Difluoroalkylation/C-H Annulation Cascade Reaction Induced by Visible-Light Photoredox Catalysis

Article abstract of DOI:10.1021/acs.joc.6b01825

We report the first example of difluoroalkylation/C-H annulation cascade reactions of cyclopropyl olefins induced by visible-light photoredox catalysis regioselectively affording partially hydrogenated naphthalenes and quinolines with a variety of difluorinated side chains. The alkylation reagent could be extended to monofluoro and trifluoro reagents, nitrile and malonate. The regioselectivity was investigated by means of density functional theory calculations.

Full text of DOI:10.1021/acs.joc.6b01825

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Note
Difluoroalkylation/C-H annulation cascade reaction
induced by visible-light photoredox catalysis
Jin Li, Jingzhi Chen, Wei Jiao, Guoqiang Wang, Ying Li, Xu Cheng, and Guigen Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01825 • Publication Date (Web): 23 Sep 2016
Downloaded from http://pubs.acs.org on September 25, 2016
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Difluoroalkylation/CꢀH annulation cascade reaction induced
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by visibleꢀlight photoredox catalysis
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Jin Li,[a] Jingzhi Chen,[a] Wei Jiao,[a] Guoqiang Wang,[b] Ying Li,[a] Xu Cheng*[a] and Guigen Li[a,c]
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[a] Institute of Chemistry and Biomedical Science, School of Chemistry and Chemical Engineering,
Nanjing University, Nanjing, China
[b] Institute of Theoretical and Computational Chemistry, School of Chemistry and Chemical
Engineering, Nanjing University, Nanjing, China
[c] Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas, United States
Eꢀmail: chengxu@nju.edu.cn
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Abstract: We report the first example of difluoroalkylation/CꢀH annulation cascade reactions of
cyclopropyl olefins induced by visibleꢀlight photoredox catalysis regioselectively afford partially
hydrogenated naphthalenes and quinolines with a variety of difluorinated side chains. The alkylation
reagent could be extended to monofluoro and trifluoro reagents, nitrile and malonate. The
regioselectivity was investigated by means of density functional theory calculations.
Difluoroalkylation is a powerful strategy for introducing fluorine atoms into pharmaceuticals,[1]
agricultural chemicals,[2] imaging agents,[3] and functional materials.[4] This reaction can be achieved
with transition metal catalysis to form sp3ꢀsp2 and sp3ꢀsp CꢀC bonds.[5] Recently, photoredox catalysis
has emerged as a highly efficient method for facilitating difluoroalkylation reactions.[6] Difluoroacetate
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is a common, inexpensive, and easy to use reagent for such reactions. Photoredox reactions of
difluoroacetate frequently involve a highly reactive radical species, and the difluoroacetate radical has
been successfully integrated into alkenes,[7] alkynes, arenes,[8] and hydrazones.[9] We hypothesized that
it might be advantageous to utilize the radical species for further transformation, resulting in a cascade
reaction.
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The cyclopropyl group is known for its reactivity toward αꢀradicals to give a linear carbon radical,
and cyclopropyl compounds have been used as radical clocks.[10] For example, αꢀcyclopropylstyrene
has been used as a radical clock for several transition metalꢀcatalyzed reactions that proceed via a
radical pathway.[11] However, the potential of cyclopropyl ring opening has not been thoroughly
explored. We hypothesized that photoredox catalysis would facilitate annulation reactions of αꢀ
cyclopropylstyrene substrates, especially those with coordinative heterocyclic structures. Herein, we
report our investigation of radical alkylation/CꢀH annulation cascade reactions of αꢀcyclopropylstyrene
substrates, as well as pyridine substrates.
Scheme 1. Plan for difluoroalkylation/CꢀH annulation reaction.
Our strategy is illustrated in Scheme 1. The reaction starts with oxidative quenching of an iridium
photoredox catalyst to generate a difluoroacetate radical, which adds to the double bond of the αꢀ
cyclopropylstyrene substrate. Opening of the cyclopropyl ring generates a terminal radical.
Subsequently, addition of the radical to the arene ring, oxidation of the resulting aryl radical by the
catalyst, and deprotonation give the target molecule, which has two new CꢀC bonds and a new ring.
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Table 1. Optimization of conditions for difluoroalkyation/CꢀH annulation cascade reaction[a]
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Entry
1
Photocatalyst
Ru(bpy)3Cl2
Solvent
CH3CN
CH3CN
CH3CN
CH3CN
DMF
Base
Yield (%)[b]
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
Cs2CO3
Na2CO3
NaHCO3
K3PO4
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0
2
Ir(ppy)3
3
Ir(ppy)2(dtbbpy)PF6
Ir[dF(CF3)ppy]2(dtbbpy)PF6
Ir(ppy)2(dtbbpy)PF6
Ir(ppy)2(dtbbpy)PF6
Ir(ppy)2(dtbbpy)PF6
Ir(ppy)2(dtbbpy)PF6
Ir(ppy)2(dtbbpy)PF6
Ir(ppy)2(dtbbpy)PF6
Ir(ppy)2(dtbbpy)PF6
Ir(ppy)2(dtbbpy)PF6
Ir(ppy)2(dtbbpy)PF6
Ir(ppy)2(dtbbpy)PF6
none
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0
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0
6
DMSO
CH2Cl2
EtOH
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0
9
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
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trace
0
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16[c]
17[d]
Na2HPO4
none
K2HPO4
K2HPO4
K2HPO4
Ir(ppy)2(dtbbpy)PF6
Ir(ppy)2(dtbbpy)PF6
0
trace
[a] Reaction conditions: 1a (0.22 mmol), 2a (0.2 mmol), base (0.24 mmol), photocatalyst (0.002 mmol, 1.0 mol %),
anhydrous solvent (2.0 mL), 24ꢀW blue LED strips, 12 h, rt. DMF = N,Nꢀdimethylformamide, DMSO = dimethyl
sulfoxide. [b] Isolated yields. [c] No light. [d] In air.
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We began by investigating the reaction of αꢀcyclopropylstyrene (1a) and ethyl bromodifluoroacetate
(2a) in the presence of various photocatalysts (Table 1). When the reaction was carried out in MeCN
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under nitrogen with Ru(bpy)3Cl2 or Ir(ppy)2(dtbbpy)PF6 as a catalyst and with illumination by blue
LEDs (24 W), the target annulated compound (3a) was obtained as the major product (entries 1 and 3).
Two other widely used iridium complexes failed to catalyze this conversion (entries 2 and 4). Little or
none of the desired product was obtained when the reaction was carried out in DMF, DMSO, CH2Cl2 or
ethanol (entries 5ꢀ8). Screening of various bases revealed that K2HPO4 gave the best results (entries 9ꢀ
14). The reaction did not proceed in the absence of light (entry 16) or in the absence of a photocatalyst
(entry 15). An inert atmosphere was necessary to ensure complete conversion of the starting material
(entry 17).
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Table 2. Difluoroalkylation/CꢀH annulation cascade reactions of substrates 1[a]
[a] Reaction conditions: 1 (0.22 mmol), 2a (0.2 mmol), Ir(ppy)2(dtbbpy)PF6 (0.002 mmol, 1.0 mol %), anhydrous
CH3CN (2.0 mL), 24
ꢀW blue LED strips, r.t., 12ꢀ36 h. Yields of isolated products are reported.
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With the optimized conditions in hand (Table 1, entry 3), we explored the substrate scope of the
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difluoroalkylation/CꢀH annulation cascade by using αꢀcyclopropylstyrenes 1 as substrates and 2a as the
radical donor (Table 2). We began by investigating styrenes with electronꢀwithdrawing and electronꢀ
donating substituents at the para position of the phenyl ring and found that the corresponding products
(3bꢀ3g) could be obtained in acceptable yields.
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Orthoꢀmethoxyꢀsubstituted substrate 1h afforded annulated product 3h in moderate yield. We were
interested to observe that metaꢀmethoxyꢀsubstituted styrene 1i underwent the sterically hindered orthoꢀ
annulation as the major reaction to afford 3i in 48% yield, along with a 8% yield of paraꢀannulation
product 3i’. Density functional theory calculations on the transition states for the two regioisomers were
carried out at the UB3LYP/6ꢀ31G(d,p) level to elucidate the reason for the regioselectivity (Scheme 2).
The calculations revealed that the orthoꢀannulation transition state (TSꢀ3i) was 2.3 kcal/mol lower in
Gibbs free energy than the transition state for the paraꢀannulation (TSꢀ3i’). In addition, the calculated
energy of intermediate intꢀ3i was 1.9 kcal/mol lower than that of intermediate intꢀ3i. The
regioselectivity may have been due to the stabilizing effect of the heteroatom adjacent to the carbon
radical.[12]
A
TSꢀ3i
TSꢀ3i’
intꢀ3i
intꢀ3i’
Scheme 2. Density functional theory calculations to elucidate
the regioselectivity of the reaction to produce 3i.
Substrates 1j and 1k, which have dimethoxy substitution, afforded the corresponding products in 61%
and 50% yields, respectively. Substrate 1l, with a tetrasubstituted double bond, was also compatible
with the protocol; the corresponding product was obtained as the sole product in 61% yield. We next
turned our attention to pyridine substrates. To our delight, pyridine substrates gave bicyclic compounds
with different connectivity patterns; specifically, the reactions of 1mꢀ1o yielded quinoline and
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isoquinoline compounds 3mꢀ3o with an unsaturated phenyl ring, making this reaction complementary to
the hydrogenation of quinolines, which affords benzopiperidine compounds for the first time. When
subsitutes were introduced to the cycloproyl moiety of substrates 1p and 1q, the annulation cascade
reaction happened in the similar manner, offering products 3p and 3q respectively. The average
moderate yield might rise from the step of ringꢀopening of cyclopropyl to both Z and E alkene radical
speices, and only Z intermediate underwent subsequent annulation reaction to give desired product 3.
Table 3. Radical addition/CꢀH annulation cascade reactions of
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αꢀcyclopropylstyrene 1b with radical donors 2
[a] Reaction conditions: 1b (0.22 mmol), 2 (0.2 mmol), Ir(ppy)2(dtbbpy)PF6 (0.002 mmol, 1.0 mol %), anhydrous
CH3CN (2.0 mL), 24ꢀW blue LED strips, r.t., 8ꢀ36 h. Yields are for products isolated by chromatography. [b]The
reaction was carried out with Togni’s reagent.
Scheme 3. Difluoroalkylation/CꢀH annulation cascade reaction of an internal alkene
Subsequently, we evaluated various alternative αꢀbromo compounds as radical donors (Table 3). The
radical addition/CꢀH annulation cascade could be carried out with bromodifluoroacetamides to
afford aliphatic amine 3r and aniline 3s. Monofluoroacetate 3t could also be obtained in an
acceptable yield. The trifluoromethyl radical derived from Togni’s reagent gave corresponding
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product 3u in 59% yield.
αꢀBromoacetonitrile was converted to annulated product 3v, along
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with unidentified decomposition products. Malonate 3w was obtained in moderate yield. In
addition to the terminal olefins, a substrate with an internal double bond, that is, a
methylenecyclopropane group was prepared and subjected to the standard conditions, which
afforded expected annulation product 3x in 63% yield (Scheme 3).
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Scheme 4. Synthesis on a gram scale and subsequent functional group transformations
The reaction could be scaled up to 3.45 mmol of 1g, which yielded 1 gram of product 3g (Scheme 4,
eq. 1). When the LED power was 24 W, which was the same as that used for the smallꢀscale reactions,
prolonged reaction time (24 h) was required to ensure full conversion. To demonstrate the potential
synthetic applications of this reaction, we carried out several functional group manipulations.
Specifically, ester 3g could be hydrolyzed at room temperature to afford free acid 4g, reduced to αꢀ
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difluoroalcohol 5g with LiAlH4, or hydrogenated at 1 atm with Pd/C catalysis to give 6g. All of these
conversions were accomplished in excellent yields. Nitrile 3v could be reduced to aldehyde 7v in 80%
yield, and epoxidation of 3u with mꢀCPBA for 1.5 h afforded 8u in 75% yield.
In summary, we developed a protocol for visibleꢀlightꢀinduced photoredox difluoroalkylation/CꢀH
annulation cascade reactions for the construction of substituted dihydronaphthalenes. The reaction could
accommodate substrates bearing phenyl rings with various substitution patterns. Partially hydrogenated
substituted quinolones could be prepared from pyridine substrates by means of this protocol. Various
radical donors could be used for this transformation as well. Derivatization of the annulation products
afforded a variety functionalized bicyclic compounds.
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Experimental Section
1. General Information
All reactions that required anhydrous conditions were carried by standard procedures under
nitrogen atmosphere. Unless otherwise noted, materials were purchased from commercial suppliers and
used without further purification. The solvents were dried by distillation over the appropriate drying
reagents. Other chemicals were obtained from commercial sources, and were used without further
purification.
Column chromatography was generally performed on silica gel (300ꢀ400 mesh) and reactions were
monitored by thinꢀlayer chromatography (TLC) using 254 nm UV light to visualize the course of the
reactions.
1H NMR (400MHz), 13C NMR (100MHz) and 19F (376MHz) were measured on 400M
spectrometer. Chemical shifts are expressed in parts per million (ppm) with respect to the residual
solvent peak. Coupling constants are reported as Hertz (Hz), signal shapes and splitting patterns are
indicated as follows: s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet. IR spectra were
recorded as a thin film on a KBr disk (2 cm diameter) using an FTꢀIR spectrometer and reported in
wavenumbers (cmꢀ1).
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Highꢀresolution mass spectra (HRMS) were equipped with an ESI, EI source and a TOF detector
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mass spectrometer. The melting points were measured with digital melting point detector.
2. General procedure for Synthesis of substrates
General Procedure A: [13]
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To a flask charged with methyltriphenylphosphonium bromide (3.57 g, 10 mmol, 2 equiv) and 30
mL anhydrous THF at 0 °C was added nꢀbutyllithium (4 mL, 2.5 M in hexanes, 10 mmol, 2 equiv). The
reaction was allowed to warm to room temperature spontaneously and then stirred for 1 hour.
Cyclopropyl(aryl)methanone (5 mmol, 1 equiv) in anhydrous THF (3 mL) was added dropwise and the
reaction was stirred for 12 hours at 40 °C. After being quenched with brine, the mixture was extracted
with petroleum ether 3 times. The combined organic layers were washed with water three times, dried
(MgSO4), and concentrated. The residue was purified by flash chromatography to afford the desired
product.
General Procedure B: [14]
To a flask containing isopropyltriphenylphosphonium iodide (4.32 g, 10 mmol, 2 equiv) and 30 mL
anhydrous THF at 0 °C was added nꢀbutyllithium (4 mL, 2.5 M in hexanes, 10 mmol, 2 equiv). The
reaction was allowed to warm to room temperature spontaneously and then stirred for 1 hour.
Cyclopropyl(phenyl)methanone (5 mmol, 1 equiv) was added dropwise as a solution in dry THF (3 mL)
and the reaction was allowed to stir for 12 hours at 40 °C. After being quenched with brine, the mixture
was extracted with petroleum ether 3 times. The combined organic layers were washed with water three
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times, dried (MgSO4), and concentrated. The residue was purified by flash chromatography to afford the
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desired product 1l.
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General Procedure C: [15]
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To a solution of (3ꢀBromopropyl)triphenylphosphonium bromide (2.87 g, 6 mmol, 1.2 equiv) in
anhydrous THF (10 mL) was added t-BuOK (1.35 g, 12 mmol, 2.4 equiv) in anhydrous THF (10 mL)
dropwise. The resulting suspension was heated at reflux for 10 minutes and pꢀMethoxybenzaldehyde
(680 mg, 5 mmol, 1 equiv) was added as a solution in anhydrous THF (5 mL). The mixture was refluxed
for 2 hours. After cooling to room temperature, the mixture was layered with petroleum ether (20 mL)
and the cloudy suspension was filtered through celite. The residue was washed thoroughly with
petroleum ether. The filtrate was concentrated and purified by chromatography on silica gel affording
the desired product lx.
3. General procedure for the synthesis of products
An ovenꢀdried reaction vial was equipped with a magnetic stir bar, compound 1 (0.22 mmol),
Ir(ppy)2(dtbbpy)PF6 (0.002 mmol), compound 2 (0.2 mmol) and K2HPO4 (0.24 mmol). The flask was
evacuated and backfilled with nitrogen for 3 times. Anhydrous CH3CN (2 mL) was added with syringe.
The vial was placed at a distance (app. 5 cm) from 24w blue LEDs, and the resulting solution was
stirred at ambient temperature. After the complete conversion of substrates as judged by TLC or GCꢀMS
analysis, the mixture was concentrated under reduced pressure. The residue was purified by
chromatography on silica gel to afford the 3aꢀx.
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4. Spectroscopic data for the substrates
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α
ꢀcyclopropylstyrene 1a: This is a known compound[16] [CAS: 825ꢀ76ꢀ3]and prepared according to the
general procedure A (684 mg, yield: 95%), column chromatography on silica gel (petroleum ether). 1H
NMR (400 MHz, CDCl3) δ = 7.63 ꢀ 7.60 (m, 2H), 7.39 ꢀ 7.33 (m, 2H), 7.33 ꢀ 7.27 (m, 1H), 5.30 (s, 1H),
4.95 (s, 1H), 1.72 ꢀ 1.61 (m, 1H), 0.88 ꢀ 0.83 (m, 2H), 0.64 ꢀ 0.59 (m, 2H). 13C NMR (100 MHz, CDCl3)
δ = 149.3, 141.6, 128.1, 127.4, 126.0, 109.0, 15.6, 6.7. These data are consistent with the reported value.
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αꢀcyclopropylꢀ4ꢀmethylstyrene 1b: This is prepared according to the general procedure A (735 mg,
yield: 93%), chromatography on silica gel (petroleum ether). Colourless oil. IR (film) (cmꢀ1): 3084,
3050, 3007, 2866, 1625, 1512, 1427, 1021, 939, 888, 824, 732. 1H NMR (400 MHz, CDCl3) δ = 7.53 (d,
J = 8.0 Hz, 2H), 7.18 (d, J = 7.9 Hz, 2H), 5.28 (s, 1H), 4.93 (s, 1H), 2.39 (s, 3H), 1.73 ꢀ 1.62 (m, 1H),
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0.90 ꢀ 0.81 (m, 2H), 0.63 ꢀ 0.59 (m, 2H). C NMR (100 MHz, CDCl3) δ = 149.1, 138.7, 137.1, 128.8,
125.9, 108.2, 21.1, 15.6, 6.6. HRMS (EI) ([M]+) Calcd. For C12H14: 158.1096; found: 158.1093.
αꢀCyclopropylꢀ4ꢀfluorostyrene 1c: This is a known compound[17] [CAS: 827ꢀ87ꢀ2] and prepared
according to the general procedure A (786 mg, yield: 97%), chromatography on silica gel (petroleum
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ether). H NMR (400 MHz, CDCl3) δ = 7.64 ꢀ 7.51 (m, 2H), 7.09 ꢀ 6.96 (m, 2H), 5.23 (s, 1H), 4.92 (s,
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1H), 1.66 ꢀ 1.56 (m, 1H), 0.88 ꢀ 0.81 (m, 2H), 0.63 ꢀ 0.53 (m, 2H). C NMR (100 MHz, CDCl3) δ =
163.6, 161.1, 148.3, 137.6 (d, J = 3.3 Hz), 127.4 (d, J = 7.9 Hz), 115.0 (d, J = 21 Hz), 114.8, 108.9 (d, J
= 1.3 Hz), 15.7, 6.6. These data are consistent with the reported value.
α
ꢀcyclopropylꢀ4ꢀchlorostyrene 1d: This is a known compound[18] [CAS: 1009ꢀ33ꢀ2] and prepared
according to the general procedure A (881 mg, yield: 99%), chromatography on silica gel (petroleum
1
ether). H NMR (400 MHz, CDCl3) δ = 7.57 ꢀ 7.49 (m, 2H), 7.35 ꢀ 7.27 (m, 2H), 5.27 (s, 1H), 4.96 (s,
13
1H), 1.65 ꢀ 1.56 (m, 1H), 0.87 ꢀ 0.81 (m, 2H), 0.62 ꢀ 0.55 (m, 2H). C NMR (100 MHz, CDCl3) δ =
148.2, 140.0, 133.2, 128.2, 127.4, 109.6, 15.5, 6.6. These data are consistent with the reported value.
αꢀcyclopropylꢀ4ꢀbromostyrene 1e: This is prepared according to the general procedure A (1.01 g, yield:
91%), chromatography on silica gel (petroleum ether). Colourless oil. IR (film) (cmꢀ1): 3083, 3003,
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1623, 1587, 1487, 1390, 1086, 1008, 939, 895, 829, 731. 1H NMR (400 MHz, CDCl3) δ = 7.47 (s, 4H),
5.29 (s, 1H), 4.98 (s, 1H), 1.66 ꢀ 1.57 (m, 1H), 0.89 ꢀ 0.82 (m, 2H), 0.63 ꢀ 0.57 (m, 2H). 13C NMR (101
MHz, CDCl3). δ = 148.2, 140.5, 131.2, 127.7, 121.4, 109.6, 15.5, 6.6. HRMS (EI) ([M]+) Calcd. For
C11H11Br: 222.0044; found: 222.0050.
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αꢀcyclopropylꢀ4ꢀ(trifluoromethyl)styrene 1f: This is prepared according to the general procedure A
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(996 mg, yield: 94%), chromatography on silica gel (petroleum ether). Colourless oil. IR (film) (cmꢀ
1):3088, 3007, 1617, 1405, 1328, 1167, 1125, 1066, 1016,901,850,716. 1H NMR (400 MHz, CDCl3) δ =
7.69 (d, J = 8.3 Hz, 2H), 7.59 (d, J = 8.3 Hz, 2H), 5.35 (s, 1H), 5.05 (s, 1H), 1.70 ꢀ 1.60 (m, 1H), 0.92 ꢀ
13
0.84 (m, 2H), 0.65 ꢀ 0.58 (m, 2H). C NMR (100 MHz, CDCl3) δ = 148.3, 145.2, 129.4 (q, J = 32.4
Hz), 126.4, 125.09 (q, J = 3.8 Hz), 124.3 (q, J = 27 Hz), 111.1, 15.5, 6.7. HRMS (EI) ([M]+) Calcd. For
C12H11F3: 212.0813; found: 212.0809.
α
ꢀcyclopropylꢀ4ꢀmethoxystyrene 1g: This is a known compound[17] [CAS: 829ꢀ17ꢀ4] and prepared
according to the general procedure A (844 mg, yield: 97%), chromatography on silica gel (petroleum
ether/EtOAc = 97:3, v/v). 1H NMR (400 MHz, CDCl3) δ = 7.59 (d, J = 7.9 Hz, 2H), 6.92 (d, J = 7.9 Hz,
2H), 5.25 (s, 1H), 4.90 (s, 1H), 3.86 (s, 3H), 1.69 ꢀ 1.65 (m, 1H), 0.86 (d, J = 7.1 Hz, 2H), 0.63 (s, 2H).
13C NMR (101 MHz, CDCl3) δ = 159.1, 148.6, 134.2, 127.1, 113.5, 107.4, 55.3, 15.7, 6.5. These data
are consistent with the reported value.
α
ꢀcyclopropylꢀ2ꢀmethoxystyrene 1h: This is a known compound[19] [CAS: 1355988ꢀ71ꢀ4] and prepared
according to the general procedure A (783 mg, yield: 90%), chromatography on silica gel (petroleum
ether/EtOAc = 98:2, v/v). 1H NMR (400 MHz, CDCl3) δ = 7.26 (td, J = 8.0, 1.8 Hz, 1H), 7.14 (dd, J =
7.4, 1.7 Hz, 1H), 6.96 ꢀ 6.89 (m, 2H), 5.13 (dd, J = 1.5, 0.8 Hz, 1H), 4.97 (d, J = 1.7 Hz, 1H), 3.84 (s,
13
3H), 1.80 ꢀ 1.73 (m, 1H), 0.73 ꢀ 0.67 (m, 2H), 0.50 ꢀ 0.43 (m, 2H). C NMR (100 MHz, CDCl3) δ =
156.6, 149.3, 131.3, 130.1, 128.3, 120.2, 111.3, 110.7, 55.5, 16.7, 6.6. These data are consistent with the
reported value.
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α
ꢀcyclopropylꢀ3ꢀmethoxystyrene 1i: This is a known compound[20] [CAS: 1883688ꢀ65ꢀ0] and prepared
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according to the general procedure A (792 mg, yield: 91%), chromatography on silica gel (petroleum
ether/EtOAc = 98:2, v/v). 1H NMR (400 MHz, CDCl3) δ = 7.32 (t, J = 7.7 Hz, 1H), 7.25 (d, J = 7.6 Hz,
1H), 7.22 (s, 1H), 6.90 (d, J = 7.9 Hz, 1H), 5.34 (s, 1H), 5.00 (s, 1H), 3.89 (s, 3H), 1.77 ꢀ 1.64 (m, 1H),
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0.90 (d, J = 7.6 Hz, 2H), 0.70 ꢀ 0.63 (m, 2H). C NMR (101 MHz, CDCl3) δ = 159.4, 149.2, 143.2,
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129.0, 118.7, 112.6, 112.1, 109.2, 55.1, 15.6, 6.7. These data are consistent with the reported value.
αꢀcyclopropylꢀ1,2ꢀdimethoxystyrene 1j: This is prepared according to the general procedure A (1.04 g,
yield: 92%), chromatography on silica gel (petroleum ether/EtOAc = 95:5, v/v). Colourless oil. IR (film)
1
(cmꢀ1): 3081, 3002, 2933, 2835, 1575, 1471, 1425, 1262, 1229, 1057, 1010, 894, 748. H NMR (400
MHz, CDCl3) δ = 7.00 (t, J = 7.9 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H), 5.08 (s,
1H), 4.98 (s, 1H), 3.87 (s, 3H), 3.80 (s, 3H), 1.80 ꢀ 1.64 (m, 1H), 0.75 ꢀ 0.67 (m, 2H), 0.53 ꢀ 0.47 (m,
2H). 13C NMR (100 MHz, CDCl3) δ = 152.7, 148.9, 146.3, 136.9, 123.5, 122.1, 111.2, 111.2, 60.8, 55.8,
16.9, 6.8. HRMS (ESI) ([M+Na]+) Calcd. For C13H16O2Na: 227.1042, found: 227.1043.
αꢀcyclopropylꢀ3,4ꢀdimethoxystyrene 1k: This is prepared according to the general procedure A (1.05 g,
yield: 93%), chromatography on silica gel (petroleum ether/EtOAc = 5:1, v/v). White solid, mp. 55ꢀ57
1
oC. IR (film) (cmꢀ1): 2996, 2962, 2941, 2841, 1217, 1144, 1021, 867. H NMR (400 MHz, CDCl3) δ =
7.19 (d, J = 8.3 Hz, 1H), 7.14 (s, 1H), 6.85 (d, J = 8.3 Hz, 1H), 5.21 (s, 1H), 4.87 (s, 1H), 3.91 (s, 3H),
13
3.89 (s, 3H), 1.67 ꢀ 1.58 (m, 1H), 0.83 (q, J = 5.6 Hz, 2H), 0.59 (q, J = 5.3 Hz, 2H). C NMR (100
MHz, CDCl3) δ = 148.8, 148.7, 148.5, 134.6, 118.5, 110.8, 109.5, 107.7, 55.9, 55.8, 15.7, 6.6. HRMS
(ESI) ([M+Na]+) Calcd. For C13H16O2Na: 227.1042, found: 227.1043.
α
ꢀcyclopropylꢀβ,βꢀDimethylstyrene 1l: This is a known compound[21] [CAS: 34564ꢀ76ꢀ6] and prepared
according to the general procedure B (645 mg, yield: 75%), chromatography on silica gel (petroleum
ether/EtOAc = 97:3, v/v). 1H NMR (400 MHz, CDCl3) δ = 7.28 (t, J = 7.3 Hz, 2H), 7.19 (t, J = 7.0 Hz,
1H), 6.97 (d, J = 7.3 Hz, 2H), 1.95 (s, 3H), 1.85 ꢀ 1.77 (m, 1H), 1.49 (s, 3H), 0.58 (d, J = 7.4 Hz, 2H),
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0.14 (d, J = 2.0 Hz, 2H). C NMR (100 MHz, CDCl3) δ = 141.0, 135.3, 129.8, 128.7, 127.6, 125.8,
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22.7, 20.1, 13.6, 5.0. These data are consistent with the reported value.
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αꢀcyclopropylꢀ2ꢀPyridylethylene 1m: This is prepared according to the general procedure A (620 mg,
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yield: 85%), chromatography on silica gel (petroleum ether/EtOAc = 9:1, v/v). Colourless oil. IR (film)
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(cmꢀ1): 3080, 3003, 1770, 1584, 1563, 1468, 1430, 1245, 803, 746. H NMR (400 MHz, CDCl3) δ =
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8.60 (d, J = 4.6 Hz, 1H), 7.66 (q, J = 7.9 Hz, 2H), 7.17 (t, J = 5.8 Hz, 1H), 5.89 (s, 1H), 5.12 (s, 1H),
13
1.88 ꢀ 1.80 (m, 1H), 0.91 ꢀ 0.83 (m, 2H), 0.63 ꢀ 0.57 (m, 2H). C NMR (100 MHz, CDCl3) δ = 158.2,
148.9, 148.5, 136.3, 122.2, 120.4, 112.5, 14.1, 6.9. HRMS (ESI) ([M+H]+) Calcd. For C10H12N:
146.0964, found: 146.0966.
αꢀcyclopropylꢀ3ꢀPyridylethylene 1n: This is prepared according to the general procedure A (642 mg,
yield: 88%), chromatography on silica gel (petroleum ether/EtOAc = 9:1, v/v). Colourless oil. IR (film)
(cmꢀ1): 3084, 3006, 1624, 1475, 1409, 1022, 897, 814, 718. 1H NMR (400 MHz, CDCl3) δ = 8.83 (d, J =
1.9 Hz, 1H), 8.50 (dd, J = 4.8, 1.5 Hz, 1H), 7.87 ꢀ 7.84 (m, 1H), 7.27 ꢀ 7.24 (m, 1H), 5.32 (s, 1H), 5.03
(s, 1H), 1.66 ꢀ 1.57 (m, 1H), 0.89 ꢀ 0.83 (m, 2H), 0.62 ꢀ 0.56 (m, 2H). 13C NMR (100 MHz, CDCl3) δ =
148.5, 147.5, 146.4, 136.9, 133.3, 123.0, 110.8, 15.3, 6.5. HRMS (ESI) ([M+H]+) Calcd. For C10H12N:
146.0964, found: 146.0965.
αꢀcyclopropylꢀ4ꢀPyridylethylene 1o: This is prepared according to the general procedure A (606 mg,
yield: 83%), chromatography on silica gel (petroleum ether/EtOAc = 9:1, v/v). Colourless oil. IR (film)
1
(cmꢀ1): 3082, 3004, 1623, 1474, 1022, 897, 813, 718. H NMR (400 MHz, CDCl3) δ = 8.83 (d, J = 1.9
Hz, 1H), 8.51 (dd, J = 4.8, 1.5 Hz, 1H), 7.87 ꢀ 7.85 (m, 1H), 7.27 ꢀ 7.24 (m, 1H), 5.32 (s, 1H), 5.03 (s,
13
1H), 1.65 ꢀ 1.56 (m, 1H), 0.88 ꢀ 0.84 (m, 2H), 0.62 ꢀ 0.58 (m, 2H). C NMR (100 MHz, CDCl3) δ =
148.5, 147.5, 146.4, 136.9, 133.3, 123.0, 110.8, 15.3, 6.5. HRMS (ESI) ([M+H]+) Calcd. For C10H12N:
146.0964, found: 146.0965.
α
ꢀcyclopropanecarboxylateꢀstyrene 1p: This is a known compound[22] [CAS: 54143ꢀ12ꢀ3] and prepared
according to the general procedure A (930 mg, yield: 86%), chromatography on silica gel (petroleum
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ether/EtOAc = 98:2, v/v). Colourless oil. 1H NMR (400 MHz, CDCl3) δ = 7.51 (d, J = 7.2 Hz, 2H), 7.37
ꢀ 7.28 (m, 3H), 5.38 (s, 1H), 5.03 (s, 1H), 4.19 (q, J = 7.1 Hz, 2H), 2.31 ꢀ 2.26 (m, 1H), 1.81 ꢀ 1.76 (m,
1H), 1.51 ꢀ 1.46 (m, 1H), 1.30 (t, J = 7.1 Hz, 3H), 1.23 ꢀ 1.18 (m, 1H). 13C NMR (100 MHz, CDCl3) δ =
173.5 (s), 146.2 (s), 140.2 (s), 128.3 (s), 127.8 (s), 126.0 (s), 111.1 (s), 60.6 (s), 26.0 (s), 22.2 (s), 15.3
(s), 14.3 (s). These data are consistent with the reported value.
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α
ꢀcyclopropaneꢀ1,1ꢀdicarboxylateꢀstyrene 1p: This is a known compound[23] [CAS: 1943680-29-2]
and prepared according to the general procedure A (1400 mg, yield: 77%), chromatography on silica gel
1
(petroleum ether/EtOAc = 95:5, v/v). Colourless oil. H NMR (400 MHz, CDCl3) δ = 7.64 (d, J = 7.3
Hz, 2H), 7.40 ꢀ 7.27 (m, 8H), 5.73 (s, 1H), 5.32 (s, 1H), 4.02 ꢀ 3.94 (m, 3H), 3.92 ꢀ 3.86(m, 1H), 3.70 ꢀ
13
3.63 (m, , 2H), 0.97 ꢀ 0.97 (m, 6H). C NMR (100 MHz, CDCl3) δ = 166.7 (s), 166.5 (s), 140.9 (s),
139.1 (s), 134.7 (s), 128.8 (s), 128.3 (s), 128.2 (s), 127.8 (s), 127.4 (s), 126.0 (s), 114. 8 (s), 61.4 (s),
61.4 (s), 44.9 (s), 34.8 (s), 34.4 (s), 13.8 (s), 13.8 (s). These data are consistent with the reported value.
1ꢀ(cyclopropylidenemethyl)ꢀ4ꢀmethoxybenzene 1x: This a known compound[24] [CAS: 55088ꢀ84ꢀ1] and
prepared according to the general procedure C (584 mg, yield: 73%), chromatography on silica gel
1
(petroleum ether/EtOAc = 95:5, v/v). H NMR (400 MHz, CDCl3) δ = 7.48 (d, J = 4.0 Hz, 2H), 6.93 ꢀ
6.84 (m, 2H), 6.73 ꢀ 6.67 (m, 1H), 3.82 (s, 3H), 1.42 ꢀ 1.38 (m, 2H), 1.19 ꢀ 1.15 (m, 2H). 13C NMR (100
MHz, CDCl3) δ = 158.5, 131.2, 127.6, 121.7, 117.5, 113.9, 55.2, 4.0, 0.5. These data are consistent with
the reported value.
5. Spectroscopic data for products
Ethyl 3ꢀ(3,4ꢀdihydronaphthalenꢀ1ꢀyl)ꢀ2,2ꢀdifluoropropanoate 3a[5b]
:
33 mg, yield: 63%,
chromatography on silica gel (petroleum ether/EtOAc = 95:5, v/v). Colourless oil. IR (film) (cmꢀ1):
2921, 2850, 1770, 1222, 1089. 1H NMR (400 MHz, CDCl3) δ = 7.26 ꢀ 7.13 (m, 4H), 6.09 (t, J = 4.5 Hz,
1H), 4.15 (q, J = 7.1 Hz, 2H), 3.25 (t, J = 15.9 Hz, 2H), 2.75 (t, J = 8.0 Hz, 2H), 2.31 ꢀ 2.26 (m, 2H),
13
1.22 (t, J = 7.2 Hz, 3H). C NMR (100 MHz, CDCl3) δ = 164.1 (t, J = 32.6 Hz), 136.3, 133.9, 131.6,
127.6, 127.3 (t, J = 4.4 Hz), 127.2, 126.3, 115.5 (t, J = 252.3 Hz), 62.7, 37.3 (t, J = 24.2 Hz), 28.0, 23.2,
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13.8. 19F NMR (376 MHz, CDCl3) δ = ꢀ103.32. HRMS (ESI) ([M+Na]+) Calcd. For C15H16F2O2Na:
289.1010, found: 289.1010.
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Ethyl 2,2ꢀdifluoroꢀ3ꢀ(6ꢀmethylꢀ3,4ꢀdihydronaphthalenꢀ1ꢀyl)propanoate 3b: 36 mg, yield: 65%,
chromatography on silica gel (petroleum ether/EtOAc = 95:5, v/v). Colourless oil. IR (film) (cmꢀ1):
2984, 2933, 2831.80, 1770, 1221, 1185, 1086, 828. 1H NMR (400 MHz, CDCl3) δ = 7.13 (d, J = 7.9 Hz,
1H), 7.00 (d, J = 7.9 Hz, 1H), 6.95 (s, 1H), 6.01 (t, J = 4.5 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 3.22 (t, J =
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15.9 Hz, 2H), 2.70 (t, J = 8.0 Hz, 2H), 2.31 (s, 3H), 2.28 ꢀ 2.23 (m, 2H), 1.23 (t, J = 7.1 Hz, 3H). C
NMR (100 MHz, CDCl3) δ = 164.1 (t, J = 33 Hz), 136.9, 136.3, 131.3, 130.5, 128.5, 127.3 (t, J = 4.4
Hz), 126.8, 122.9, 115.6 (t, J = 251 Hz), 62.7, 37.4 (t, J = 24 Hz), 28.1, 23.3, 21.1, 13.8. 19F NMR (376
MHz, CDCl3) δ = ꢀ103.27. HRMS (ESI) ([M+Na]+) Calcd. For C16H18F2O2Na: 303.1167, found:
303.1169.
Ethyl 2,2ꢀdifluoroꢀ3ꢀ(6ꢀfluoroꢀ3,4ꢀdihydronaphthalenꢀ1ꢀyl)propanoate 3c: 34 mg, yield: 34%,
chromatography on silica gel (petroleum ether/EtOAc = 95:5, v/v). Colourless oil. IR (film) (cmꢀ1):
1
2935, 1769, 1497, 1245, 1086. H NMR (400 MHz, CDCl3) δ = 7.20 (dd, J = 8.4, 5.6 Hz, 1H), 6.90 –
6.83 (m, 2H), 6.03 (t, J = 4.6 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.21 (t, J = 15.9 Hz, 2H), 2.73 (t, J = 8.0
Hz, 2H), 2.29 ꢀ 2.24 (m, 2H), 1.24 (t, J = 7.1 Hz, 4H). 13C NMR (100 MHz, CDCl3) δ = 164.0 (t, J = 32
Hz), 161.7 (d, J = 245 Hz), 139.0 (d, J = 8 Hz), 130.8 (d, J = 1.9 Hz), 130.1 (d, J = 3Hz), 126.7 (t, J = 4
Hz), 124.5 (d, J = 8.3 Hz), 115.4 (t, J = 251Hz), 114.8 (d, J = 22Hz), 112.7 (d, J = 21Hz), 62.8, 37.5 (t,
19
J = 36Hz), 28.2 (d, J = 1.4 Hz), 22.9, 13.8. F NMR (376 MHz, CDCl3) δ = ꢀ103.40, ꢀ115.09. HRMS
(ESI) ([M+Na]+) Calcd. For C15H15F3O2Na: 307.0916, found: 307.0926.
Ethyl 3ꢀ(6ꢀchloroꢀ3,4ꢀdihydronaphthalenꢀ1ꢀyl)ꢀ2,2ꢀdifluoropropanoate 3d: 38 mg, yield: 64%,
chromatography on silica gel (petroleum ether/EtOAc = 95:5, v/v). Colourless oil. IR (film) (cmꢀ1):
1
2984, 2939, 2385, 1769, 1487, 1221, 1186, 1102, 1084, 844. H NMR (400 MHz, CDCl3) δ = 7.16 (s,
2H), 7.12 (s, 1H), 6.08 (t, J = 4.6 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.21 (t, J = 15.9 Hz, 2H), 2.72 (t, J
= 8.0 Hz, 2H), 2.30 ꢀ 2.25 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ = 164.0 (t, J
= 32.6 Hz), 138.2, 132.5, 132.4, 132.0, 127.7, 126.7 (t, J = 4.3 Hz), 126.3, 124.2, 115.4 (t, J = 251 Hz),
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62.8, 37.3 (t, J = 24 Hz), 27.9, 23.0, 13.8. 19F NMR (376 MHz, CDCl3) δ = ꢀ103.41. HRMS (ESI)
([M+Na]+) Calcd. For C15H15ClF2O2Na: 323.0621, found: 323.0619.
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Ethyl 3ꢀ(6ꢀbromoꢀ3,4ꢀdihydronaphthalenꢀ1ꢀyl)ꢀ2,2ꢀdifluoropropanoate 3e: 40 mg, yield: 58%,
chromatography on silica gel (petroleum ether/EtOAc = 95:5, v/v). Colourless oil. IR (film) (cmꢀ1):
2984, 2937, 2832.65, 1768, 1488, 1221, 1185, 1094, 827. 1H NMR (400 MHz, CDCl3) δ = 7.32 (dd, J =
8.3, 2.0 Hz, 1H), 7.27 (s, 1H), 7.10 (d, J = 8.3 Hz, 1H), 6.09 (t, J = 4.5 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H),
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3.20 (t, J = 15.9 Hz, 2H), 2.72 (t, J = 8.0 Hz, 2H), 2.29 ꢀ 2.24 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H). C
NMR (100 MHz, CDCl3) δ = 164.0 (t, J = 32.6 Hz), 138.5, 132.9, 132.2, 130.5, 129.325, 126.8, 124.5,
120.7, 115.4 (t, J = 251 Hz), 62.8, 37.3 (t, J = 24 Hz), 27.8, 23.0, 13.8. 19F NMR (376 MHz, CDCl3) δ =
ꢀ103.43. HRMS (ESI) ([M+Na]+) Calcd. For C15H15BrF2O2Na: 367.0115, found: 367.0113.
Ethyl 2,2ꢀdifluoroꢀ3ꢀ(6ꢀ(trifluoromethyl)ꢀ3,4ꢀdihydronaphthalenꢀ1ꢀyl)propanoate 3f: 37 mg, yield:
56%, chromatography on silica gel (petroleum ether/EtOAc = 95:5, v/v). Colourless oil. IR (film) (cmꢀ1):
2984, 2941, 2837, 1770, 1324, 1168, 1122, 1093, 843. 1H NMR (400 MHz, CDCl3) δ = 7.45 (d, J = 8.1
Hz, 1H), 7.38 (s, 1H), 7.34 (d, J = 8.1 Hz, 1H), 6.21 (t, J = 4.3 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.26 (t,
J = 15.9 Hz, 2H), 2.80 (t, J = 8.0 Hz, 2H), 2.35 ꢀ 2.30 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ = 163.9 (t, J = 32.5 Hz), 137.2, 136.9, 134.3, 128.9 (q, J = 32 Hz), 126.8 (t, J = 4.0 Hz),
124.3 (q, J = 3.7 Hz), 124.1 (q, J = 270 Hz), 123.1 (q, J = 270 Hz), 123.1, 115.3 (t, J = 251 Hz), 62.9,
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37.3 (t, J = 24 Hz), 27.8, 23.0, 13.8. F NMR (376 MHz, CDCl3) δ = ꢀ62.54, ꢀ103.56. HRMS (ESI)
([M+Na]+) Calcd. For C16H15F5O2Na: 357.0884, found: 357.0893.
Ethyl 2,2ꢀdifluoroꢀ3ꢀ(6ꢀmethoxyꢀ3,4ꢀdihydronaphthalenꢀ1ꢀyl)propanoate 3g: 40 mg, yield: 68%,
chromatography on silica gel (petroleum ether/EtOAc = 95:5, v/v). Colourless oil. IR (film) (cmꢀ1):
2986, 2937, 2835, 1770, 1608, 1568, 1502, 1434, 1374, 1253, 1085, 1039. 1H NMR (400 MHz, CDCl3)
δ = 7.17 (d, J = 8.2 Hz, 1H), 6.72 (d, J = 9.6 Hz, 2H), 5.94 (s, 1H), 4.16 (q, J = 7.1 Hz, 2H), 3.80 (s, 3H),
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3.21 (t, J = 15.9 Hz, 2H), 2.72 (t, J = 7.9 Hz, 2H), 2.28 ꢀ 2.23 (m, 2H), 1.23 (t, J = 7.2 Hz, 3H). C
NMR (100 MHz, CDCl3) δ = 164.1 (t, J = 32.6 Hz), 158.6, 138.2, 129.0, 127.0, 126.9 (t, J = 5 Hz),
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124.1, 115.6 (t, J = 251 Hz), 113.9, 110.7, 62.7, 55.2, 37.5 (t, J = 24 Hz), 28.6, 23.2, 13.8. F NMR
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(376 MHz, CDCl3) δ = ꢀ103.24. HRMS (ESI) ([M+Na]+) Calcd. For C16H18F2O3Na: 319.1116, found:
319.1120.
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Ethyl 2,2ꢀdifluoroꢀ3ꢀ(8ꢀmethoxyꢀ3,4ꢀdihydronaphthalenꢀ1ꢀyl)propanoate 3h: 31 mg, yield: 53%,
chromatography on silica gel (petroleum ether/EtOAc = 95:5, v/v). Colourless oil. IR (film) (cmꢀ1):
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2922, 2838, 1769, 1574, 1461, 1262, 1083. H NMR (400 MHz, CDCl3) δ = 7.16 (t, J = 8.0 Hz, 1H),
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6.90 (d, J = 7.8 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 6.09 (t, J = 4.6 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.83
(s, 3H), 3.23 (t, J = 15.9 Hz, 2H), 2.74 (t, J = 8.2 Hz, 2H), 2.27 ꢀ 2.21 (m, 2H), 1.22 (t, J = 7.2 Hz, 3H).
13C NMR (100 MHz, CDCl3) δ = 164.1 (t, J = 32 Hz), 156.0, 1345.0, 131.9, 127.2 (t, J = 4 Hz), 126.3,
124.3, 115.9, 115.5 (t, J = 251 Hz), 110.0, 77.3, 77.0, 76.7, 62.7, 55.6, 37.7 (t, J = 24 Hz), 22.6, 19.6,
13.8. 19F NMR (376 MHz, CDCl3) δ = ꢀ103.40. HRMS (ESI) ([M+H]+) Calcd. For C16H19F2O3:
297.1297, found: 297.1298.
Ethyl 2,2ꢀdifluoroꢀ3ꢀ(5ꢀmethoxyꢀ3,4ꢀdihydronaphthalenꢀ1ꢀyl)propanoate 3i: 28 mg, yield: 48%,
chromatography on silica gel (petroleum ether/EtOAc = 9:51, v/v). Colourless oil. IR (film) (cmꢀ1):
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2937, 2837, 1768, 1754, 1461, 1262, 1083. H NMR (400 MHz, CDCl3) δ = 7.16 (t, J = 8.1 Hz, 1H),
6.90 (d, J = 7.8 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 6.09 (t, J = 4.6 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.83
(s, 3H), 3.23 (t, J = 15.9 Hz, 2H), 2.75 (t, J = 8.2 Hz, 2H), 2.27 ꢀ 2.21 (m, 2H), 1.22 (t, J = 7.2 Hz, 3H).
13C NMR (100 MHz, CDCl3) δ = 164.1 (t, J = 32.6 Hz), 156.0, 135.0, 131.9, 127.2 (t, J = 4.5 Hz), 126.3,
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124.3, 115.9, 115.5 (t, J = 250 Hz), 109.9, 62.7, 55.6, 37.7 (t, J = 24.2 Hz), 37.7, 22.6, 19.6, 13.8. F
NMR (376 MHz, CDCl3) δ = ꢀ103.39. HRMS (ESI) ([M+Na]+) Calcd. For C16H18F2O3Na: 319.1116,
found: 319.1120.
Ethyl 3ꢀ(7,8ꢀdimethoxyꢀ3,4ꢀdihydronaphthalenꢀ1ꢀyl)ꢀ2,2ꢀdifluoropropanoate 3j: 40 mg, yield: 61%,
chromatography on silica gel (petroleum ether/EtOAc = 9:1, v/v). Colourless oil. IR (film) (cmꢀ1): 2939,
2835, 1768.05, 1474, 1261, 1088, 1059, 1021, 803. 1H NMR (400 MHz, CDCl3) δ = 6.85 (d, J = 8.2 Hz,
1H), 6.72 (d, J = 8.1 Hz, 1H), 6.14 (t, J = 4.8 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 3.83 (s, 3H), 3.77 (s,
3H), 3.62 (t, J = 16.3 Hz, 2H), 2.55 (t, J = 7.4 Hz, 2H), 2.14 ꢀ 2.09 (m, 2H), 1.20 (t, J = 7.1 Hz, 3H). 13C
NMR (100 MHz, CDCl3) δ = 164.2 (t, J = 33 Hz), 151.8, 146.3, 134.2, 131.3, 127.3, 127.3 (t, J = 5 Hz),
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122.2, 116.0 (t, J = 250 Hz), 110.7, 62.4, 60.5, 55.9, 39.3 (t, J = 24 Hz), 39.1, 38.8, 28.7, 23.5, 13.7. 19F
NMR (376 MHz, CDCl3) δ = ꢀ103.81. HRMS (ESI) ([M+Na]+) Calcd. For C17H20F2O4Na: 349.1222,
found: 349.1226.
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Ethyl 3ꢀ(5,6ꢀdimethoxyꢀ3,4ꢀdihydronaphthalenꢀ1ꢀyl)ꢀ2,2ꢀdifluoropropanoate 3k: 33 mg, yield: 50%,
chromatography on silica gel (petroleum ether/EtOAc = 9:1, v/v). Colourless oil. IR (film) (cmꢀ1): 2936,
2837, 1770, 1490, 1270, 1225, 1089. 1H NMR (400 MHz, CDCl3) δ = 6.98 (d, J = 8.5 Hz, 1H), 6.73 (d,
J = 8.5 Hz, 1H), 5.96 (t, J = 4.6 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 3.78 (s, 3H), 3.20 (t, J =
15.9 Hz, 2H), 2.79 (t, J = 2 Hz, 2H), 2.26 ꢀ 2.21 (m, 2H), 1.23 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ = 164.1 (t, J = 32.6 Hz), 152.2, 145.7, 130.3, 129.5, 127.8, 126.9, 119.0, 115.6, 109.0, 62.7,
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60.4, 55.6, 37.6 (t, J = 24Hz), 22.7, 20.6, 13.8. F NMR (376 MHz, CDCl3) δ = ꢀ103.17. HRMS (ESI)
([M+Na]+) Calcd. For C17H20F2O4Na: 349.1222, found: 349.1226.
Ethyl 3ꢀ(3,4ꢀdihydronaphthalenꢀ1ꢀyl)ꢀ2,2ꢀdifluoroꢀ3ꢀmethylbutanoate 3l: 36 mg, yield: 61%,
chromatography on silica gel (petroleum ether/EtOAc = 95:5, v/v). Colourless oil. IR (film) (cmꢀ1):
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2983, 2922, 2853, 1761, 1301, 1248, 1128, 1098, 1057, 705. H NMR (400 MHz, CDCl3) δ = 7.31 ꢀ
7.26 (m, 2H), 7.08 (d, J = 7.0 Hz, 2H), 5.84 (t, J = 7.0 Hz, 1H), 4.33 (d, J = 7.1 Hz, 2H), 3.25 (t, J = 6.8
Hz, 2H), 2.23 (q, J = 6.9 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H), 1.27 (s, 6H). 13C NMR (100 MHz, CDCl3) δ
= 164.0 (t, J = 34 Hz), 144.8, 138.8, 129.6, 129.1, 127.8, 126.9, 118.4 (t, J = 257 Hz), 62.6, 45.3 (t, J =
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21 Hz), 32.7, 32.3, 23.1 (t, J = 4 Hz), 14.0. F NMR (376 MHz, CDCl3) δ = ꢀ108.11. HRMS (ESI)
([M+Na]+) Calcd. For C17H20F2O2Na: 317.1323, found: 317.1312.
Ethyl 3ꢀ(5,6ꢀdihydroquinolinꢀ8ꢀyl)ꢀ2,2ꢀdifluoropropanoate 3m: 27 mg, yield: 50%, chromatography
on silica gel (petroleum ether/EtOAc = 9:1, v/v). Colourless oil. IR (film) (cmꢀ1): 2987, 1938, 2835,
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1768, 1443, 1223, 1197, 1088; H NMR (400 MHz, CDCl3) δ = 8.33 (d, J = 4.8 Hz, 1H), 7.37 (d, J =
7.4 Hz, 1H), 7.03 (dd, J = 7.1, 5.2 Hz, 1H), 6.36 (t, J = 4.3 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.50 (t, J =
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16.2 Hz, 2H), 2.81 (t, J = 8.1 Hz, 2H), 2.38 ꢀ 2.33 (m, 2H), 1.18 (t, J = 7.1 Hz, 3H); C NMR (100
MHz, CDCl3) δ = 164.2 (t, J = 33 Hz), 152.5, 146.4, 134.9, 134.7, 131.2, 129.9 (t, J = 4.8 Hz), 121.9,
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115.4 (t, J = 249 Hz), 62.4, 35.6 (t, J = 25 Hz), 27.1, 22.8, 13.7; 19F NMR (376 MHz, CDCl3) δ = ꢀ
103.37. HRMS (ESI) ([M+H]+) Calcd. For C14H16F2NO2: 268.1144, found: 268.1142.
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Ethyl 3ꢀ(7,8ꢀdihydroquinolinꢀ5ꢀyl)ꢀ2,2ꢀdifluoropropanoate 3n: 25 mg, yield: 47%, chromatography on
silica gel (petroleum ether/acetone = 4:1, v/v). Colourless oil. IR (film) (cmꢀ1): 2986, 2940, 2833, 1766,
1442, 1225, 1185, 1092. 1H NMR (400 MHz, CDCl3) δ = 8.30 (d, J = 4.9 Hz, 1H), 7.49 (d, J = 7.8 Hz,
1H), 7.12 (dd, J = 7.6, 5.1 Hz, 1H), 6.11 (t, J = 4.4 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.19 (t, J = 16.0
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Hz, 2H), 2.95 (t, J = 8.2 Hz, 2H), 2.45 ꢀ 2.40 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H). C NMR (101 MHz,
CDCl3) δ = 163.9 (t, J = 32 Hz), 157.0, 147.0, 132.9, 129.8, 129.4, 126.0 (t, J = 4.1 Hz), 121.6, 115.3 (t,
J = 251 Hz), 62.9, 36.8 (t, J = 24 Hz), 30.4, 23.0, 13.8. 19F NMR (376 MHz, CDCl3) δ = ꢀ103.44.
HRMS (ESI) ([M+H]+) Calcd. For C14H16F2NO2: 268.1144, found: 268.1141.
Ethyl 3ꢀ(7,8ꢀdihydroisoquinolinꢀ5ꢀyl)ꢀ2,2ꢀdifluoropropanoate 3o: 30 mg, yield: 56%, chromatography
on silica gel (petroleum ether/EtOAc = 2:1, v/v). Colourless oil. IR (film) (cmꢀ1): 2982, 2937, 2833,
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1764, 1442, 1225, 1185, 1092. H NMR (400 MHz, CDCl3) δ = 8.30 (d, J = 4.8 Hz, 1H), 7.49 (d, J =
7.8 Hz, 1H), 7.11 (dd, J = 7.5, 5.1 Hz, 1H), 6.10 (t, J = 4.3 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.19 (t, J =
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15.9 Hz, 2H), 2.95 (t, J = 8.2 Hz, 2H), 2.44 ꢀ 2.39 (m, 2H), 1.23 (t, J = 7.1 Hz, 3H). C NMR (100
MHz, CDCl3) δ = 163.8 (t, J = 32Hz), 157.0, 147.0, 132.9, 129.8, 129.4, 126.0 (t, J = 4.1 Hz), 121.6,
115.3 (t, J = 251Hz), 62.9, 36.7, 36.5, 30.4, 23.0, 13.8. 19F NMR (376 MHz, CDCl3) δ = ꢀ103.47.
HRMS (ESI) ([M+H]+) Calcd. For C14H16F2NO2: 268.1144, found: 268.1141.
Ethyl 4ꢀ(3ꢀethoxyꢀ2,2ꢀdifluoroꢀ3ꢀoxopropyl)ꢀ1,2ꢀdihydronaphthaleneꢀ1ꢀcarboxylate 3p: 46 mg, yield:
68%, chromatography on silica gel (petroleum ether/EtOAc = 95:5, v/v). Colourless oil. IR (film) (cmꢀ
1): 2984, 2920, 2850, 1770, 1732, 1373, 1299, 1224, 1185, 1093, 1030, 759. 1H NMR (400 MHz, CDCl3)
δ = 7.30 ꢀ 7.25 (m, 2H), 7.23 ꢀ 7.18 (m, 2H), 6.05 (t, J = 4.4 Hz, 1H), 4.23 ꢀ 4.10 (m, 4H), 3.70 (t, J =
6.6 Hz, 1H), 3.33 ꢀ 3.14 (m, 2H), 2.84 ꢀ 2.77 (m, 1H), 2.53 ꢀ 2.46 (m, 1H), 1.27 ꢀ 1.19 (m, 6H). 13C
NMR (100 MHz, CDCl3) δ = 173.13 (s), 163.9 (t, J = 32 Hz), 133.4 (s), 133.0 (s), 129.6 (s), 128.3 (s),
127.5 (s), 127.5 (s), 127.2 (t, J = 4 Hz), 123.3 (s), 115.3 (t, J = 251 Hz), 62.8 (s), 60.9 (s), 43.9 (s), 37.1
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(t, J = 24 Hz), 26.02 (s), 14.1 (s), 13.8 (s).19F NMR (376 MHz, CDCl3) δ = ꢀ103.22. HRMS (ESI)
([M+Na]+) Calcd. For C18H20F2O4Na: 361.1222, found: 361.1231.
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Diethyl 4ꢀ(3ꢀethoxyꢀ2,2ꢀdifluoroꢀ3ꢀoxopropyl)ꢀ2ꢀphenylnaphthaleneꢀ1,1(2H)ꢀdicarboxylate 3q: 58
mg, yield: 60%, chromatography on silica gel (petroleum ether/EtOAc = 9:1, v/v). Colourless oil. IR
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(film) (cmꢀ1): 2983, 2920, 2850, 1757, 1735, 1222, 1182, 1092, 1048, 757, 699. H NMR (400 MHz,
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CDCl3) δ = 7.57 (d, J = 7.7 Hz, 1H), 7.39 ꢀ 7.33 (m, 2H), 7.31 ꢀ 7.28 (m, 1H), 7.17 ꢀ 7.11 (m, 3H), 7.01
(d, J = 6.6 Hz, 2H), 6.17 (d, J = 6.3 Hz, 1H), 4.50 (d, J = 6.2 Hz, 1H), 4.19 ꢀ 4.13 (m, 3H), 4.07 ꢀ 4.01
(m, 1H), 3.91 (q, J = 7.1 Hz, 2H), 3.40 (q, J = 15.4 Hz, 1H), 3.20 (q, J = 15.4 Hz, 1H), 1.22 (d, J = 7.2
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Hz, 3H), 1.13 (t, J = 7.1 Hz, 3H), 1.05 (t, J = 7.1 Hz, 3H). C NMR (100 MHz, CDCl3) δ = 169.2 (s),
168.8 (s), 163.8 (t, J = 32 Hz), 137.2 (s), 133.3 (s), 132.9 (s), 131.8 (s), 129.9 (s), 129.1 (s), 128.2 (s),
128.1 (s), 127.8 (s), 127.7 (s), 124.8 (t, J = 4 Hz), 123.3 (s) , 115.4 (t, J = 251 Hz), 63.2 (s), 62.9 (s),
61.9 (s), 61.3 (s), 46.4 (s), 37.1 (t, J = 25 Hz), 13.8 (s), 13.7 (s). 19F NMR (376 MHz, CDCl3) δ = ꢀ
102.36. HRMS (ESI) ([M+Na]+) Calcd. For C27H28F2O6Na: 509.1746, found: 509.1763.
N,Nꢀdiethylꢀ2,2ꢀdifluoroꢀ3ꢀ(6ꢀmethylꢀ3,4ꢀdihydronaphthalenꢀ1ꢀyl)propanamide 3r: 41 mg, yield: 66%,
chromatography on silica gel (petroleum ether/EtOAc = 9:1, v/v). Colourless oil. IR (film) (cmꢀ1): 2978,
2935, 1660, 1241, 1082, 1062, 824. 1H NMR (400 MHz, CDCl3) δ = 7.17 (d, J = 7.9 Hz, 1H), 7.00 (d, J
= 7.9 Hz, 1H), 6.95 (s, 1H), 6.02 (t, J = 4.5 Hz, 1H), 3.38 (m, 6H), 2.73 (t, J = 8.0 Hz, 2H), 2.32 ꢀ 2.24
(m, 5H), 1.13 (m, 6H). 13C NMR (100 MHz, CDCl3) δ = 163.1 (t, J = 29Hz), 136.6, 136.1, 132.0, 130.7,
128.4, 127.9 (t, J = 2.9 Hz), 126.8, 123.3, 118.4 (t, J = 254 Hz), 41.9 (t, J = 7 Hz), 41.7, 37.2 (t, J = 24
Hz), 28.2, 23.4, 21.1, 14.3, 12.2. 19F NMR (376 MHz, CDCl3) δ = ꢀ98.40. HRMS (ESI) ([M+Na]+)
Calcd. For C18H23F2NONa: 330.1640, found: 330.1635.
2,2ꢀdifluoroꢀ3ꢀ(6ꢀmethylꢀ3,4ꢀdihydronaphthalenꢀ1ꢀyl)ꢀNꢀphenylpropanamide 3s: 46 mg, yield: 71%,
chromatography on silica gel (petroleum ether/EtOAc = 9:1, v/v). White solid, mp. 120ꢀ122 oC. IR (film)
(cmꢀ1): 3325, 2928, 2829, 1697, 1602, 1541, 1447, 1240, 1073, 753, 690. 1H NMR (400 MHz, CDCl3) δ
= 7.80 (s, 1H), 7.42 (dd, J = 8.5, 1.0 Hz, 2H), 7.33 (t, J = 7.9 Hz, 2H), 7.24 (d, J = 7.9 Hz, 1H), 7.18
(dd, J = 10.5, 4.2 Hz, 1H), 7.04 (d, J = 7.9 Hz, 1H), 6.95 (s, 1H), 6.07 (t, J = 4.6 Hz, 1H), 3.36 (t, J =
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16.2 Hz, 2H), 2.65 (t, J = 8.0 Hz, 2H), 2.32 (s, 3H), 2.25 ꢀ 2.20 (m, 2H). 13C NMR (100 MHz, CDCl3) δ
= 161.9 (t, J = 29Hz), 137.0, 136.2, 135.8, 131.2, 131.2, 129.1, 128.6, 127.3 (t, J = 4.4 Hz), 126.9,
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125.5, 123.2, 120.3, 117.8 (t, J = 255 Hz), 36.8 (t, J = 24Hz), 28.1, 23.3, 21.1. F NMR (376 MHz,
CDCl3) δ = ꢀ103.48. HRMS (ESI) ([MꢀH]ꢀ) Calcd. For C20H18F2NO: 326.1362, found: 326.1368.
Ethyl 2ꢀfluoroꢀ3ꢀ(6ꢀmethylꢀ3,4ꢀdihydronaphthalenꢀ1ꢀyl)propanoate 3t: 33 mg, yield: 62%,
chromatography on silica gel (petroleum ether/acetone = 10:1, v/v). Colourless oil. IR (film) (cmꢀ1):
2982, 2931, 2831, 1761, 1739, 1285, 1195, 1078, 1029, 828. 1H NMR (400 MHz, CDCl3) δ = 7.13 (d, J
= 7.8 Hz, 1H), 7.02 (d, J = 7.9 Hz, 1H), 6.99 (s, 1H), 5.96 (t, J = 4.5 Hz, 1H), 5.12 ꢀ 4.96 (m, 1H), 4.25 ꢀ
4.20 (m, 2H), 3.18 ꢀ 3.02 (m, 1H), 2.9 ꢀ 2.86 (m, 1H), 2.79 ꢀ 2.66 (m, 2H), 2.32 (s, 3H), 2.29 ꢀ 2.24 (m,
2H), 1.29 (t, J = 8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ = 169.8 (d, J = 23 Hz), 136.8, 136.7, 131.1,
130.3 (d, J = 2.6 Hz), 128.7, 128.0, 126.9, 122.2, 87.8 (d, J = 185 Hz), 61.5, 35.9 (d, J = 22 Hz) , 28.2,
23.2, 21.1, 14.1. 19F NMR (376 MHz, CDCl3) δ = ꢀ188.60. HRMS (ESI) ([M+Na]+) Calcd. For
C16H19FO2Na: 285.1261, found: 285.1267.
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7ꢀmethylꢀ4ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ1,2ꢀdihydronaphthalene 3u: 27 mg, yield: 59%, chromatography on
silica gel (petroleum ether/EtOAc = 95:5, v/v). Colourless oil. IR (film) (cmꢀ1): 2932, 2833, 1353, 1270,
1
1258, 1132, 1097, 826. H NMR (400 MHz, CDCl3) δ = 7.13 (d, J = 7.8 Hz, 1H), 7.04 (d, J = 8.0 Hz,
1H), 6.99 (s, 1H), 6.08 (t, J = 4.5 Hz, 1H), 3.22 (q, J = 10.7 Hz, 2H), 2.76 (t, J = 8.1 Hz, 2H), 2.35 ꢀ
13
2.29 (m, 5H). C NMR (100 MHz, CDCl3) δ = 137.1, 136.3, 131.0, 130.9, 129.2, 128.7, 126.9, 126.6
(q, J = 5.6, 2.7 Hz), 126.1 (q, J = 275, 175 Hz), 122.7, 77.3, 77.0, 76.7, 36.8 (q, J =30, 29 Hz), 28.0,
23.3, 21.1. 19F NMR (376 MHz, CDCl3) δ = ꢀ64.52. HRMS (EI) ([M]+) Calcd. For C13H13F3: 226.0964;
found: 226.0966.
3ꢀ(6ꢀmethylꢀ3,4ꢀdihydronaphthalenꢀ1ꢀyl)propanenitrile 3v 15 mg, yield: 43%, chromatography on
silica gel (petroleum ether/EtOAc = 95:5, v/v). Colourless oil. IR (film) (cmꢀ1): 2927, 2854, 2246, 1456,
1
1259, 1046.07, 825, 800, 668. H NMR (400 MHz, CDCl3) δ = 7.02 (s, 2H), 7.00 (s, 1H), 5.94 (t, J =
4.5 Hz, 1H), 2.79 (t, J = 7.3 Hz, 2H), 2.72 (t, J = 8.0 Hz, 2H), 2.56 (t, J = 7.4 Hz, 2H), 2.33 (s, 3H), 2.30
ꢀ 2.25 (m, 2H). 13C NMR (100 MHz, CDCl3) δ = 137.1, 136.9, 133.0, 130.5, 128.9, 127.0, 126.4, 121.8,
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119.4, 28.7, 28.1, 23.0, 211, 16.8. HRMS (ESI) ([M+Na]+) Calcd. For C14H15NNa: 220.1096, found:
220.1095.
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Diethyl 2ꢀ((6ꢀmethylꢀ3,4ꢀdihydronaphthalenꢀ1ꢀyl)methyl)malonate 3w: 37 mg, yield: 58%,
chromatography on silica gel (petroleum ether/EtOAc = 95:5, v/v). Colourless oil. IR (film) (cmꢀ1):
2981, 2933, 2831, 1749, 1733, 1368, 1229, 1148, 1042, 828. 1H NMR (400 MHz, CDCl3) δ = 7.13 (d, J
= 7.8 Hz, 1H), 7.01 (d, J = 7.8 Hz, 1H), 6.96 (s, 1H), 5.86 (t, J = 4.5 Hz, 1H), 4.21 ꢀ 4.15 (m, 4H), 3.62
(t, J = 7.5 Hz, 1H), 3.05 (d, J = 7.5 Hz, 2H), 2.66 (t, J = 8.0 Hz, 2H), 2.31 (s, 3H), 2.23 ꢀ 2.20 (m, 2H),
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1.24 (t, J = 7.1 Hz, 6H). C NMR (100 MHz, CDCl3) δ = 169.2, 136.8, 136.7, 132.6, 131.1, 128.7,
127.0, 126.3, 122.2, 61.3, 51.1, 31.8, 28.3, 23.1, 21.1, 14.1. HRMS (ESI) ([M+Na]+) Calcd. For
C19H24O4Na: 339.1567, found: 339.1569.
Ethyl 2,2ꢀdifluoroꢀ2ꢀ(6ꢀmethoxyꢀ3,4ꢀdihydronaphthalenꢀ2ꢀyl)acetate 3x: 36 mg, yield: 63%,
chromatography on silica gel (petroleum ether/EtOAc = 95:5, v/v). Colourless oil. IR (film) (cmꢀ1):
2940, 2839, 1763, 1608, 1502, 1274, 1248, 1196, 1088, 1037. 1H NMR (400 MHz, CDCl3) δ = 7.07 (d,
J = 8.0 Hz, 1H), 6.82 (s, 1H), 6.73 ꢀ 6.71 (m, 2H), 4.34 (q, J = 7.1 Hz, 2H), 3.81 (s, 3H), 2.85 (t, J = 8.2
Hz, 2H), 2.44 ꢀ 2.40 (m, 2H), 1.35 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ = 164.0 (t, J = 35
Hz), 160.1, 137.4, 129.0, 128.2 (t, J = 9.1 Hz), 127.7 (t, J = 23Hz), 125.0, 113.8, 111.5, 62.9, 55.3, 27.9,
21.0 (t, J = 2.9 Hz), 14.0. 19F NMR (376 MHz, CDCl3) δ = ꢀ106.76. HRMS (ESI) ([M+Na]+) Calcd. For
C15H16F2O3Na: 305.0960, found: 305.0965.
6. The derivations of annulation product
Hydrolysis of 3g:
To a solution of 3g (30 mg, 0.1 mmol) in EtOH (2 mL) was added sodium hydroxide solution (80
mg, 2.0 mmol, 20 equiv in 2 mL H2O) at room temperature. The resulting suspension was stirred at
room temperature for 3.5 hours. After addition of H2O (10 mL), the aqueous mixture was washed with
EtOAc (3 × 5 mL). The organic layers were discarded. The aquesou solution was acidified to pH 1 with
2M HCl solution. The suspension was extracted with EtOAc (3 × 10 mL). The combined organic layers
were dried (MgSO4), filtered, concentrated to afford oil product 4g without further purification.
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2,2ꢀdifluoroꢀ3ꢀ(6ꢀmethoxyꢀ3,4ꢀdihydronaphthalenꢀ1ꢀyl)propanoic acid 4g: 26 mg, yield: 95%.
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Colourless oil. IR (film) (cmꢀ1): 2937, 2836, 1759, 1609, 1501, 1252, 1086, 1039. H NMR (400 MHz,
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5
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7
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CDCl3) δ = 7.19 (d, J = 8.0 Hz, 1H), 6.73 ꢀ 6.71 (m, 3H), 5.96 (s, 1H), 3.79 (s, 3H), 3.22 (t, J = 16.0 Hz,
2H), 2.71 (t, J = 7.9 Hz, 2H), 2.28 ꢀ 2.25 (m, 2H). 13C NMR (100 MHz, CDCl3) δ = 158.6, 138.3, 129.4,
127.1, 126.7 (t, J = 3.7 Hz), 124.2, 114.0, 110.8, 77.3, 77.0, 76.7, 55.3, 37.3 (t, J = 24 Hz), 28.5, 23.2.
19F NMR (376 MHz, CDCl3) δ = ꢀ104.07. HRMS (ESI) ([M+H]+) Calcd. For C14H15F2O3: 269.0984,
found: 269.0988.
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Reduction of 3g:
To the solution of 3g (30 mg, 0.1 mmol) in anhydrous THF (2 mL) was added LiAlH4 (114 mg, 0.3
mmol). The mixture refluxed for 2 hours and then cooled to room temperature. The mixture was
cautiously quenched with H2O (2 mL) and diluted with diethyl ether (10 mL) and 2 M HCl (2 mL). The
organic layer was washed with brine (20 mL), dried (MgSO4), and concentrated. The residue was
purified by chromatography on silica gel (petroleum ether/EtOAc = 5:1, v/v) to provide desired product
oil product 5g.
2,2ꢀdifluoroꢀ3ꢀ(6ꢀmethoxyꢀ3,4ꢀdihydronaphthalenꢀ1ꢀyl)propanꢀ1ꢀol 5g: 23 mg, yield: 63%. Colourless
oil. IR (film) (cmꢀ1): 2931, 2833, 1608, 1500, 1252, 1143.05, 1075, 1039. 1H NMR (400 MHz, CDCl3) δ
= 7.26 (d, J = 8.0 Hz ,1H), 6.75 ꢀ 6.72 (m, 2H), 5.97 (t, J = 4.5 Hz, 1H), 3.80 (s, 3H), 3.72 (t, J = 12.6
Hz, 2H), 3.08 (t, J = 16.0 Hz, 2H), 2.74 (t, J = 8.0 Hz, 2H), 2.30 ꢀ 2.25 (m, 2H), 1.91 (s, 1H). 13C NMR
(100 MHz, CDCl3) δ = 158.6, 138.3, 128.8, 128.5 (t, J = 4.8 Hz), 127.5, 124.5, 122.6 (t, J = 243 Hz),
114.0, 110.8, 63.5 (t, J = 32 Hz), 55.2, 36.3 (t, J = 25 Hz), 28.7, 23.2. 19F NMR (376 MHz, CDCl3) δ = ꢀ
104.94. HRMS (ESI) ([M+H]+) Calcd. For C14H17F2O2: 255.1191, found: 255.1196.
Hydrogenation of 3g:
A suspension of 3g (44 mg, 0.15 mmol) and 10% Pd/C catalyst (35 mg, 0.016 mmol) on ethyl
o
acetate (3 mL) was stirred vigorously under hydrogen atmosphere (ballon) at 40 C for 4 hours. The
filtered solution was concentrated and the residue was purified by silica gel chromatography (petroleum
ether/EtOAc = 95:5, v/v) to give the desired product oil product 6g.
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Ethyl 2,2ꢀdifluoroꢀ3ꢀ(6ꢀmethoxyꢀ1,2,3,4ꢀtetrahydronaphthalenꢀ1ꢀyl)propanoate 6g: 33mg, yield:63%.
Colourless oil. IR (film) (cmꢀ1): 2936, 2867, 2838, 1768, 1609, 1502, 1316, 1279, 1255, 1231, 1H NMR
(400 MHz, CDCl3) δ = 7.07 (d, J = 8.5 Hz, 1H), 6.72 (dd, J = 8.5, 2.5 Hz, 1H), 6.60 (d, J = 2.2 Hz, 1H),
4.33 (q, J = 7.1 Hz, 2H), 3.77 (s, 3H), 3.15 ꢀ 3.10 (m, 1H), 2.80 ꢀ 2.67 (m, 2H), 2.48 ꢀ 2.29 (m, 2H), 1.94
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ꢀ 1.74 (m, 4H), 1.36 (t, J = 7.1 Hz, 3H). C NMR (100 MHz, CDCl3) δ = 164.4 (t, J = 32 Hz), 157.7,
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138.3, 131.4, 129.7, 116.3 (t, J = 250 Hz), 113.6, 112.4, 62.9, 55.2, 41.5 (t, J = 22 Hz), 31.2 (t, J = 3.5
19
Hz), 29.6, 28.3, 19.1, 13.9. F NMR (376 MHz, CDCl3) δ = ꢀ102.60 (t, J = 69 Hz), ꢀ105.32 (t, J = 69
Hz). HRMS (ESI) ([M+Na]+) Calcd. For C16H20F2O3Na: 321.1273, found: 321.1276.
Reduction of 3v:
To a solution of 3v (18 mg, 0.1 mmol) in anhydrous toluene (2 mL) was dropwise added DIBALꢀH
o
(1.0 M in hexane, 0.12 mL, 0.12 mmol, 1.2 equiv) at ꢀ50 C. The reaction was stirred for 1 hour at ꢀ40
oC under argon and then slowly warmed to room temperature. The reaction was quenched with 2 M HCl
(2 mL) was stirred for 0.5 hours. The aqueous layer was extracted with EtOAc (3 × 3 mL). The
combined organic layers were washed with brine, dried (Na2SO4), and concentrated. The residue was
purified by column chromatography on silica gel (petroleum ether/DCM = 1:1, v/v) to afford oil product
7v.
3ꢀ(6ꢀmethylꢀ3,4ꢀdihydronaphthalenꢀ1ꢀyl)propanal 7v: 16 mg, yield: 80%. Colourless oil. IR (film)
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(cmꢀ1): 2928, 2884, 2829, 2720, 1724, 1498, 1450, 1237, 1021, 827. H NMR (400 MHz, CDCl3) δ =
9.82 (t, J = 1.5 Hz, 1H), 7.11 (d, J = 7.8 Hz, 1H), 7.02 (d, J = 7.9 Hz, 1H), 6.98 (s, 1H), 5.82 (t, J = 4.6
Hz, 1H), 2.82 ꢀ 2.74 (m, 2H), 2.74 ꢀ 2.64 (m, 4H), 2.32 (s, 3H), 2.27 ꢀ 2.20 (m, 2H). 13C NMR (100
MHz, CDCl3) δ = 202.3, 136.7, 136.7, 134.5, 131.5, 128.65, 126.9, 124.6, 122.2, 42.5, 28.3, 25.0, 23.1,
21.1. HRMS (ESI) ([MꢀH]ꢀ) Calcd. For C14H15O: 199.1128, found: 199.1119.
Epoxidation of 3u:
A solution of mꢀchloroperbenzoic acid (0.15 mmol, 1.5 equiv) in anhydrous DCM (1.0 mL) was
o
added dropwise to a solution of product 3u (0.1 mmol) in anhydrous DCM (0.5 mL) at 0 C. The
achieved solution was warmed to room temperature then stirred for 1.5 hours. The reaction mixture was
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washed with 2.5 M NaOH for 3 times. The organic layer was dried (NaSO4) and concentrated under
reduced pressure. The residue purified by column chromatography on silica gel (petroleum ether/EtOAc
= 95:5, v/v) to afford oil product 8u.
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5ꢀmethylꢀ7bꢀ(2,2,2ꢀtrifluoroethyl)ꢀ1a,2,3,7bꢀtetrahydronaphtho[1,2ꢀb]oxirene 8u: 18 mg, yield: 75%.
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Colourless oil. IR (film) (cmꢀ1): 2921, 2851, 1368, 1353, 1251, 1139, 1113, 1075, 812. H NMR (400
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MHz, CDCl3) δ = 7.40 (d, J = 7.9 Hz, 1H), 7.05 (d, J = 7.9 Hz, 1H), 6.95 (s, 1H), 3.73 (s, 1H), 3.59 ꢀ
3.48 (m, 2H), 2.82 ꢀ 2.73 (m, 1H), 2.56 (dd, J = 15.7, 5.4 Hz, 1H), 2.44 ꢀ 2.32 (m, 2H), 2.32 (s, 3H),
1.91 (td, J = 13.8, 5.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ = 138.3, 136.9, 129.8, 128.9, 127.0,
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126.7, 125.5 (q, J = 276 Hz), 60.5, 52.7, 38.5 (q, J = 276 Hz), 25.2, 21.6, 21.0. F NMR (376 MHz,
CDCl3) δ = ꢀ61.20 (s). HRMS (EI) ([M]+) Calcd. For C13H13F3O: 242.0918; found: 242.0924.
Acknowledgements
This work was supported by the National Science Foundation of China (nos. 21572099 and
21332005), the Natural Science Foundation of Jiangsu Province (no. BK20151379), the Ph.D. Programs
Foundation of the Ministry of Education of China (no. 20130091120047), and SRF for ROCS, SEM.
Supporting Information
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Data of DFT calculations, H and C NMR spectra for all pure products. This material is available
free of charge via the Internet at http//pubs.acs.org.
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