Copper-Catalyzed Radical Cascade Difluoromethylation/Cyclization of 2-(3-Arylpropioloyl)benzaldehydes: A Route to Difluoromethylated Naphthoquinones

Article abstract of DOI:10.1021/acs.joc.7b00964

A novel copper-catalyzed cascade difluoromethylation/cyclization of 2-(3-arylpropioloyl)benzaldehydes has been developed. This method affords an efficient and straightforward access to structurally diverse difluoromethylated naphthoquinones in one pot, starting from readily available starting materials. The reaction represents the first trans-acyldifluoromethylation of internal alkynes, which features aldehydes as acceptors for the addition of alkenyl radicals. Furthermore, this protocol can also access to monofluoromethylated naphthoquinone and difluoromethylated indanones in the same reaction condition.

Full text of DOI:10.1021/acs.joc.7b00964

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Article
Copper-Catalyzed Radical Cascade Difluoromethylation/
Cyclization of 2-(3-Arylpropioloyl)benzaldehydes:
A Route to Difluoromethylated Naphthoquinones
Yan Zhang, Shangyi Ye, Mingming Ji, Lisha Li, Dongmei Guo, and Gangguo Zhu
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 06 Jun 2017
Downloaded from http://pubs.acs.org on June 6, 2017
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Copper-Catalyzed Radical Cascade Difluoromethylation/Cyclization of
2-(3-Arylpropioloyl)benzaldehydes: A Route to Difluoromethylated Naphthoquinones
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Yan Zhang,* Shangyi Ye, Mingming Ji, Lisha Li, Dongmei Guo and Gangguo Zhu
Department of Chemistry, Zhejiang Normal University, 688 Yingbin Road, Jinhua 321004, China
zhangyan001@zjnu.edu.cn
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A
novel
copper-catalyzed
cascade
difluoromethylation/cyclization
of
2-(3-arylpropioloyl)benzaldehydes has been developed. This method affords an efficient and
straightforward access to structurally diverse difluoromethylated naphthoquinones in one pot, starting
from
readily
available
starting
materials.
The
reaction
represents
the
first
trans-acyldifluoromethylation of internal alkynes, which features aldehydes as acceptors for the
addition of alkenyl radicals. Furthermore, this protocol can also access to monofluoromethylated
naphthoquinone and difluoromethylated indanones in the same reaction condition.
INTRODUCTION
The difluoromethylene group (CF2) is a valuable and significant structural motif in medicinal
chemistry,1 which can function as bioisostere for an oxygen atom or a carbonyl group to improve the
biological activity of small molecules.2 Therefore, the development of new methods to introduce a
CF2 group into diverse organic structures has attracted considerable attention. The past several years
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we have witnessed rapid advances in copper or palladium-catalyzed fluoromethylation reactions for
the construction of C(sp3)-CF2 bonds by difluoroalkyl radical addition to alkenes.3,4 However,
compared to difluoromethylation for the preparation of C(sp3)-CF2 bond containing organic substrates,
strategies for incorporation of a CF2 group onto alkenes have been less explored.
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To date, the common strategies to construct C(sp2)-CF2 bonds are mostly limited to the
transition-metal-mediated cross-coupling reactions and Heck-type reactions.5,6 In contrast to those, the
construction of C(sp2)-CF2 bonds by difluoroalkyl radical addition to alkynes is rare, presumably due
to the decreased reactivity even it is definitely the most direct and atom economic means. Recently, Fu
and Liang groups realized a C(sp2)-CF2 bond construction for the synthesis of 3-difluoroacetylated
coumarins and indoloazepinone derivatives, which features a radical cyclization onto the aryl
substituent (Scheme 1a).7 More interestingly, Nevado and Liang groups independently reported a
novel intermolecular three-component reaction involving terminal alkynes, boronic acids and
fluoroalkyl iodides to form trisubstituted difluoroalkenes (Scheme 1b).8 Therefore, the continuing
investigation of direct and efficient approaches towards C(sp2)-CF2 bond containing compounds is
still important.
Scheme 1. Representative Methods for The Construction of C(sp2)-CF2 Bonds by Radical
Addition to Alkynes
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Naphthoquinone motifs are prevalent in a number of natural products and bioactive molecules. For
examples, menadione and its derivative M5 have antimalarial property,9 and coprisidins A and B were
newly discovered natural naphthoquinone-oxindole alkaloids.10 To the best of our knowledge, there is
only one report by Davioud-Charvet for introducing CF2 onto naphthoquinones.11 However, it relys on
the transformation of certain functional groups which inevitably requires additional steps for
pre-functionalization. Driven by our interest in radical reactions and fluorine chemistry,12 we explored
the possibility of radical addition/cyclization of internal alkynes to form difluoromethylated
naphthoquinones. Of note, the method described here is the first example of Cu-catalyzed radical
difluoromethylation of disubstituted alkynes, in which aldehydes as acceptors for the addition of
carbon-centered radicals (Scheme 1c).
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RESULTS AND DISCCUSION
Table 1. Evaluation of The Reaction Conditionsa
entry
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[Cu]
CuBr
CuOAc
Cu(MeCN)4PF6
CuCN
CuTc
ligand
L1
L1
-
L1
L1
L1
-
L1
L2
L3
L4
L5
L6
L7
L8
solvent
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
yieldb (%)
0
0
trace
15
50
59
0
5
6
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
7
8c
9
trace
0
10
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12
13
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15
16d
17
68
63
51
20
0
Cu2O
Cu2O
trace
Cu2O
Cu2O
L8
L1
MeCN
EA
64
40
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Cu2O
Cu2O
L1
L1
DCE
DMF
10
0
a Reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol), [Cu] (20 mol%), ligand (40 mol%), K2CO3d(0.2
o
b
c
mmol), MeCN (2.0 mL), 90 C, 12 h. Yields of the isolated products are given. Without K2CO3. 0.4
mmol 2a is used.
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Initially, we utilized 1aa and bromodifluoroacetate (BrCF2COOEt) 2a as the model substrates to
optimize the reaction conditions, as BrCF2COOEt is commercially available, stable and can be easily
postfunctionalized. We believed that a single electron transfer (SET) between the Cu(I) catalyst and
organohalide may produce the desired difluoromethyl radical. Although 3aa was obtained with a poor
yield in the presence of CuCN and 2,2’-bipyridine (L1) in MeCN at 90 oC (Table 1, entry 4), we were
delighted to find that an improved yield was obtained by employing Cu2O as a catalyst (Table 1, entry
6). However other copper salts are not suitable catalysts (entries 1-3). We also find reactions nearly
can’t be conducted in the absence of ligand, thus demonstrating the important role of the diamine
ligand in the organocopper complex (Table 1, entry 7). The existence of K2CO3 also had a significant
impact on the reaction efficiency, and a very low conversion was observed in the absence of K2CO3
(Table 1, entry 8). To further improve the reaction efficiency, a range of diamine ligands were
investigated (Table 1, entries 9-15). Among the ligands tested, 5,5’-dimethyl-2,2’-bipyridine L3 gave
3aa in the best isolated yield of 68% (entry 10). Replacement of MeCN with EtOAc, CH2ClCH2Cl, or
DMF led to inferior results (entries 17-19). The structure of difluoromethylated naphthoquinone 3aa
was unambiguously identified by the single-crystal X-ray analysis (Figure S2. See the supporting
information).13
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Table 2. Substrate Scopea
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a Reaction conditions: 1aa (0.2 mmol), 2 (0.6 mmol), Cu2O (20 mol%), L3 (40 mol%), K2CO3 (0.2
mmol), MeCN (2 mL), 90 oC, 12 h. Isolated yields.
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To ascertain the scope of this method, a variety of 2-(3-arylpropioloyl)benzaldehydes 1 were
investigated, and the results are shown in Table 2. In general, the electronic effect of the substituents
on Ar2 does not obviously influence the reaction efficiency, and moderate to good yields of
difluoromethylated naphthoquinones 3 were obtained (Table 2, 3aa-3pa). It is noteworthy that
important functional groups such as ether, ester, chloride, bromide are compatible with the reaction
conditions (3fa-3oa), which may offer an opportunity for further derivatizations. What’s more, the
reaction of 1aa, 1da, and 1ha afforded the corresponding product 3aa, 3da, and 3ha in 68%, 66%,
and 61% yield, respectively, indicating that the steric hindrance of Ar2 has little impact on the reaction.
Heteroaryl substituents were also compatible with the reaction, despite the expected products were
provided in relatively lower yields (3qa and 3ra). Then the Ar1 group was varied. Substrates bearing
either electron-withdrawing or donating groups will obviously effect the reactivity of aldehydes. In
particular, electron-rich groups, such as Me, OMe have a obvious negative effect on this
transformation (3xa-3ab). In addition, We also tried to use BrCF2PO(OEt)2, BrCF2CNEt2 and
BrCFHCOOEt as the radical precursor, but they give no desired product or with low yield (3ae).
Table 3. Cu-Catalyzed Radical Cyclization Toward Difluoromethylated Indanonesa
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a Reaction conditions: 1aa (0.2 mmol), 2 (0.6 mmol), Cu2O (20 mol%), L3 (40 mol%), K2CO3 (0.2
mmol), MeCN (2 mL), 90 oC, 12 h. Isolated yields.
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It is possible that the strong para-directing effect (+C) of methoxy, substrates 1ae and 1af could not
convert to the naphthoquinone motifs. In contrast, it features a radical cyclization onto the aryl
substituent to form indanones, whereas the formyl groups remain unchanged (4a and 4b). These
unpredicted results motivated us to think that substrates without aldehyde moiety will also produce
difluoromethylated indanones in this standard reaction conditions. Then the substrate scope of this
cyclization was explored (Table 3). However, four analogues were synthesized in comparatively low
yields (4c-4f).
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Scheme 2. Proposed Mechanism
Finally, in order to study the possibility of a radical propagation mechanism, the reaction between
1aa and 2 was repeated in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO). As a result,
3aa was not formed, and the TEMPO-CF2COOEt adduct 63d was detected by the 19F NMR analysis
(8% yield) (eq 1). The radical clock reaction with α-cyclopropylstyrene (1') as a radical trapping
reagent provided the known product 76a in 16% yield, determined by 19F NMR spectroscopy. Thus, a
radical mechanism is depicted in Scheme 2 for this Cu-catalyzed difluoromethylation/cyclization
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reaction. First, the CF2COOEt radical, generated by a single electron transfer (SET) from Cu(I) to
BrCFXCOOEt 2, adds to the C-C triple bond of 1 to deliver an alkenyl radical B. Theoretically,
there are two possible ways for the radical transference of radical B. In path a, a subsequent
cyclization of the alkenyl radical to aldehyde provides an alkoxyl radical C, which could be converted
into the carbon radical D via a 1,2-hydrogen atom transfer (HAT).14 Subsequently, oxidation of D by
Cu(II) species results in a cationic intermediate E, accompanied by the regeneration of Cu(I) catalyst.
Finally, difluoromethylated naphthoquinones 3 are generated from E via the K2CO3-promoted
deprotonation; And in path b, alkenyl radical B undergoes radical addition to generate
cyclohexadienyl radical C’,7,15 then oxidation and deprotonation yield the products 4. Overall, there
exist excellent regio- and chemoselectivity in this reaction.
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CONCLUSION
In summary, compared with the enormous progress of trifluoromethylation research within of
the last few years, methodology for the introduction of the CF2 and CF groups into organic
molecules through radical addition reactions is relatively rare. We disclose a novel Cu-catalyzed
intramolecular difluoromethylation/cyclization of 2-(3-arylpropioloyl)benzaldehydes, allowing
the direct formation of a C(sp2)-CFXCO2Et bond and the construction of a naphthoquinone ring
in one reaction. This reaction features aldehydes as acceptors for the addition of carbon radicals,
which represents the first trans-acyldifluoromethylation of internal alkynes, offering a novel
approach to the direct synthesis of polysubstituted difluoromethylated alkenes.
EXPERIMENTAL SECTION
General Information
1H, 13C and 19F NMR spectra were recorded on 600 or 400 spectrometer using CDCl3 as the solvent.
Chemical shifts were referenced relative to residual solvent signal (CDCl3: 1H NMR: δ 7.26 ppm, 13
C
NMR: δ 77.16 ppm). The following abbreviations are used to describe peak patterns where
appropriate: br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. Coupling
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constants (J) are reported in Hertz (Hz). HRMS were performed on AB Sciex LC 30A-Triple TOF
4600 apparatus (ESI). Melting points were measured with micro melting point apparatus.
General Experimental Procedure for the synthesis of 2-(3-arylpropioloyl)benzaldehyde 1
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In a 100 mL flask with a stir-bar was charged with o-bromobenzaldehyde (20 mmol) and p-TsOH (2
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mmol). MeOH (40 mL) and trimethyl orthoformate (50 mmol) were added and the solution was
o
heated to 70 C for 3-8 hours. Aqueous NaHCO3 solution (3 mmol) was then added and most of the
THF was evaporated. The solution was extracted with ethyl acetate (20 mL * 3). The combined
organic layer was dried over anhydrous Na2SO4, concentrated to afford the o-bromoacetal product (4.6
g, 100% yield), which was used in the next step without further purification.
To a 50 mL flask charged with o-bromoacetal (20 mmol) was added anhydrous THF (20 mL), and
cooled to -78 oC. n-BuLi (24 mmol, 2.5 M in hexane) was then added over 30 min to the solution and
o
the reaction was kept at -78 C for another 1 h. Next, DMF (60 mmol) was added to the reaction
solution over 20 min. The combined organic layer was then warmed to RT and kept for 1 h. The
solution was then quenched with saturated aqueous NH4Cl (20 mL), extracted with ethyl acetate (30
mL * 3). The combined organic layer was washed with saturated NaCl, dried over anhydrous Na2SO4.
Then it was concentrated and the residue was subject to flash column chromatography on silica gel
using ethyl acetate/petroleum ether (v/v, 1:10) as eluent to give the aldehyde product (2.9 g, 80%
yield).
To a 50 mL two-necked flask charged with phenylacetylene/phenylbromoacetylene (6 mmol) was
evacuated and backfilled with Argon. Then anhydrous THF (20 mL) was added and cooled to -78 oC.
n-BuLi (6 mmol, 2.5 M in hexane) was then added in 30 min to the solution and the reaction was kept
o
at -78 C for another 1 h. The above aldehyde (5 mmol) was added and the mixture was allowed to
warmed to RT and kept for 1h. The solution was then quenched with saturated aqueous NH4Cl (20
mL), extracted with ethyl acetate (30 mL * 3). The combined organic layer was washed with saturated
NaCl, dried over anhydrous Na2SO4. Then it was concentrated and the residue was used in the next
step without further purification.
To a 100 mL flask charged with the above secondary alcohol (4 mmol) was added anhydrous DCM
(30 mL) and MnO2 (40 mmol). The solution was kept vigorously stirring at room temperature for 10 h.
Afterwards, the solution was filtered by diatomite and the filtrate was concentrated. The residue was
diluted with THF (20 mL) and aqueous HCl solution (20 mL, 2 N). Afterwards, the solution was kept
stirring at RT for 3 h. The residue was extracted with ethyl acetate (30 mL* 2), washed with saturated
NaCl, dried over anhydrous Na2SO4. Then it was concentrated and the residue was subject to flash
column chromatography on silica gel using ethyl acetate/petroleum ether (v/v, 1:10) as eluent to give
product 2-(3-phenylpropioloyl)benzaldehyde 1 (0.73 g, 78% yield for the above two steps).
For selected characterization of substrates 1, see:
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o
1
2-(3-(o-tolyl)propioloyl)benzaldehyde (1aa). Yellow solid; m.p. 50-52 C; H NMR (400MHz,
CDCl3) δ 10.60 (s, 1H), 8.33 (dd, J1 = 7.6 Hz, J2 = 1.6 Hz, 1H), 7.93 (dd, J1 = 7.2 Hz, J2 = 1.2 Hz, 1H),
7.78-7.70 (m, 2H), 7.63 (d, J = 7.2 Hz, 1H), 7.40(dt, J1 = 8.8 Hz, J2 = 1.2 Hz, 1H), 7.30-7.22 (m, 2H),
2.56 (s, 3H); 13C NMR (151MHz, CDCl3) δ 192.1, 178.4, 142.6, 138.6, 137.5, 133.9, 133.4, 132.9,
131.9, 131.4, 130.0, 128.5, 126.1, 119.4; HRMS (ESI) (m/z): calcd for C17H12O2Na ([M+Na]+),
271.0729; found 271.0722.
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2-(3-(2-methoxy-4-methylphenyl)propioloyl)benzaldehyde (1ha). Yellow solid; m.p. 104-105 C;
1H NMR (600MHz, CDCl3) δ 10.60 (s, 1H), 8. 50 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 7.2 Hz, 1H),
7.76-7.70 (m, 2H), 7.42 (s, 1H), 7.28 (d, J =6.6 Hz, 1H), 6.86 (d, J = 9.0 Hz, 1H) , 3.95 (s, 3H), 2.32 (s,
3H); 13C NMR (151MHz, CDCl3) δ 192.5, 178.5, 160.3, 138.8, 137.6, 135.4, 134.0, 132.8, 132.8,
132.6, 130.3, 128.3, 110.9, 108.5, 92.6, 91.9, 56.1, 20.3; HRMS (ESI) (m/z): calcd for C18H14O3Na
([M+Na]+), 301.0835; found 301.0837.
o
1
2-(3-(3,4,5-trimethoxyphenyl)propioloyl)benzaldehyde (1ja). Yellow solid; m.p. 101-103 C; H
NMR (600MHz, CDCl3) δ 10.50(s, 1H), 8.26 (d, J = 7.8 Hz, 1H), 7.89 (d, J = 7.2 Hz, 1H), 7.74-7.67
(m, 2H), 6.88 (s, 2H), 3.88-3.86 (m, 9H); 13C NMR (151MHz, CDCl3) δ 192.1, 178.3, 153.4, 141.6,
138.5, 137.4, 133.4, 132.9, 131.9, 128.5, 114.1, 110.7, 95.2, 87.3, 61.1, 56.4; HRMS (ESI) (m/z):
calcd for C19H16O5 Na ([M+Na]+), 347.0890; found 347.0880.
o
1
2-(3-(2-bromophenyl)propioloyl)benzaldehyde (1ma). White solid; m.p. 99-101 C; H NMR
(600MHz, CDCl3) δ 10.60 (s, 1H), 8.54 (d, J = 7.2 Hz, 1H), 7.96 (d, J = 7.2 Hz, 1H), 7.80-7.70 (m,
4H), 7.42-7.37 (m, 2H); 13C NMR (151MHz, CDCl3) δ 192.2, 178.2, 138.1, 137.6, 135.5, 133.7, 133.0,
132.9, 132.4, 128.5, 127.6, 127.0, 122.2, 91.9, 90.7; HRMS (ESI) (m/z): calcd for C16H9BrO2Na
([M+Na]+), 334.9678; found 334.9667.
Ethyl 4-(3-(2-formylphenyl)-3-oxoprop-1-yn-1-yl)benzoate (1oa). White solid; m.p. 109-112 oC; 1H
NMR (600MHz, CDCl3) δ 10.50 (s, 1H), 8. 31 (d, J = 7.2 Hz, 1H), 8.09 (d, J = 7.8 Hz, 2H), 7.94 (d, J
= 6.6 Hz, 1H), 7.77-7.73 (m, 4H), 4.40 (q, J = 7.2 Hz, 2H), 1.41 (t, J =6.6 Hz, 3H); 13C NMR
(151MHz, CDCl3) δ 191.9, 178.2, 165.5, 138.0, 137.5, 133.7, 133.0, 132.9, 132.5, 130.0, 129.7, 128.6,
123.8, 92.6, 89.0, 61.5, 14.3; HRMS (ESI) (m/z): calcd for C19H14O4Na ([M+Na]+), 329.0784; found
329.0777.
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2-(3-(furan-2-yl)propioloyl)benzaldehyde (1ra). Brown solid; m.p. 82-83 C; H NMR (600MHz,
CDCl3) δ 10.50 (s, 1H), 8.25 (d, J = 7.8 Hz, 1H), 7.92 (d, J = 7.2 Hz, 1H), 7.75-7.70 (m, 2H), 7.60 (s,
1H), 7.08 (d, J =3.0 Hz, 1H), 8.54 (d, J = 1.2 Hz, 1H); 13C NMR (151MHz, CDCl3) δ 192.1, 177.7,
147.3, 137.9, 137.5, 134.6, 133.0, 132.0, 128.6, 122.8, 112.3, 93.5, 84.7; HRMS (ESI) (m/z): calcd for
C14H8O3Na ([M+Na]+), 247.0365; found 247.0361.
2-(3-(4-(tert-butyl)phenyl)propioloyl)-6-methoxybenzaldehyde (1ae). White solid; m.p. 106-108
oC; 1H NMR (600MHz, CDCl3) δ 10.50 (s, 1H), 8.71 (s, 1H), 8. 38 (d, J = 7.2 Hz, 1H), 7.64 (d, J = 7.8
Hz, 2H), 7.44 (d, J = 7.8 Hz, 2H), 7.11 (d, J = 8.4 Hz, 1H), 4.04 (s, 3H), 1.33 (s, 9H); 13C NMR
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(151MHz, CDCl3) δ 188.8, 176.2, 165.7, 154.8, 136.4, 133.2, 131.6, 130.3, 125.9, 124.6, 116.9, 112.0,
94.5, 86.5, 56.5, 35.2, 31.2; HRMS (ESI) (m/z): calcd for C21H20O3Na ([M+Na]+), 343.1304; found
343.1294.
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General Experimental Procedure for Cu-Catalyzed Radical Cyclization of 1 and 2a.
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Under a N2 atmosphere, to a 25 mL sealed tube containing 1 (0.2 mmol, 1.0 equiv.), 2a (121mg,
0.6 mmol, 3.0 equiv.), Cu2O (5.8 mg, 0.04 mmol, 0.2 equiv.), 5,5'-dimethyl-2,2'-bipyridine (14.7
mg, 0.08 mmol, 0.4 equiv.) and K2CO3 (27.6 mg, 0.2 mmol, 1.0 equiv.) were added dry MeCN (2
o
mL). After stirring at 90 C for 12 h, the reaction mixture was cooled to room temperature and
concentrated. Column purification on silica gel using ethyl acetate/petroleum ether (v/v = 1:10) as
the eluent gave the desired product 3.
Ethyl 2-(1,4-dioxo-3-(o-tolyl)-1,4-dihydronaphthalen-2-yl)-2,2-difluoroacetate (3aa): 50.3 mg, 68%
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yield; Yellow solid; m.p. 73-74 C; H NMR (600MHz, CDCl3) δ 8.19-8.16 (m, 2H), 7.86-7.85 (m,
2H), 7.38 (dt, J1 = 7.8 Hz, J2 = 1.2 Hz, 1H), 7.32-7.27 (m, 2H), 7.13 (d, J = 7.8 Hz, 1H), 4.39 (q, J =
7.2 Hz, 2H), 2.22 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H); 13C NMR (151MHz, CDCl3) δ 183.5, 183.4, 162.6
(t, J = 31.7 Hz), 149.7, 136.9 (t, J = 20.5 Hz), 135.2, 134.8, 134.6, 131.8, 131.7, 131.3, 129.7, 129.1,
127.6, 127.3, 126.6, 125.2, 111.5 (t, J = 254.3 Hz), 63.3, 20.0, 13.9; 19F NMR (565MHz, CDCl3) δ
-99.7 (d, J = 282.5 Hz, 1F), -103.7 (d, J = 288.2 Hz, 1F); HRMS (ESI) (m/z): calcd for C21H16F2O4Na
([M+Na]+), 393.0909; found 393.0917.
Ethyl 2-(1,4-dioxo-3-(p-tolyl)-1,4-dihydronaphthalen-2-yl)-2,2-difluoroacetate (3ba): 45.1 mg, 61%
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yield; Oil; H NMR (600MHz, CDCl3) δ 8.18-8.15 (m, 2H), 7.85-7.83 (m, 2H), 7.29 (d, J = 7.8 Hz,
2H), 7.23 (d, J = 7.8 Hz, 2H), 4.38 (q, J = 7.2 Hz, 2H), 2.43 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H); 13C
NMR (151MHz, CDCl3) δ 184.1, 183.7, 162.9 (t, J = 31.7 Hz), 149.2, 139.7, 136.0 (t, J = 21.1 Hz),
131.8, 131.4, 129.1, 128.5, 128.3, 127.3, 126.5, 111.6 (t, J = 255.2 Hz), 63.3, 21.6, 14.0; 19F NMR
(565MHz, CDCl3) δ -98.8; HRMS (ESI) (m/z): calcd for C21H16F2O4Na ([M+Na]+), 393.0909; found
393.0906.
Ethyl 2-(3-(3,5-dimethylphenyl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-2,2-difluoroacetate (3ca):
47.6 mg, 62% yield; Yellow solid; m.p. 132-134 oC; 1H NMR (600MHz, CDCl3) δ 8.14-8.11 (m, 2H),
7.10 (s, 1H), 6.92 (s, 2H), 4.36 (q, J = 7.2 Hz, 2H), 2.37 (s, 6H), 1.34 (t, J = 7.2 Hz, 3H); 13C NMR
(151MHz, CDCl3) δ 184.0, 183.6, 166.2, 162.8 (t, J = 31.7 Hz), 149.3, 137.1, 135.9 (t, J = 19.6 Hz),
134.8, 134.5, 131.7, 131.2, 131.11, 131.08, 127.2, 126.6, 126.4, 111.5 (t, J = 255.2 Hz), 63.2, 21.4,
13.9; 19F NMR (565MHz, CDCl3) δ -99.0; HRMS (ESI) (m/z): calcd for C22H18F2O4Na ([M+Na]+),
407.1065; found 407.1064.
Ethyl 2-(3-(2,6-dimethylphenyl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-2,2-difluoroacetate (3da):
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47.4 mg, 50.7% yield; Oil; H NMR (600MHz, CDCl3) δ 8.18-8.15 (m, 2H), 7.85-7.83 (m, 2H), 7.23
(t, J = 7.8 Hz, 1H), 7.10 (d, J = 7.8 Hz, 2H), 4.36 (q, J = 7.2 Hz, 2H), 2.15 (s, 6H), 1.33 (t, J = 7.2 Hz,
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3H); 13C NMR (151MHz, CDCl3) δ 183.4, 183.1, 162.6 (t, J = 31.7 Hz), 149.5, 137.4 (t, J = 19.6 Hz),
134.9, 134.7, 134.6, 131.8, 131.7, 131.4, 128.6, 127.3, 127.1, 126.7, 111.6 (t, J = 255.2 Hz), 63.3, 20.2,
13.9; 19F NMR (565MHz, CDCl3) δ -104.5; HRMS (ESI) (m/z): calcd for C22H18F2O4Na ([M+Na]+),
407.1065; found 407.1064.
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Ethyl 2-(3-(4-(tert-butyl)phenyl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-2,2-difluoroacetate (3ea):
51.9 mg, 63% yield; Yellow solid; m.p. 134-135 oC; 1H NMR (400MHz, CDCl3) δ 8.18-8.14 (m, 2H),
7.84-7.82 (m, 2H), 7.50-7.47 (m, 2H), 7.29-7.27 (m, 2H), 4.37 (q, J = 7.2 Hz, 2H), 1.39-1.34 (m, 12H);
13C NMR (151MHz, CDCl3) δ 184.1, 183.4, 163.0 (t, J = 30.2 Hz), 152.7, 149.2, 135.9 (t, J = 19.6
Hz), 134.8, 134.6, 131.8, 131.4, 129.0, 128.2, 127.3, 126.5, 124.7, 111.6 (t, J = 249.2 Hz), 63.3, 34.9,
31.4, 14.0; 19F NMR (565MHz, CDCl3) δ -98.8; HRMS (ESI) (m/z): calcd for C24H22F2O4Na
([M+Na]+), 435.1378; found 435.1376.
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Ethyl 2-(1,4-dioxo-3-(3-phenoxyphenyl)-1,4-dihydronaphthalen-2-yl)-2,2-difluoroacetate (3fa): 45.7
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mg, 51% yield; Yellow solid; m.p. 92-94 C; H NMR (600MHz, CDCl3) δ 8.14-8.11 (m, 2H),
7.82-7.81 (m, 2H), 7.41 (t, J = 7.8 Hz, 1H), 7.34 (m, 2H), 7.11 (t, J = 7.2 Hz, 2H), 7.06-7.03 (m, 3H),
6.96 (s, 1H), 4.34 (q, J = 7.2 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H); 13C NMR (151MHz, CDCl3) δ 183.7,
183.5, 162.7 (t, J = 31.7 Hz), 157.0, 156.7, 148.2, 127.3, 126.6, 123.8, 123.6, 119.8, 119.4, 110.2,
111.5 (t, J = 255.2 Hz), 63.4, 13.9; 19F NMR (565MHz, CDCl3) δ -99.2 (d, J = 28.2 Hz); HRMS (ESI)
(m/z): calcd for C26H18F2O5Na ([M+Na]+), 471.1014; found 471.1010.
Ethyl 2,2-difluoro-2-(3-(4-methoxyphenyl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl)acetate (3ga) : 51.0
mg, 66% yield; Oil; 1H NMR (600MHz, CDCl3) δ 8.14-8.10 (m, 2H), 7.81-7.79 (m, 2H), 7.81-7.79 (m,
2H), 7.28 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 4.34 (q, J = 7.2 Hz, 2H), 3.86 (s, 3H), 1.32 (t, J
= 7.2 Hz, 3H); 13C NMR (151MHz, CDCl3) δ 184.1, 183.7 (t, J = 3.0 Hz), 163.0 (t, J = 31.7 Hz),
160.9, 148.6, 135.5 (t, J = 19.6 Hz), 134.7, 134.5, 131.7, 131.3, 131.2, 127.3, 126.4, 123.2, 113.2,
111.7 (t, J = 253.7 Hz), 63.3, 55.4, 13.9; 19F NMR (565MHz, CDCl3) δ -98.5; HRMS (ESI) (m/z):
calcd for C21H16F2O5Na ([M+Na]+), 409.0858; found 409.0854.
Ethyl
2,2-difluoro-2-(3-(2-methoxy-4-methylphenyl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl)acetate
(3ha): 48.8 mg, 61% yield; Yellow solid; m.p. 92-93 oC; 1H NMR (600MHz, CDCl3) δ 8.14-8.11 (m,
2H), 7.80-7.79 (m, 2H), 7.21 (dd, J1 = 8.4 Hz, J2 = 1.8 Hz, 1H), 6.94 (d, J = 1.2 Hz, 1H), 6.87 (d, J =
8.4 Hz, 1H), 4.39-4.33 (m, 2H), 3.73 (s, 3H), 2.32 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H); 13C NMR
(151MHz, CDCl3) δ 183.5, 183.2, 162.9 (t, J = 31.7 Hz), 154.6, 147.8, 136.8 (t, J = 21.1 Hz), 134.6,
134.3, 132.0, 131.4, 131.2, 129.9, 127.2, 126.5, 121.0, 111.6 (t, J = 255.2 Hz), 110.8, 63.2, 56.0, 20.6,
14.0; 19F NMR (565MHz, CDCl3) δ -100.8 (d, J = 282.5 Hz, 1F), -102.9 (d, J = 282.5 Hz, 1F); HRMS
(ESI) (m/z): calcd for C22H18F2O5Na ([M+Na]+), 423.1014; found 423.1015.
Ethyl 2-(3-(benzo[d][1,3]dioxol-5-yl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-2,2-difluoroacetate (3ia):
52 mg, 65% yield; Oil; 1H NMR (600MHz, CDCl3) δ 8.13-8.09 (m, 2H), 7.81-7.79 (m, 2H), 6.88-6.86
(m, 1H), 6.81-6.79 (m, 2H), 6.02 (s, 2H), 4.35 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H); 13C NMR
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(151MHz, CDCl3) δ 183.9, 183.6, 162.9 (t, J = 31.7 Hz), 149.0, 148.5, 147.3, 136.0 (t, J = 21.1 Hz),
134.8, 134.6, 131.7, 131.3, 127.3, 126.5, 124.5, 123.8 (t, J = 3.0 Hz), 111.6 (t, J = 255.2 Hz), 110.0 (t,
J = 1.5 Hz), 107.9, 101.6, 63.3, 13.9; 19F NMR (565MHz, CDCl3) δ -97.8; HRMS (ESI) (m/z): calcd
for C21H14ClF2O6Na ([M+Na]+), 423.0650; found 423.0653.
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53.5 mg, 60% yield; Red solid; m.p. 161-162 C; H NMR (600MHz, CDCl3) δ 8.15-8.11 (m, 2H),
7.82-7.81 (m, 2H), 6.55 (s, 2H), 4.36 (q, J = 7.2 Hz, 2H), 3.90 (s, 3H), 3.86 (s, 6H), 1.34 (t, J = 7.2 Hz,
3H); 13C NMR (151MHz, CDCl3) δ 183.9, 183.6, 163.0 (t, J = 31.7 Hz), 152.7, 148.9, 139.2, 136.2 (t,
J = 21.1 Hz), 134.9, 134.7, 131.7, 131.3, 127.3, 126.6, 126.4, 111.6 (t, J = 255.2 Hz), 106.9, 63.4, 61.1,
56.3, 14.0; 19F NMR (565MHz, CDCl3) δ -99.0; HRMS (ESI) (m/z): calcd for C23H20F2O7Na
([M+Na]+), 469.1069; found 469.1062.
Ethyl 2,2-difluoro-2-(3-(4-fluorophenyl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl)acetate (3ka): 47.9
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mg, 64% yield; Yellow solid; m.p. 50-52 C; H NMR (600MHz, CDCl3) δ 8.15-8.12 (m, 2H),
7.83-7.82 (m, 2H), 7.31-7.29 (m, 2H), 7.14 (t, J = 8.4 Hz, 2H), 4.36 (q, J = 7.2 Hz, 2H), 1.34 (t, J =
7.2 Hz, 3H); 13C NMR (151MHz, CDCl3) δ 183.9, 183.4, 163.6 (d, J = 249.2 Hz), 162.8 (t, J = 31.7
Hz), 148.0, 136.5 (t, J = 19.6 Hz), 134.9, 134.8, 131.7, 131.3, 131.2, 127.4, 126.6, 115.1, 115.0, 111.6
(t, J = 255.2 Hz), 63.5, 14.0; 19F NMR (565MHz, CDCl3) δ -98.3 (2F), -111.4 (1F); HRMS (ESI)
(m/z): calcd for C20H13F3O4Na ([M+Na]+), 397.0658; found 397.0651.
Ethyl 2,2-difluoro-2-(3-(4-fluoro-2-methylphenyl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl)acetate (3la):
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56.6 mg, 73% yield; Oil; H NMR (600MHz, CDCl3) δ 8.15-8.13 (m, 2H), 7.84-7.83 (m, 2H),
7.07-7.04 (m, 1H), 6.99 (dd, J1 = 9.6 Hz, J2 = 2.4 Hz, 1H), 6.95 (dt, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 4.36
(q, J = 7.2 Hz, 2H), 2.18 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H); 13C NMR (151MHz, CDCl3) δ 183.5, 183.2,
163.6 (d, J = 247.6 Hz), 162.6 (t, J = 31.7 Hz), 148.9, 138.1, 137.4 (t, J = 21.1 Hz), 134.9, 131.7,
131.4, 129.4, 127.4, 126.8, 116.9, 116.7, 112.5, 112.4, 111.5 (t, J = 255.2 Hz); 19F NMR (565MHz,
CDCl3) δ -99.6 (d, J = 282.5 Hz, 1F), -103.5 (d, J = 288.2 Hz, 1F), -113.4 (1F); HRMS (ESI) (m/z):
calcd for C21H15F3O4Na ([M+Na]+), 411.0814; found 411.0841.
Ethyl 2-(3-(2-bromophenyl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-2,2-difluoroacetate(3ma): 52.1
mg, 60% yield; Oil; 1H NMR (600MHz, CDCl3) δ 8.15 (d, J = 3.0 Hz, 2H), 7.83 (m, 2H), 7.65 (d, J =
7.8 Hz, 1H), 7.40 (m, 1H), 7.32 (m, 1H), 7.22 (d, J = 7.2 Hz, 1H), 4.37 (q, J = 7.2 Hz, 2H), 1.34 (t, J =
7.2 Hz, 3H); 13C NMR (151MHz, CDCl3) δ 183.3, 182.6, 162.5 (t, J = 31.7 Hz), 148.4, 136.9 (t, J =
21.1 Hz), 135.0, 134.7, 133.7, 132.3, 131.7, 131.4, 130.5, 129.4, 127.4, 127.0, 126.7, 121.9, 111.4 (t, J
= 255.2 Hz), 63.5, 14.0; 19F NMR (565MHz, CDCl3) δ -99.9 (d, J = 288.2 Hz, 1F), -103.6 (d, J =
288.2 Hz, 1F); HRMS (ESI) (m/z): calcd for C20H13BrF2O4Na ([M+Na]+), 456.9857; found 456.9857.
Ethyl 2-(3-(4-chlorophenyl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-2,2- difluoroacetate (3na): 44.5
mg, 57% yield; Oil; 1H NMR (600MHz, CDCl3) δ 8.14-8.12 (m, 2H), 7.83-7.82 (m, 2H), 7.43-7.42 (m,
2H), 7.25-7.24 (m, 2H), 4.37 (q, J = 7.2 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H); 13C NMR (151MHz, CDCl3)
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δ 183.7, 183.3, 162.7 (t, J = 31.7 Hz), 147.8, 136.5 (t, J = 21.1 Hz), 135.8, 135.0, 134.8, 131.6, 131.3,
130.5 (t, J = 3.0 Hz), 129.6, 128.1, 127.4, 126.6, 111.5 (t, J = 255.2 Hz), 63.5, 14.0; 19F NMR
(565MHz, CDCl3) δ -98.8; HRMS (ESI) (m/z): calcd for C20H13ClF2O4Na ([M+Na]+), 413.0362;
found 413.0351.
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Ethyl 4-(3-(2-ethoxy-1,1-difluoro-2-oxoethyl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl)benzoate (3oa):
47.1 mg, 55% yield; Yellow solid; m.p. 146-147 oC; 1H NMR (600MHz, CDCl3) δ 8.16-8.14 (m, 4H),
7.86-7.84 (m, 2H), 7.40 (m, 2H), 4.44-4.38 (m, 4H), 1.43 (t, J = 7.2 Hz, 3H), 1.36 (t, J = 7.2 Hz, 3H);
13C NMR (151MHz, CDCl3) δ 183.5, 183.2, 166.2, 162.6 (t, J = 31.7 Hz), 148.1, 136.6 (t, J = 21.1
Hz), 135.9, 135.0, 134.8, 133.1, 131.6, 131.2, 128.9, 127.3, 126.7, 111.5 (t, J = 255.2 Hz), 63.5, 61.3,
14.4, 13.9; 19F NMR (565MHz, CDCl3) δ -99.0; HRMS (ESI) (m/z): calcd for C23H18F2O6Na
([M+Na]+), 451.0963; found 451.0959.
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Ethyl 2-(1,4-dioxo-3-phenyl-1,4-dihydronaphthalen-2-yl)-2,2-difluoroacetate (3pa): 45.6 mg, 64%
yield; Oil; 1H NMR (600MHz, CDCl3) δ 8.15-8.13 (m, 2H), 7.83-7.81 (m, 2H), 7.47-7.44 (m, 3H), 7.
32-7.30 (m, 2H), 4.36 (q, J = 7.2 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H); 13C NMR (151MHz, CDCl3) δ
184.0, 183.6, 162.8 (t, J = 31.7 Hz), 149.0, 136.2 (t, J = 21.1 Hz), 134.9, 134.6, 131.7, 131.34, 131.26,
129.4, 129.0 (t, J = 3.0 Hz), 127.7, 127.3, 126.6, 111.6 (t, J = 255.2 Hz), 63.4, 14.0; 19F NMR
(565MHz, CDCl3) δ -98.9; HRMS (ESI) (m/z): calcd for C20H14F2O4Na ([M+Na]+), 379.0752; found
379.0749.
Ethyl 2-(1,4-dioxo-3-(thiophen-2-yl)-1,4-dihydronaphthalen-2-yl)-2,2-difluoroacetate (3qa): 29 mg,
40% yield; Yellow solid; m.p. 103-107 oC; 1H NMR (400MHz, CDCl3) δ 8.17-8.10 (m, 2H), 7.82-7.80
(m, 2H), 7.76 (dd, J1 = 5.2 Hz, J2 = 0.8 Hz, 1H), 7.46-7.45 (m, 1H), 7.17-7.15 (m, 1H), 4.34 (q, J =
7.2 Hz, 2H), 1.32 (t, J = 7.2 Hz, 2H); 13C NMR (151MHz, CDCl3) δ 183.7, 183.2, 163.0 (t, J = 31.7
Hz), 143.0, 134.8, 133.9, 133.5, 131.3, 129.7, 128.3, 127.4, 126.8, 126.6, 123.5, 111.5 (t, J = 255.2
Hz), 63.2, 14.0; 19F NMR (565MHz, CDCl3) δ -98.2; HRMS (ESI) (m/z): calcd for C18H12F2O4SNa
([M+Na]+), 385.0316; found 385.0310.
Ethyl 2,2-difluoro-2-(3-(furan-2-yl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl)acetate (3ra): 24.9 mg,
o
1
36% yield; Yellow solid; m.p. 82-83 C; H NMR (600MHz, CDCl3) δ 8.15-8.14 (m, 1H), 8.10-8.09
(m, 1H), 7.81-7.79 (m, 2H), 7.73 (d, J = 1.8 Hz, 1H), 7.31 (d, J = 3.6 Hz, 1H), 6.65 (q, J = 1.8 Hz, 1H),
4.35 (q, J = 7.2 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H); 13C NMR (151MHz, CDCl3) δ 183.2, 182.6, 163.2 (t,
J = 31.7 Hz), 146.9, 144.0, 136.0, 134.8, 134.7, 131.8, 131.3, 127.2, 126.5, 121.1, 113.2, 111.1 (t, J =
255.2 Hz), 102.5, 100.1, 63.2, 14.0; 19F NMR (565MHz, CDCl3) δ -101.8; HRMS (ESI) (m/z): calcd
for C18H13F2O5 ([M+H]+), 347.0724; found 347.0726.
Ethyl 2-(3-(4-(tert-butyl)phenyl)-7-fluoro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-2,2-difluoroacetate
(3sa): 51.6 mg, 60% yield; Yellow solid; m.p. 151-152 oC; 1H NMR (600MHz, CDCl3) δ 8.20 (dd, J1
= 8.4 Hz, J2 = 4.8 Hz, 1H), 7.80 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz, 1H), 7.49 (d, J = 8.4 Hz, 3H), 7.28 (d, J
= 8.4 Hz, 2H), 4.38 (q, J = 7.2 Hz, 2H), 1.39 (s, 9H), 1.36 (t, J = 7.2 Hz, 3H); 13C NMR (151MHz,
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CDCl3) δ 183.2, 182.4, 166.7 (t, J = 258.2 Hz), 162.8 (t, J = 31.7 Hz), 152.9, 149.3, 136.0 (t, J = 21.1
Hz), 134.4, 129.9, 129.0, 128.0, 127.8, 124.7, 122.0 (d, J = 24.2 Hz), 114.0 (d, J = 24.2 Hz), 111.5 (t, J
= 255.2 Hz), 63.4, 34.9, 31.3, 14.0; 19F NMR (565MHz, CDCl3) δ -98.6 (2F), -99.9 (1F); HRMS (ESI)
(m/z): calcd for C24H21F3O4Na ([M+Na]+), 453.1284; found 453.1273.
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Ethyl 2-(3-(4-(tert-butyl)phenyl)-5-fluoro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-2,2-difluoroacetate
(3ta): 55 mg, 64% yield; Yellow solid; m.p. 143-144 oC; 1H NMR (600MHz, CDCl3) δ 7.97 (dd, J1 =
7.8 Hz, J2 = 1.2 Hz, 1H), 7.80-7.76 (m, 1H), 7.52-7.48 (m, 1H), 7.47-7.45 (m, 2H), 7.24 (d, J = 8.4 Hz,
2H), 4.33 (q, J = 7.2 Hz, 2H), 1.35 (s, 9H), 1.33 (t, J = 7.2 Hz, 3H); 13C NMR (151MHz, CDCl3) δ
182.8, 181.8, 162.8 (t, J = 31.7 Hz), 161.1 (d, J = 270.3 Hz), 152.9, 150.0, 136.0 (d, J = 8.4 Hz),
135.1(t, J = 21.1 Hz), 133.0, 129.1, 127.8, 124.7, 123.6 (d, J = 21.1 Hz), 122.9, 119.7 (d, J = 4.5 Hz),
111.4 (t, J = 255.2 Hz), 63.4, 34.9, 31.4, 14.0; 19F NMR (565MHz, CDCl3) δ -98.8 (2F), -110.8 (1F);
HRMS (ESI) (m/z): calcd for C24H21F3O4Na ([M+Na]+), 453.1284; found 453.1273.
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Ethyl 2-(3-(4-(tert-butyl)phenyl)-6-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-2,2-difluoroacetate
(3ua): 49.1 mg, 55% yield; Yellow solid; m.p. 83-85 oC; 1H NMR (600MHz, CDCl3) δ 8.09-8.07 (m,
2H), 7.75 (dd, J1 = 8.4 Hz, J2 = 1.8 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 4.34 (q,
J = 7.2 Hz, 2H), 1.36 (s, 9H), 1.33 (t, J = 7.2 Hz, 3H); 13C NMR (151MHz, CDCl3) δ 183.2, 182.7,
162.8 (t, J = 31.7 Hz), 153.0, 149.1, 141.9, 136.0 (t, J = 21.1 Hz), 134.7, 132.9, 129.6, 129.0, 128.3,
127.8, 127.2, 124.8, 111.5 (t, J = 255.2 Hz), 63.4, 35.0, 31.4, 14.0; 19F NMR (565MHz, CDCl3) δ
-98.6; HRMS (ESI) (m/z): calcd for C24H21ClF2O4Na ([M+Na]+), 469.0988; found 469.0974.
Ethyl 2-(3-(4-(tert-butyl)phenyl)-7-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)- 2,2-difluoroacetate
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(3va): 51.7 mg, 58% yield; Oil; H NMR (600MHz, CDCl3) δ 8.10-8.07 (m, 2H), 7.75 (dd, J1 = 8.4
Hz, J2 = 2.4 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 4.34 (q, J = 7.2 Hz, 2H), 1.36
(s, 9H), 1.34 (t, J = 7.2 Hz, 3H); 13C NMR (151MHz, CDCl3) δ 183.2, 182.7, 162.8 (t, J = 31.7 Hz),
153.0, 149.4, 141.7, 135.8, 134.8, 132.4, 130.0, 129.1, 127.9, 126.5, 124.7, 111.5 (t, J = 247.6 Hz),
63.4, 35.0, 31.4, 14.0; 19F NMR (565MHz, CDCl3) δ -98.6; HRMS (ESI) (m/z): calcd for
C24H21ClF2O4Na ([M+Na]+), 469.0988; found 469.0979.
Ethyl 2-(3-(4-(tert-butyl)phenyl)-5-methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-2,2-difluoroacetate
(3wa): 46.9 mg, 55% yield; Yellow solid; m.p. 130-132 oC; 1H NMR (600MHz, CDCl3) δ 8.07 (dd, J1
= 7.8 Hz, J2 = 0.6 Hz, 1H), 7.68 (t, J = 7.8 Hz, 1H), 7.64 (m, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.27 (d, J
= 8.4 Hz, 2H), 4.37 (q, J = 7.2 Hz, 2H), 2.78 (s, 3H), 1.39 (s, 9H), 1.34 (t, J = 7.2 Hz, 3H); 13C NMR
(151MHz, CDCl3) δ 185.8, 184.0, 162.9 (t, J = 31.7 Hz), 152.5, 150.2, 142.2, 138.7, 134.9 (t, J = 21.1
Hz), 133.7, 132.8, 129.6, 128.9, 128.7, 125.4, 124.6, 111.5 (t, J = 255.2 Hz), 34.9, 31.4, 23.0, 14.0; 19F
NMR (565MHz, CDCl3) δ -99.1; HRMS (ESI) (m/z): calcd for C25H24F2O4Na ([M+Na]+), 449.1535;
found 449.1519.
Ethyl
2-(3-(4-(tert-butyl)phenyl)-6-methoxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-2,2-
difluoroacetate (3xa): 46.9 mg, 53% yield; Yellow solid; m.p. 162-164 oC; 1H NMR (600MHz, CDCl3)
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δ 8.08 (d, J = 9.0 Hz, 1H), 7.56 (d, J = 2.4 Hz, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.29-7.27 (m, 3H), 4.36
(q, J = 7.2 Hz, 2H), 3.97 (s, 3H), 1.39 (s, 9H), 1.35 (t, J = 7.2 Hz, 3H); 13C NMR (151MHz, CDCl3) δ
184.3, 182.5, 164.8, 163.0 (t, J = 31.7 Hz), 152.6, 148.8, 136.0 (t, J = 21.1 Hz), 133.8, 129.1, 129.0,
128.3, 125.5, 124.6, 121.1, 111.7 (t, J = 255.2 Hz), 110.5, 63.2, 56.1, 34.9, 31.4, 14.0; 19F NMR
(565MHz, CDCl3) δ -98.6; HRMS (ESI) (m/z): calcd for C25H24F2O5Na ([M+Na]+), 465.1484; found
465.1472.
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Ethyl
2,2-difluoro-2-(3-(4-fluoro-2-methylphenyl)-7-methyl-1,4-dioxo-1,4-dihydronaphthalen
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-2-yl)acetate (3ya): 41.8 mg, 52% yield; Oil; H NMR (600MHz, CDCl3) δ 8.02 (d, J = 7.8 Hz, 1H),
7.93 (m, 1H), 7.62-7.61 (m, 1H), 7.06-7.04 (m, 1H), 6.99-6.93 (m, 2H), 4.38-4.34 (m, 2H), 2.53 (s,
3H), 2.16 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H); 13C NMR (151MHz, CDCl3) δ 183.6, 183.3, 163.1 (d, J =
247.6 Hz), 162.7 (t, J = 31.7 Hz), 148.9, 146.2, 138.1, 137.3 (t, J = 21.1 Hz), 135.7, 131.3, 129.5,
129.4, 127.8, 127.6, 127.0, 116.8 (t, J = 22.6 Hz), 112.4 (t, J = 22.6 Hz), 111.5 (t, J = 255.2 Hz), 63.4,
22.1, 20.18, 14.0; 19F NMR (565MHz, CDCl3) δ -98.9 (d, J = 282.5 Hz, 1F), -99.9 (d, J = 282.5 Hz,
1F); HRMS (ESI) (m/z): calcd for C22H17F3O4Na ([M+Na]+), 425.0971; found 425.0964.
Ethyl
2,2-difluoro-2-(6-fluoro-3-(2-methoxyphenyl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl)acetate
(3za): 56.6 mg, 70% yield; Oil; 1H NMR (600MHz, CDCl3) δ 8.17 (dd, J1 = 8.4 Hz, J2 = 4.8 Hz, 1H),
7.77 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz, 1H), 7.48-7.42 (m, 2H), 7.13 (dd, J1 = 7.2 Hz, J2 = 1.8 Hz, 1H),
7.03 (dt, J1 = 7.8 Hz, J2 = 1.2 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.35 (dq, J1 = 8.4 Hz, J2 = 1.2 Hz,
2H), 3.76 (s, 3H), 1.34 (dt, J = 7.2 Hz, 3H); 13C NMR (151MHz, CDCl3) δ 182.2, 182.1, 166.6 (d, J =
259.7 Hz), 162.8 (t, J = 31.7 Hz), 156.6, 147.8, 137.1 (t, J = 19.6 Hz), 134.6 (d, J = 9.1 Hz), 131.0,
130.0 (d, J = 9.1 Hz), 129.5, 128.1, 121.7 (d, J = 22.6 Hz), 121.0, 120.2, 113.9 (d, J = 22.6 Hz), 111.5
(t, J = 255.2 Hz), 110.8, 63.3, 55.8, 14.0; 19F NMR (565MHz, CDCl3) δ -100. 8 (d, J = 288.2 Hz, 1F),
-102.8 (d, J = 288.2 Hz, 1F), -100.3 (s, 1F); HRMS (ESI) (m/z): calcd for C21H15F3O5Na ([M+Na]+),
427.0764; found 427.0761.
Ethyl
2,2-difluoro-2-(3-(4-fluoro-2-methylphenyl)-5-methyl-1,4-dioxo-1,4-
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dihydronaphthalen-2-yl)acetate (3ab): 40.2 mg, 50% yield; Oil; H NMR (600MHz, CDCl3) δ 8.06
(dd, J1 = 7.2 Hz, J2 = 1.2 Hz, 1H), 7.68 (t, J = 7.8 Hz, 1H), 7.63 (m, 1H), 7.08-7.05 (m, 1H), 7.01-6.94
(m, 2H), 4.36 (q, J = 7.2 Hz, 2H), 2.71 (s, 3H), 2.18 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H); 13C NMR
(151MHz, CDCl3) δ 185.2, 183.6, 163.1 (d, J = 247.6 Hz), 162.6 (d, J = 31.7 Hz), 149.9, 142.4, 138.8,
138.1 (d, J = 7.6 Hz), 136.3 (t, J = 21.1 Hz), 133.9, 132.8, 129.5, 129.4 (d, J = 9.1 Hz), 128.1, 125.6,
116.7 (d, J = 21.1 Hz), 112.4 (d, J = 22.6 Hz), 111.4 (t, J = 255.2 Hz), 63.4, 20.2, 14.0; 19F NMR
(565MHz, CDCl3) δ -100.05 (d, J = 282.5 Hz, 1F), -100.3 (d, J = 104.0 Hz, 1F), -113.5 (s, 1F); HRMS
(ESI) (m/z): calcd for C22H17F3O4Na ([M+Na]+), 425.0971; found 425.0963.
Ethyl 2-(3-(3,5-dimethylphenyl)-7-fluoro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-2,2-difluoroacetate
(3ac): 57.1 mg, 71% yield; Yellow solid; m.p. 100-102 oC; 1H NMR (600MHz, CDCl3) δ 8.17 (dd, J1
= 8.4 Hz, J2 = 2.4 Hz, 1H), 7.77 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz, 1H), 7.47 (dt, J1 = 8.4 Hz, J2 = 2.4 Hz,
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1H), 7.49 (d, J = 8.4 Hz, 3H), 7.28 (d, J = 8.4 Hz, 2H), 4.38 (q, J = 7.2 Hz), 7.10 (s, 1H), 6.90 (s, 2H),
4.36 (q, J = 7.2 Hz, 2H), 2.36 (s, 6H), 1.34 (t, J = 7.2 Hz, 3H); 13C NMR (151MHz, CDCl3) δ 183.2,
182.4, 166.7 (d, J = 259.7 Hz), 162.8 (t, J = 31.7 Hz), 149.6, 137.3, 136.0 (t, J = 21.1 Hz), 134.4 (d, J
= 9.1 Hz), 131.2, 130.8, 129.9 (d, J = 9.1 Hz), 127.9, 126.6, 122.0 (d, J = 24.2 Hz), 113.9 (d, J = 24.2
Hz), 111.5 (t, J = 255.2 Hz), 63.4, 21.4, 14.0; 19F NMR (565MHz, CDCl3) δ -98.9, -99.9; HRMS (ESI)
(m/z): calcd for C22H17F3O4Na ([M+Na]+), 425.0971; found 425.0962.
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Ethyl 2-(6-chloro-1,4-dioxo-3-(o-tolyl)-1,4-dihydronaphthalen-2-yl)-2,2-difluoroacetate (3ad): 49.3
mg, 61% yield; Yellow solid; m.p. 110-112 oC; 1H NMR (600MHz, CDCl3) δ 8.14-8.12 (m, 2H), 7.80
(dd, J1 = 8.4 Hz, J2 = 2.4 Hz, 1H), 7.38 (t, J = 7.2 Hz, 1H), 7.32-7.27 (m, 2H), 7.11 (d, J = 7.2 Hz, 1H),
4.38 (q, J = 7.2 Hz, 2H), 2.21 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H); 13C NMR (151MHz, CDCl3) δ 182.6,
182.4, 162.6 (t, J = 31.7 Hz), 149.7, 142.0, 137.1 (t, J = 19.6 Hz), 135.2, 134.7, 132.8, 131.5, 129.8,
129.6, 129.3, 128.4, 127.6, 127.2, 125.3, 111.4 (t, J = 256.7 Hz), 63.4, 20.0, 13.9; 19F NMR (565MHz,
CDCl3) δ -99.6 (d, J = 284.0 Hz, 1F), -103.6 (d, J = 278.3 Hz, 1F); HRMS (ESI) (m/z): calcd for
C21H15ClF2O4Na ([M+Na]+), 427.0519; found 427.0513.
Ethyl 2-(3-(3,5-dimethylphenyl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-2-fluoroacetate (3ae): 30 mg,
41% yield; Yellow solid; m.p. 100-102 oC; 1H NMR (400MHz, CDCl3) δ 8.17-8.14 (m, 2H), 7.81-7.79
(m, 2H), 7.13 (s, 1H), 6.97 (s, 2H), 5.58 (d, J = 46 Hz, 1H), 4.30 (m, 2H), 2.37 (s, 6H), 1.31 (t, J = 7.2
Hz, 3H); 13C NMR (151MHz, CDCl3) δ 183.8 (d, J = 181.1 Hz), 168.0 (d, J = 24.1 Hz), 150.9, 138.2,
134.4, 132.3, 132.1, 131.8, 131.7, 130.9, 127.5, 127.1, 126.8, 84.0 (d, J = 187.1 Hz), 62.2, 21.5, 14.2;
19F NMR (565MHz, CDCl3) δ -180.4; HRMS (ESI) (m/z): calcd for C22H19FO4Na ([M+Na]+),
389.1159; found 389.1163.
Ethyl 2-(3-(4-(tert-butyl)phenyl)-7-formyl-6-methoxy-1-oxo-1H-inden-2-yl)-2,2-difluoroacetate (4a):
40.7 mg, 46% yield; Yellow solid; m.p. 88-90 oC; 1H NMR (400MHz, CDCl3) δ 9.52 (s, 1H), 7.65 (d,
J = 8.0 Hz, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 1H), 4.21 (q, J
= 7.2 Hz, 2H), 3.89 (s, 3H), 1.36 (s, 9H), 1.30 (t, J = 7.2 Hz, 3H); 13C NMR (151MHz, CDCl3) δ
190.2, 189.7, 163.2, 162.6 (t, J = 33.2 Hz), 161.7, 153.6, 146.1, 129.8, 128.0 (t, J = 24.2 Hz), 127.4,
126.9, 125.8, 125.3, 122.7, 111.4, 110.9 (t, J = 250.7 Hz), 63.4, 56.8, 35.0, 31.3, 13.9; 19F NMR
(565MHz, CDCl3) δ -98.8; HRMS (ESI) (m/z): calcd for C25H24F2O5Na ([M+Na]+), 465.1484; found
465.1474.
Ethyl 2,2-difluoro-2-(3-(4-fluoro-2-methylphenyl)-7-formyl-6-methoxy-1-oxo-1H-inden-2-yl)acetate
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(4b): 41.8 mg, 50% yield; Oil; H NMR (600MHz, CDCl3) δ 9.51 (s, 1H), 7.67 (d, J = 8.4 Hz, 1H),
7.16-7.13 (m, 1H), 7.00-6.96 (m, 2H), 6.86 (d, J = 8.4 Hz, 1H), 4.25 (q, J = 7.2 Hz, 2H), 3.88 (s, 3H),
2.24 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H); 13C NMR (151MHz, CDCl3) δ 190.1, 189.4, 164.2, 163.5, 162.6,
162.4 (t, J = 31.7 Hz), 160.3, 145.0, 137.9 (t, J = 7.6 Hz), 129.5 (t, J = 22.6 Hz), 128.5, 127.7, 125.4,
122.3, 117.5 (d, J = 21.1 Hz), 113.4 (d, J = 21.1 Hz), 111.4, 110.8 (t, J = 250.7 Hz), 63.6, 56.8, 19.9,
13.9; 19F NMR (565MHz, CDCl3) δ -100. 2 (d, J = 288.2 Hz, 1F), -102.4 (d, J = 288.2 Hz, 1F), -111.5
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(s, 1F); HRMS (ESI) (m/z): calcd for C22H17F3O5Na ([M+Na]+), 441.0920; found 441.0909.
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Ethyl 2,2-difluoro-2-(1-oxo-3-phenyl-1H-inden-2-yl)acetate(4c): 30 mg, 45% yield; Yellow oil; H
NMR (600MHz, CDCl3) δ 7.57 (d, J = 6.6 Hz, 1H), 7.54-7.51 (m, 5H), 7.42-7.36 (m, 2H), 7.10 (d, J =
7.2 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H); 13C NMR (151MHz, CDCl3) δ 192.7,
162.9 (t, J = 33.2 Hz), 143.9, 134.0, 130.9, 130.8, 130.5, 130.1, 129.0 (t, J = 18.1 Hz), 128.5, 128.2,
124.4 (t, J = 24.1 Hz), 123.5, 123.4, 111.2 (t, J = 249.0 Hz), 63.4, 13.9; 19F NMR (565MHz, CDCl3) δ
-98.1; HRMS (ESI) (m/z): calcd for C19H14F2O3Na ([M+Na]+), 351.0803; found 351.0805.
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Ethyl 2,2-difluoro-2-(1-oxo-3-(p-tolyl)-1H-inden-2-yl)acetate(4d): 27.4 mg, 40% yield; Yellow oil; 1H
NMR (600MHz, CDCl3) δ 7.56 (d, J = 6.6 Hz, 1H), 7.44 (d, J = 7.8 Hz, 2H), 7.42-7.36 (m, 2H), 7.33
(d, J = 7.8 Hz, 2H), 7.14 (d, J = 7.2 Hz, 1H), 4.28 (q, J = 7.2 Hz, 2H), 2.45 (s, 3H), 1.31 (t, J = 7.2 Hz,
3H); 13C NMR (151MHz, CDCl3) δ 192.9, 163.0 (t, J = 33.2 Hz), 144.0, 141.1, 133.8, 130.8, 130.3,
129.3, 128.4, 127.9, 124.0 (t, J = 24.1 Hz), 123.5, 123.4, 111.3 (t, J = 249.0 Hz), 63.4, 21.7, 14.0; 19
NMR (565MHz, CDCl3) δ -98.0; HRMS (ESI) (m/z): calcd for C20H16F2O3Na ([M+Na]+), 365.0960;
F
found 365.0965.
Ethyl 2-(3-(4-(tert-butyl)phenyl)-1-oxo-1H-inden-2-yl)-2,2-difluoroacetate(4e): 30 mg, 39% yield;
Yellow oil; 1H NMR (600MHz, CDCl3) δ 7.56 (dd, J1 = 6.6 Hz, J2 = 0.6 Hz, 1H), 7.54-7.53 (m, 2H),
7.50-7.48 (m, 2H), 7.43-7.40 (m, 1H), 7.39-7.36 (m, 1H), 7.17 (d, J = 7.2 Hz, 1H), 4.24 (q, J = 7.2 Hz,
2H), 1.38 (s, 9H), 1.29 (t, J = 7.2 Hz, 3H); 13C NMR (151MHz, CDCl3) δ 192.9, 163.0 (t, J = 33.2 Hz),
154.2, 144.0, 133.8, 130.8, 130.3, 128.2, 127.9, 125.5, 124.0 (t, J = 24.1 Hz), 123.6, 123.4, 111.3 (t, J
= 249.0 Hz), 63.3, 35.1, 31.3, 13.9; 19F NMR (565MHz, CDCl3) δ -97.8; HRMS (ESI) (m/z): calcd for
C23H22F2O3Na ([M+Na]+), 407.1429 ; found 407.1432.
Ethyl 2-(3-(4-chlorophenyl)-1-oxo-1H-inden-2-yl)-2,2-difluoroacetate(4f): 25.4 mg, 35% yield;
1
Yellow oil; H NMR (600MHz, CDCl3) δ 7.57 (d, J = 6.6 Hz, 1H), 7.52-7.48 (m, 4H), 7.44-7.38 (m,
2H), 7.07 (d, J = 6.6 Hz, 1H), 4.32 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H); 13C NMR (151MHz,
CDCl3) δ 192.5, 161.9, 143.7, 136.8, 134.1, 131.1, 130.0, 129.7, 129.2, 129.0, 124.9 (t, J = 24.1 Hz),
123.7, 123.2, 111.1(t, J = 250.5 Hz), 63.6, 14.0; 19F NMR (565MHz, CDCl3) δ -98.3; HRMS (ESI)
(m/z): calcd for C19H13ClF2O3Na ([M+Na]+), 385.0413; found 385.0414.
ACKNOWLEDGMENTS
We thank the Natural Science foundation of Zhejiang Province (LQ17B020001) and National Natural
Science Foundation of China (21672191).
Supporting Information. Spectroscopic data of products 3 and 4, as well as X-ray data of 3aa. This
material is available free of charge via the Internet at http://pubs.acs.org.
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