.24 (d, J = 8.8 Hz, 2H), 8.03 (d, J = 8.8 Hz, 2H), 7.34 – 7.29 (m, 2H),
7.26 – 7.21 (m, 3H), 4.88 (s, 1H), 4.83 (s, 1H), 4.20 (q, J = 9.4 Hz, 1H), 4.07 (d, J = 9.7 Hz, 1H), 2.45
– 2.42 (m, 1H), 2.22 – 2.17 (m, 1H), 1.73 (s, 3H), 1.18 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 199.0,
152.2, 140.6, 139.2, 129.3, 128.3, 128.2, 126.8, 123.8, 109.0, 48.9, 45.2, 41.6, 35.6, 22.0, 18.7.
HRMS (ESI) calc. for C21H21NO3 (M+Na)+: 358.1414, found: 358.1413.
4.2.8. (3-methyl-2-phenyl-3-(prop-1-en-2-yl)cyclobutyl)(p-tolyl)methanone (3h)
3h (major) and diastereomers as a mixture: Yield (52.8 mg,58%); 1H NMR (600 MHz, DMSO-d6) δ
7.89 (d, J = 8.0 Hz, 1.49H), 7.79 (d, J = 8.0 Hz, 0.36H), 7.69 (d, J = 8.0 Hz, 0.15H), 7.34 – 7.24 (m,
7.54H), 7.17 – 7.21 (m, 1.75H), 720 – 7.17(m, 0.29H), 5.04 (s, 0.20H), 4.98 (s, 0.08H), 4.86 (s, 0.16H),
4.84 (s, 0.08H), 4.82 (s, 0.74H), 4.77 (s, 0.76H), 4.53 (q, J = 9.5 Hz, 0.74H), 4.18 (q, J = 8.9 Hz,
0.22H), 3.89 (d, J = 9.8 Hz, 0.75H), 3.59 (d, J = 8.6 Hz, 0.21H), 2.36 – 2.34 (m, 2.71H),2.33(s, 0.29),
2.16 – 2.10 (m, 1.53H),2.05 – 2.02(m, 0.21), 1.70(s, 0.24), 1.68 (s, 2.24H), 1.32 (s, 0.54H), 1.09 (s,
2.22H), 1.06 (s, 0.58H).13C NMR (150 MHz, DMSO-d6) δ 200.3, 200.1, 153.1, 147.7, 144.1, 144.1,
140.8, 140.1, 133.6, 133.3, 129.7, 129.4, 128.9, 128.9, 128.8, 128.7, 128.4, 128.4, 128.2, 126.9, 126.8,
111.8, 108.9, 52.7, 48.4, 46.6, 45.0, 41.4, 36.0, 34.1, 28.9, 21.8, 21.6, 21.2, 20.4, 19.0.
o
White solid, mp 112–114 C; 1H NMR (600 MHz, DMSO-d6) δ 7.89 (d, J = 8.1 Hz, 2H), 7.34 –
17

ACCEPTED MANUSCRIPT
7.27 (m, 6H), 7.22 – 7.19 (m, 1H), 4.82 (s, 1H), 4.77 (s, 1H), 4.54 (q, J = 9.5 Hz, 1H), 3.88 (d, J = 9.8
Hz, 1H), 2.36 (s, 3H), 2.16 – 2.10 (m, 2H), 1.68 (s, 3H), 1.09 (s, 3H). 13C NMR (150 MHz, DMSO-d6
)
δ 200.3, 153.1, 144.1, 140.1, 133.6, 129.7, 128.9, 128.8, 128.5, 126.8, 108.9, 48.3, 45.0, 36.0, 21.8,
21.6, 19.1. HRMS (ESI) calc. for C22H24O (M+Na)+: 327.1719, found: 327.1718.
4.2.9. (2-methoxyphenyl)(3-methyl-2-phenyl-3-(prop-1-en-2-yl)cyclobutyl)methanone (3i)
Yield (58.0 mg, 60%); Yellow liquid ; 1H NMR (600 MHz, CDCl3) δ 7.57 (dd, J = 7.6, 1.7 Hz, 1H),
7.43 – 7.39 (m, 1H), 7.23 – 7.25 (m, 2H), 7.19 (d, J = 7.4 Hz, 2H), 7.16 (t, J = 7.2 Hz, 1H), 6.96 (t, J =
7.5 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 4.88 (s, 1H), 4.81 (s, 1H), 4.26 (q, J = 9.5 Hz, 1H), 4.09 (d, J =
9.9 Hz, 1H), 3.84 (s, 3H), 2.22 – 2.23 (m, 1H), 2.12 – 2.06 (m, 1H), 1.74 (s, 3H), 1.07 (s, 3H). 13C
NMR (150 MHz, CDCl3) δ 158.2, 152.7, 140.4, 132.98, 130.2, 128.1, 127.9, 126.0, 120.7, 111.3, 108.8,
55.5, 48.2, 44.6, 44.5, 35.9, 21.7, 18.9. HRMS (ESI) calc. for C22H24O2 (M+Na)+: 343.1669, found:
343.1671.
4.2.10. (3-methoxyphenyl)(3-methyl-2-phenyl-3-(prop-1-en-2-yl)cyclobutyl)methanone (3j)
Yield (51.8 mg, 54%); Yellow liquid ; 1H NMR (600 MHz, CDCl3) δ 7.51 (d, J = 7.7 Hz, 1H),
7.45 – 7.43 (m, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.29 (t, J = 7.5 Hz, 2H), 7.23 (d, J = 7.3 Hz, 2H), 7.20 (t,
J = 7.2 Hz, 1H), 7.08 – 7.06 (m, 1H), 4.89 (s, 1H), 4.82 (s, 1H), 4.16 – 4.20 (m, 1H), 4.13 (d, J = 9.7
Hz, 1H), 3.78 (s, 3H), 2.41 – 2.37 (m, 1H), 2.19 – 2.15 (m, 1H), 1.74 (s, 3H), 1.15 (s, 3H). 13C NMR
(150 MHz, CDCl3) δ 200.2, 159.9, 152.5, 140.0, 137.6, 129.5, 128.2, 128.1, 126.4, 121.0, 119.6, 112.7,
18

ACCEPTED MANUSCRIPT
108.9, 55.4, 48.2, 45.0, 41.1, 36.2, 22.0, 18.8. HRMS (ESI) calc. for C22H24O2 (M+Na)+: 343.1669,
found: 343.1667
4.2.11. (4-methoxyphenyl)(3-methyl-2-phenyl-3-(prop-1-en-2-yl)cyclobutyl)methanone (3k)
O
O
3k
o
Yield (43.1 mg, 45%); White solid, mp 96–98 C; 1H NMR (600 MHz, CDCl3) δ 7.91 (d, J = 8.9
Hz, 2H), 7.28 (t, J = 7.5 Hz, 2H), 7.24 – 7.17 (m, 3H), 6.90 (d, J = 8.9 Hz, 2H), 4.89 (s, 1H), 4.81 (s,
1H), 4.19 – 4.13 (m, 2H), 3.85 (s, 3H), 2.35 (t, J = 9.8 Hz, 1H), 2.19 – 2.13 (m, 1H), 1.74 (s, 3H), 1.15
(s, 3H). 13C NMR (150 MHz, CDCl3) δ 198.9, 163.5, 152.5, 140.1, 130.6, 128.1, 128.0, 126.2, 113.8,
108.8, 77.2, 77.0, 76.8, 55.40, 48.0, 45.0, 40.7, 36.4, 22.0, 18.8.
HRMS (ESI) calc. for C22H24O2 (M+Na)+: 343.1669, found: 343.1668.
4.2.12. 1-(3-methyl-2-phenyl-3-(prop-1-en-2-yl)cyclobutyl)ethan-1-one (3l)
Yield (27.8 mg, 41%); Yellowish oil; 1H NMR (600 MHz, DMSO-d6) δ 7.34 – 7.30 (m, 4H),
7.24-7.21 (m, 1H), 4.79 (s, 1H), 4.76 – 4.74 (m, 1H), 3.71 (m 1H), 3.61 (d, J = 10.3 Hz, 1H), 2.12 (t, J
= 10.1 Hz, 1H), 1.98 (s, 3H), 1.89 (m, 1H), 1.67 (s, 3H), 0.94 (s, 3H). 13C NMR (150 MHz, DMSO-d6)
δ 209.1, 152.9, 139.8, 128.7, 128.5, 126.9, 109.0, 49.4, 44.4, 44.0, 33.2, 28.3, 21.6, 19.1.
HRMS (ESI) calc. for C16H20O (M+Na)+: 251.1406, found: 251.1049.
4.2.13 (2-(4-bromophenyl)-3-methyl-3-vinylcyclobutyl)(phenyl)methanone (3m)
19

ACCEPTED MANUSCRIPT
3h (major) and diastereomers as a mixture: Yield (57.6 mg, 54%); 1H NMR (600 MHz, DMSO-d6) δ
7.96 (d, J = 8.4 Hz, 1.56H), 7.92 (d, J = 8.4 Hz, 0.39H), 7.75 – 7.72 (m, 1.84H), 7.66 (d, J = 8.3 Hz,
0.11H), 7.34 – 7.24 (m, 2.17H), 7.23 – 7.13 (m, 2.98H), 6.09 (dd, J = 17.2, 10.8 Hz, 0.81H), 5.84 –
5.80 (m, 0.20H), 5.05 (d, J = 17.4 Hz, 0.19H), 5.02 – 4.97 (m, 1.57H), 4.94 (d, J = 10.7 Hz, 0.19H),
4.62 (q, J = 9.6 Hz, 0.81H), 4.50 (q, J = 9.5 Hz, 0.21H), 3.80 (d, J = 10.0 Hz, 0.83H), 3.71 (d, J = 9.9
Hz, 0.20H), 2.45 (t, J = 10.0 Hz, 0.28H), 2.17 (t, J = 9.8 Hz, 0.80H), 2.10 (t, J = 10.0 Hz, 0.81H), 2.01
(t, J = 10.2 Hz, 0.26H), 1.31 (s, 0.51H), 0.96 (s, 2.39H). 13C NMR (150 MHz, DMSO-d6) δ 200.1,
147.6, 143.1, 139.5, 135.0, 132.3, 130.9, 128.5, 128.4, 128.0, 127.9, 127.8, 126.7, 126.7, 112.8, 112.0,
51.7, 48.9, 43.2, 41.9, 40.6, 36.5, 35.6, 27.2, 20.6.
o
White solid, mp 87–89 C; 1H NMR (600 MHz, DMSO-d6) δ 7.96 (d, J = 8.5 Hz, 2H), 7.74 (d, J =
8.5 Hz, 2H), 7.29 (t, J = 7.5 Hz, 2H), 7.21 – 7.17 (m, 3H), 6.09 (dd, J = 17.2, 10.8 Hz, 1H), 5.03 – 4.97
(m, 2H), 4.62 (q, J = 9.6 Hz, 1H), 3.80 (d, J = 10.0 Hz, 1H), 2.17 (t, J = 9.8 Hz, 1H), 2.10 (t, J = 10.0
Hz, 1H), 0.96 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ 200.0, 147.6, 139.5, 135.0, 132.3, 130.9,
128.5, 127.8, 126.7, 112.0, 48.9, 41.9, 36.5, 20.6.
HRMS (ESI) calc. for C20H19BrO (M+H)+: 355.0692, found: 355.0696
ASSOCIATED CONTENT
Supporting Information
Preparation of starting materials, extra information for the optimization of reaction conditions,
20

ACCEPTED MANUSCRIPT
optical spectroscopic data, olefins that resisted participating in the reaction with chalcone,
1
computational methods, coordinates and energies, copies of H NMR, 13C NMR and HRMS
spectra (PDF), and X-ray crystal structure of 3a (CIF).
ACKNOWLEDGMENTS
This work was financially supported by the National Natural Science Foundation of China (Nos
21472152 and 21672174), and the Basic and Frontier Research Project of Chongqing
(cstc2015jcyjBX0106).
References
(1) Sun, L.; Hammarstrom, L.; Akermark, B.; Styring, S. Chem. Soc. Rev. 2001, 30, 36-49.
(2) (a) Hoffmann, N. Chem. Rev. 2008, 108, 1052-1103; (b) Sun, P.; Yang, D.; Wei, W.; Jiang, M.; Wang,
Z.; Zhang, L.; Zhang, H.; Zhang, Z.; Wang, Y.; Wang, H. Green Chem. 2017, 19, 4785-4791; (c) Yang, W.;
Yang, S.; Li, P.; Wang, L. Chem. Commun. 2015, 51, 7520-7523; (d) Dong, S.; Feng, J.; Fan, M.; Pi, Y.; Hu,
L.; Han, X.; Liu, M.; Sun, J.; Sun, J. RSC Adv. 2015, 5, 14610-14630; (e) Lang, X.; Chen, X.; Zhao, J. Chem.
Soc. Rev. 2014, 43, 473-486; (f) Ciamician, G. Science 1912, 36, 385-394; (g) Xiao, W.-J.; Zhou, Q.-Q.;
Zou, Y.-Q.; Lu, L.-Q. Angew. Chem., Int. Ed. 2018, 10.1002/anie.201803102; (h) Chen, J.-R.; Yan, D.-M.;
Wei, Q.; Xiao, W.-J. ChemPhotoChem 2017, 1, 148-158.
(3) Bach, T.; Hehn, J. P. Angew. Chem., Int. Ed. 2011, 50, 1000-1045.
(4) (a) Riener, M.; Nicewicz, D. A. Chem. Sci. 2013, 4, 2625-2629; (b) Nicholls, T. P.; Leonori, D.;
Bissember, A. C. Nat. Prod. Rep. 2016, 33, 1248-1254.
(
5) (a) Albertson, A. K.; Lumb, J. P. Angew. Chem., Int. Ed. 2015, 54, 2204-2208; (b) Soriano, E.;
Fernandez, I. Chem. Soc. Rev. 2014, 43, 3041-3105; (c) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C.
Chem. Rev. 2013, 113, 5322-5363; (d) Winkler, J. D.; Bowen, C. M.; Liotta, F. Chem. Rev. 1995, 95,
2003-2020;
(6) Hurtley, A. E.; Lu, Z.; Yoon, T. P. Angew. Chem., Int. Ed. 2014, 53, 8991-8994.
(7) (a) Poplata, S.; Troster, A.; Zou, Y. Q.; Bach, T. Chem. Rev. 2016, 116, 9748-9815; (b) Duan, G. J.;
Ling, J. B.; Wang, W. P.; Luo, Y. C.; Xu, P. F. Chem. Commun. 2013, 49, 4625-4627; (c) Nanteuil, F.; Waser,
J. Angew. Chem. 2013, 125, 9179-9183; (d) Zou, Y.-Q.; Duan, S.-W.; Meng, X.-G.; Hu, X.-Q.; Gao, S.;
Chen, J.-R.; Xiao, W.-J. Tetrahedron. 2012, 68, 6914-6919.
(8) (a) Zhao, J.; Brosmer, J. L.; Tang, Q.; Yang, Z.; Houk, K. N.; Diaconescu, P. L.; Kwon, O. J. Am. Chem.
Soc. 2017, 139, 9807-9810; (b) Yoon, T. P. ACS Catal. 2013, 3, 895-902; (c) Poplata, S.; Tröster, A.; Zou,
Y.-Q.; Bach, T. Chem. Rev. 2016, 116, 9748-9815; (d) Xu, Y.; Conner, M. L.; Brown, M. K. Angew. Chem.,
Int. Ed. 2015, 54, 11918-11928; (e) Yoon, T. P. Acc. Chem. Res. 2016, 49, 2307-2315; (f) Kuz'mina, L. G.;
Vedernikov, A. I.; Lobova, N. A.; Churakov, A. V.; Howard, J. A. K.; Alfimov, M. V.; Gromov, S. P. New J.
Chem. 2007, 31, 980-994; (g) Guo, C.; Cui, L.; Chen, B.; Yuan, J.; Tian, Z. RSC Adv. 2012, 2, 9932-9937;
(h) Guo, C.; Wang, H.; Chen, B.-Z.; Tian, Z. RSC Adv. 2014, 4, 63475-63484; (i) Ischay, M. A.; Ament, M.
S.; Yoon, T. P. Chem. Sci. 2012, 3, 2807-2811; (j) Pagire, S. K.; Hossain, A.; Traub, L.; Kerres, S.; Reiser, O.
Chem. Commun. 2017, 53, 12072-12075. (k) Wei, X.; Wu, W.; Matsushita, R.; Yan, Z.; Zhou, D.; Chruma,
21

ACCEPTED MANUSCRIPT
J. J.; Nishijima, M.; Fukuhara, G.; Mori, T.; Inoue, Y.; Yang, C. J. Am. Chem. Soc. 2018, 140, 3959-3974; (l)
Rao, M.; Kanagaraj, K.; Fan, C.; Ji, J.; Xiao, C.; Wei, X.; Wu, W.; Yang, C., Org. Lett. 2018, 20, 1680-1683.
(m) Yang, C.; Inoue, Y, Chem. Soc. Rev. 2014, 43, 4123-4143.
(9) Schultz, D. M.; Yoon, T. P. Science 2014, 343, 1239176-1.
(10) Rosa, G. P.; Seca, A. M. L.; Barreto, M. d. C.; Pinto, D. C. G. A. ACS Sustainable Chem. Eng. 2017,
5, 7467-7480.
(11) (a) Kamal, A.; Reddy, J. S.; Ramaiah, M. J.; Dastagiri, D.; Bharathi, E. V.; Prem Sagar, M. V.;
Pushpavalli, S. N. C. V. L.; Ray, P.; Pal-Bhadra, M. Med. Chem. Comm. 2010, 1, 355-360; (b) Zhuang, C.;
Zhang, W.; Sheng, C.; Zhang, W.; Xing, C.; Miao, Z. Chem. Rev. 2017, 117, 7762-7810; (c) Ahmad, A.;
Wani, M. Y.; Patel, M.; Sobral, A. J. F. N.; Duse, A. G.; Aqlan, F. M.; Al-Bogami, A. S. Med. Chem. Comm.
2017, 8, 2195-2207; (d) Bagul, C.; Rao, G. K.; Makani, V. K. K.; Tamboli, J. R.; Pal-Bhadra, M.; Kamal, A.
Med. Chem. Comm. 2017, 8, 1810-1816.
(12) (a) Daniela Ilieva, B.; Iva Todorova, T. Curr. Clin. Pharmacol. 2010, 5, 1-29; (b) Sahu, N. K.;
Balbhadra, S. S.; Choudhary, J.; Kohli, D. V. Curr. Med. Chem. 2012, 19, 209-225.
(13) Singh, P.; Anand, A.; Kumar, V. Eur. J. Med. Chem. 2014, 85, 758-777.
(14) Blum, T. R.; Miller, Z. D.; Bates, D. M.; Guzei, I. A.; Yoon, T. P. Science 2016, 354, 1391-1395.
(15) (a) Toda, F.; Tanaka, K.; Kato, M. J Chem Soc Perk T 1 1998, 1315-1318; (b) Lei, T.; Zhou, C.;
Huang, M. Y.; Zhao, L. M.; Yang, B.; Ye, C.; Xiao, H.; Meng, Q. Y.; Ramamurthy, V.; Tung, C. H.; Wu, L. Z.
Angew. Chem., Int. Ed. 2017, 56, 15407-15410.
(16) Tian, H.; Chen, K. Dyes and Pigments, 1994, 26, 167-174.
(17) Christopher, D. E; David M. K; Benjamin T. T; Kimberly, E. B. Sensors 2010, 10, 3961-3988.
(18) (a) Cantrell, T. S.; Haller, W. S.; Williams, J. C. J. Org. Chem. 1969, 34, 509-519; (b) Howard, K. A.;
Koch, T. H. J. Am. Chem. Soc. 1975, 97, 7288-7298; (c) Suishu, T.; Shimo, T.; Somekawa, K. Tetrahedron.
1997, 53, 3545-3556; (d) Schuster, D. I.; Lem, G.; Kaprinidis, N. A. Chem. Rev. 1993, 93, 3-22; (e) Bach, T.
Synthesis-Stuttgart. 1998, 683-703; (f) Mori, K.; Sasaki, M. Tetrahedron. 1980, 36, 2197-2208; (g)
Margaretha, P. Helv. Chim. Acta. 1974, 57, 1866-1867; (h) Chang, X. P.; Zheng, Y.; Cui, G.; Fang, W. H.;
Thiel, W. Phys. Chem. Chem. Phys. 2016, 18, 24713-24721.
(19) Schuster, D. I.; Heibel, G. E.; Brown, P. B.; Turro, N. J.; Kumar, C. V. J. Am. Chem. Soc. 1988, 110,
8261-8263.
(20) Odo, Y.; Shimo, T.; Hori, K.; Somekawa, K. Bull. Chem. Soc. Jpn. 2004, 77, 1209-1215.
(21) Andrew, D.; Weedon, A. C. J. Am. Chem. Soc. 1995, 117, 5647-5663.
(22) (a) Rosas-Sanchez, A.; Toscano, R. A.; Lopez-Cortes, J. G.; Ortega-Alfaro, M. C. Dalton trans.
2015, 44, 578-590; (b) Miao, C. B.; Zeng, Y. M.; Shi, T.; Liu, R.; Wei, P. F.; Sun, X. Q.; Yang, H. T.
J.Org.Chem. 2016, 81, 43-50; (c) Nepali, K.; Singh, G.; Turan, A.; Agarwal, A.; Sapra, S.; Kumar, R.;
Banerjee, U. C.; Verma, P. K.; Satti, N. K.; Gupta, M. K.; Suri, O. P.; Dhar, K. L. Bio & med. chem. 2011,
19, 1950-1958.
22