Silver-Catalyzed C(sp2)-H Functionalization/C-O Cyclization Reaction at Room Temperature

Article abstract of DOI:10.1021/jo5024238

Silver-catalyzed C(sp²)-H functionalization/C-O cyclization has been developed. The scalable reaction proceeds at room temperature in an open flask. The present method exhibits good functional-group compatibility because of the mild reaction conditions. Using a AgNO₃ catalyst and a (NH₄)₂S₂O₈ oxidant in CH₂Cl₂/H₂O solvent, various lactones are obtained in good to excellent yields. A kinetic isotope effect (KIE) study indicates that the reaction may occur via a radical process.

Full text of DOI:10.1021/jo5024238

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Article
Silver-Catalyzed C(sp2)-H Functionalization/C-
O Cyclization Reaction at Room Temperature
Jian-Jun Dai, Wen-Tao Xu, Ya-Dong Wu, Wen-Man Zhang,
Ying Gong, Xia-Ping He, Xin-Qing Zhang, and Hua-Jian Xu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo5024238 • Publication Date (Web): 11 Dec 2014
Downloaded from http://pubs.acs.org on December 13, 2014
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Silver-Catalyzed C(sp2)-H Functionalization/C-O Cyclization Reaction at Room
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Temperature
JianꢀJun Dai, WenꢀTao Xu, YaꢀDong Wu, WenꢀMan Zhang, Ying Gong, XiaꢀPing He, XinꢀQing Zhang,
and HuaꢀJian Xu*
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School of Medical Engineering, Hefei University of Technology, Hefei 230009, P. R. China.
E-mail: hjxu@hfut.edu.cn
RECEIVED DATE (will be automatically inserted after manuscript is accepted).
ABSTRACT: Silverꢀcatalyzed C(sp2)ꢀH functionalization/CꢀO cyclization has been developed.
The scalable reaction proceeds at room temperature in an open flask. The present method exhibits
good functionalꢀgroup compatibility because of the mild reaction conditions. Using a AgNO3
catalyst and a (NH4)2S2O8 oxidant in CH2Cl2/H2O solvent, various lactones are obtained in good to
excellent yields. Kinetic isotope effect (KIE) study indicates that the reaction may occur via a
radical process.
INTRODUCTION
In recent years, transitionꢀmetalꢀcatalyzed CꢀH functionalization has emerged as a useful and
popular strategy for the formation of complex molecules from simple substrates.1 Among
them, CꢀH functionalization/CꢀO cyclization reactions have been successfully applied for the
rapid access to oxygenꢀcontaining heterocycles with atom economy.2 For example, in 2010 Yu
et al. reported palladiumꢀcatalyzed CꢀH activation/CꢀO cyclization directed by aliphatic
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alcohol for the synthesis of dihydrobenzofurans [Scheme 1a, Eq. (1)].2a In 2011, Liu et al. and
Yoshikai et al. independently described palladiumꢀcatalyzed CꢀH activation/CꢀO cyclization
of 2ꢀaryl phenols to prepare dibenzofurans [Scheme 1a, Eqs. (2) and (3)].2b,2m Recently, Wang
et al. further extended the palladiumꢀcatalyzed system to carboxylꢀdirected CꢀH
activation/CꢀO cyclization with the use of acetylꢀprotected glycine as the ligand [Scheme 1a,
Eqs. (4) and (5)].2c,2d In comparison to the palladium, copper recently has been shown to
catalyze the CꢀH functionalization/CꢀO cyclization of 2ꢀaryl acids. For instance, Martin et al.
and Gevorgyan et al. recently showed copperꢀcatalyzed radicalꢀbased CꢀH
functionalization/CꢀO cyclization reactions of 2ꢀaryl acids, respectively (Scheme 1b).2e,2f
Such radicalꢀbased reactions could be more practical than palladiumꢀcatalyzed CꢀH
activation/CꢀO cyclization for the synthesis of lactones3,4 because these copper catalysts are
much less expensive and no ligands are needed. Despite these notable advances, developing
milder and more efficient transition metal catalyzed radicalꢀbased CꢀH functionalization/CꢀO
cyclization reactions remains an important challenge task.
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Scheme 1. Examples of Transition-metal-catalyzed C(sp2)-H Functionalization/C-O
Cyclization.
Herein, we report a novel silverꢀcatalyzed C(sp2)ꢀH functionalization/CꢀO cyclization of
2ꢀaryl acids to form lactones under mild conditions at room temperature (RT) (Scheme 1c).5
The present work was inspired by classic Minsci reaction and the recent work of Baran et al.
on silverꢀcatalyzed radicalꢀbased CꢀH functionalization of heteroarenes.6,7 This study not only
provides a convenient, easy handle protocol into the lactones scaffolds but also further
confirms the value of radicalꢀbased CꢀH functionalization for synthetic applications.8
RESULTS AND DISSCUSION
We began our study with 2ꢀphenylbenzoic acid 1a as the probe substrate in the presence of
AgNO3 catalyst and (NH4)S2O8 oxidant at RT (Table 1). Different solvents were tested first
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(Table 1, entries 1ꢀ5). To our delight, the use of CH2Cl2/H2O (1:1, v:v) afforded the desired
product 2a in 86% yield (Table 1, entry 1). Note that low yield was obtained without the use
of water as coꢀsolvent (see Supporting Information (SI) for more details). When 10 mol %
AgNO3 and 1.5 equiv (NH4)2S2O8 were employed the yields of 2a were diminished to 76%
and 62%, respectively (Table 1, 6 and 7). Reactions catalyzed by silver salts, such as AgOAc,
AgBF4 and AgSbF6, afforded moderate yields of the desired product. To further improve the
conversion of 1a, several additives including acids and bases were investigated (Table 1,
entries 14ꢀ17). It was found that the use of KOAc as the additive afforded the desired product
2a in 93% yield with full conversion of 1a. Finally, it is important to mention that the control
experiment conducted in the absence of Ag(I) catalyst gave only trace amount of 2a (Table 1,
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entry 18).
Table 1. Optimization of the Reaction Conditionsa
Entry Catalyst
Oxidant
Additive
―
Solventb
Yield/%c
86
1
2
3d
AgNO3 (NH4)2S2O8
AgNO3 (NH4)2S2O8
AgNO3 (NH4)2S2O8
AgNO3 (NH4)2S2O8
AgNO3 (NH4)2S2O8
AgNO3 (NH4)2S2O8
AgNO3 (NH4)2S2O8
AgOAc (NH4)2S2O8
AgBF4 (NH4)2S2O8
AgSbF6 (NH4)2S2O8
CH2Cl2/H2O
EtOAc/H2O
HFIP/H2O
―
53
―
35
4
―
Acetone/H2O
CH3CN/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
68
5
―
14
6e
7f
―
72
―
61
8
―
70
9
―
71
10
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16
―
73
AgNO3
AgNO3
K2S2O8
―
82
Na2S2O8
―
78
AgNO3 (NH4)2S2O8
HOAc
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AgNO3 (NH4)2S2O8 K2HPO4 CH2Cl2/H2O
64
AgNO3 (NH4)2S2O8
KOAc
CH2Cl2/H2O
96(93)
88
AgNO3 (NH4)2S2O8 NaOAc
CH2Cl2/H2O
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AgNO3 (NH4)2S2O8 KH2PO4 CH2Cl2/H2O
75
―
(NH4)2S2O8
―
CH2Cl2/H2O
Trace
aReaction conditions: 1a (0.3 mmol), additive (0.9 mmol, 3.0 equiv), Ag catalyst (20 mol %), and oxidant (0.9 mmol, 3 equiv) in
b
c
the solvent (6 mL) at room temperature for 24 h under an air atmosphere, unless otherwise noted. The ratio is 1:1 (v:v). GC
yields with benzophenone as an internal standard added after the reaction. Yield of isolated products given in parentheses. dHFIP
= Hexafluoroisopropanol. e10 mol % AgNO3 was used. f1.5 equiv (NH4)2S2O8 was used.
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With the optimized reaction conditions in hand, we next studied the scope of 2ꢀaryl carboxylic
acids that undergo these cyclizations, and the results are summarized in Scheme 2. It was
found that a variety of 2ꢀaryl carboxylic acids can be converted to the desired product in
modest to good yields. The present reaction can tolerate well electronꢀdonating groups such as
methyl (2b, 2q, 2s), ether (2h, 2j, 2k, 2l, 2r, 2w) as well as electronꢀwithdrawing groups such
as ketone (2f). The structure of 2j was also confirmed by Xꢀray diffraction (see SI). Notably,
this reaction can even tolerate an unprotected OH group (2n). Remarkably, terminal alkene (2l)
was found to be compatible to some extent, and gave the product in a modest yield.
Furthermore, aryl halide groups such as F (2c, 2y), Cl (2d, 2t), Br (2e) were also well
compatible with the reaction, enabling additional functionalization at these positions via
transitionꢀmetalꢀcatalyzed crossꢀcoupling reactions.9 Interestingly, when metaꢀOMe
substituted substrate (1r) was subjected to this reaction, a major isomer (2r) was obtained.
However, the use of metaꢀMe substituted substrate (1s) afforded a mixture of regioisomers (2s
and 2s’) in a 1:1 ratio. Moreover, 2ꢀnaphthyl substituted substrate (1p) also gave a single
isomer (2p) at the more electronꢀrich 1ꢀposition. This result also demonstrates the
complementarity of this method to Wang’s previous Pdꢀcatalyzed CꢀH activation/CꢀO
cyclization protocol.2b Sterically hindered substrate could also undergo this transformation.
For example, the reaction of 2,6ꢀdiphenylbenzoic acid (1x) gave the desired product (2x) in a
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modest yield. Finally, heteroaromatic substrate (e.g., 3ꢀphenylthiopheneꢀ2ꢀcarboxylic acid
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(1z)) can be converted to the corresponding product (2z) in a modest yield.
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Scheme 2. Substrate Scope of 2-Aryl Carboxylic Acidsa,b
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AgNO3 (20 mol %)
KOAc (3 equiv)
Ar1
Ar1
(NH4)2S2O8 (3 equiv)
CH2Cl2/H2O (1:1), RT
Ar2
Ar2
O
2
O
HO
1
O
R
O
O
HF2CO
O
O
O
F3C
O
O
O
2j, 76%, 16 h
2k, 87%, 16 h
R = H, 2a, 93%, 24 h
R = Me, 2b, 71%, 24 h
R = F, 2c, 72%, 16 h
R = Cl, 2d, 75%, 16 h
R = Br, 2e, 88%, 16 h
R = Ac, 2f, 56%, 24 h
R = Ph, 2g, 67%, 48 h
O
NHAc
2m, 90%, 24 h
O
O
O
R = OMe, 2h, 41%, 8 h
R = CF3, 2i, 33%, 8 h
2l, 45%, 6 h
O
O
O
O
HO
O
O
O
O
2n, 65%, 24 h
2o, 62%, 24 h
2p, 64%, 24 h
2q, 76%, 18 h
R
MeO
+
O
O
O
O
F
O
O
O
O
R = Cl, 2t, 50%, 24 h
R = Me, 2u, 78%, 24 h
R = Ph, 2v, 53%, 48 h
2r, 74%, 24 h
2s + 2s' (1:1), 82%, 10 h
OMe
OMe
F
S
O
O
O
O
O
O
O
O
2x, 42%c, 48 h
2w, 73%, 12 h
2y, 63%, 24 h
2z, 40%c, 12 h
aReaction conditions: 1 (0.3 mmol), AgNO3 (20 mol %), KOAc (0.9 mmol, 3 equiv), and (NH4)S2O8 (0.9
mmol, 3 equiv), RT, CH2Cl2/H2O. b Yields of isolated products are shown. 0.2 mmol scale.
c
To further probe the utility of this silverꢀcatalyzed CꢀH functionalization/CꢀO cyclization
in preparative organic synthesis, a gramꢀscale reaction was conducted. As depicted in
Scheme 3, 3.96 g (20 mmol) scale of 1a can be converted to 2a in 89% yield at a lowered
(10 mol %) catalyst loading. Moreover, the present reaction was conducted in an open
flask. Next, treatment of 2a with LiOH2e,10 and NaBH4 gave the corresponding
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hydroxylation of benzoic acids (3) and chromene (4) in 86% and 78% yields, respectively.
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Notably, the present study provides an alternative route for the achievement remote
hydroxylated arenes.12
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Scheme 3. Gram-Scale Reaction and Further Conversion
Note that the present reaction permits a compatible reaction profile. Under the reaction conditions
described in this study, a chemoselective CꢀO cyclization of a carboxyl group in the presence of an
unprotected hydroxyl group could be accomplished in 72% yield. Considering that Yu’s group2a
reported hydroxyl group as a partner for Pdꢀcatalyzed CꢀH activation/CꢀO cyclization reactions
formed dihydrobenzofurans, subsequent treatment of the resulting aliphatic alcohol (6) under Yu’s
conditions delivered the final product in 64% yield (Scheme 4).
Scheme 4. Chemoselectivity Profile in C-H Functionalization/C-O Cyclization
Next, we carried out a kinetic isotope effect (KIE) experiment to gain more insights into the
mechanism. When a 1:1 mixture of 1a and [D5]1a was subjected to the silverꢀcatalyzed reaction
conditions, we obtained the products 2a and [D4]2a in a ratio of 1.27:1 (Scheme 5). This KIE
value of 1.27 suggests that CꢀH cleavage is not the first irreversible step in the catalytic cycle.
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Scheme 5. Intermolecular Kinetic Isotope Effect (KIE)
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Based on the mechanistic investigation above and previous reports,13 we propose a plausible
mechanism shown in Scheme 6. First, the Ag(I) is oxidized to Ag(II), which then react with 2ꢀaryl
acids (1) to give the carboxyl radical (8). Second, the carboxyl radical (8) cyclizes onto the
aromatic ring to afford the intermediate (9), which further proceeds oneꢀelectron oxidation and
proton loss to furnish the final product (2). It is worth noting that the regioselectivities of the
present reaction shown in Scheme 2 also indicate a radicalꢀbased mechanism.
Scheme 6. Proposed Reaction Mechanism
CONCLUSIONS
In summary, we have successfully achieved CꢀH functionalization/CꢀO cyclization by employing
inexpensive AgNO3 as the catalyst and environmentally friendly (NH4)2S2O8 as the oxidant. This
new reaction is operationally simple and can be conducted under mild conditions at room
temperature. A wide variety of synthetically useful yet sensitive functional groups are
wellꢀtolerated. Furthermore, chemoselectivity CꢀH functionalization/CꢀO cyclization has also been
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achieved. Further studies are currently underway to investigate the detail mechanism and the
application of this transformation.
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EXPERIMENT SECTION
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General Information
1
Chemicals and solvents (CH3CN, HFIP, EtOAc, acetone and CH2Cl2) were used as received. H
NMR, 13C NMR, 19F NMR spectra were recorded on a 400 MHz spectrometer at the ambient
temperature, using TMS as an internal standard (chemical shifts in δ). Data are reported as follows:
chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet,
dd = doublet of doublet, dt = doublet of triplet, etc.), coupling constant (Hz), and integration. Gas
chromatographic (GC) analyses were performed on a GC equipped with a flameꢀionization
detector and an Rtx@ꢀ65 (30 m × 0.32 mm ID × 0.25 ꢁm df) column using benzophenone as an
internal standard, added during reaction workup. GCꢀMS analyses were performed on a GCꢀMS
with an EI mode. High resolution mass spectra were obtained on a HRMSꢀTOF spectrometer.
Analytical thin layer chromatography (TLC) performed on preꢀcoated silica gel plates. After
elution, plate was visualized under UV illumination at 254 nm for UV active materials. Organic
solutions were concentrated under reduced pressure on a rotary evaporator. Column
chromatography was performed on silica gel (200−300 mesh) by standard techniques eluting with
solvents as indicated.
Preparation of Starting Materials14
General Procedure for Preparation of 1b-1i, 1o-1z
To a 100 mL Schlenk tube methyl 2ꢀiodobenzoate (1 mL, 6.8 mmol, 1 equiv), Pd(PPh3)2Cl2 (381
mg, 0.544 mmol, 8 mol %) and arylboronic acid (8.8 mmol, 1.3 equiv) were added, followed by a
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solution of Na2CO3 (1.44 g, 13.6 mmol, 2 equiv in 15 mL H2O) and THF (30 mL). The reaction
mixture was heated at 60 °C overnight. The resulting reaction mixture was cooled to room
temperature and added to water, the product was extracted with EtOAc three times. The combined
organic extract were dried over Na2SO4, evaporated, and purified by column chromatography. The
purified product was dissolved in a solution of NaOH (1 g) in H2O (25 mL) and MeOH (25 mL)
and stirred at 50 °C for 6 h. MeOH was removed under vacuum and the reaction mixture was
diluted with H2O, and washed with Et2O. The aqueous phase was acidified with 3N HCl, and then
extracted with Et2O three times. The combined organic phase was washed with H2O and brine,
dried over Na2SO4, filtered and the filtration was evaporated under reduced pressure to give the
desired product as a solid.
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General Procedure for Preparation of 1j-1n, 5
To a 100 mL Schlenk tube methyl 2ꢀiodobenzoate (1 mL, 6.8 mmol, 1 equiv), Pd(PPh3)2Cl2 (381
mg, 0.544 mmol, 8 mol %) and arylboronic acid (8.8 mmol, 1.3 equiv) were added, followed by a
solution of Na2CO3 (1.44 g, 13.6 mmol, 2 equiv in 15 mL H2O) and THF (30 mL). The reaction
mixture was heated at 60 °C overnight. The resulting reaction mixture was cooled to room
temperature and added to water, the product was extracted with EtOAc three times. The combined
organic extract were dried over Na2SO4, evaporated, and purified by column chromatography. The
purified product was dissolved in a solution of NaOH (1 g) in H2O (25 mL) and MeOH (25 mL)
and stirred at 50 °C for 6 h. MeOH was removed under vacuum and the reaction mixture was
diluted with H2O, and washed with Et2O. The aqueous phase was acidified with 3N HCl, and then
extracted with Et2O three times. The combined organic phase was washed with H2O and brine,
dried over Na2SO4, filtered and the filtration was evaporated under reduced pressure to give the
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desired product as a solid.
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1
4'-methyl-[1,1'-biphenyl]-2-carboxylic acid (1b)15: H NMR (400 MHz, CDCl3) δ 7.93 (dd, J = 7.8,
1.1 Hz, 1H), 7.54 (td, J = 7.6, 1.4 Hz, 1H), 7.44 – 7.32 (m, 2H), 7.27 – 7.15 (m, 4H), 2.39 (s, 3H). 13C
NMR (101 MHz, CDCl3) δ 173.9, 143.3, 138.0, 137.1, 132.1, 131.2, 130.7, 129.3, 128.9, 128.4, 127.0,
21.2.
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1.1 Hz, 1H), 7.56 (td, J = 7.6, 1.3 Hz, 1H), 7.43 (td, J = 7.7, 1.1 Hz, 1H), 7.35 – 7.31 (m, 1H), 7.31 –
7.26 (m, 2H), 7.14 – 6.97 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 173.2, 162.4 (d, J = 246.3 Hz),
142.5, 137.03 (d, J = 3.4 Hz), 132.3, 131.3, 130.9, 130.1 (d, J = 8.1 Hz), 129.1, 127.4, 115.0 (d, J =
21.6 Hz).
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4'-chloro-[1,1'-biphenyl]-2-carboxylic acid (1d)2d: H NMR (400 MHz, CDCl3) δ 7.98 (dd, J = 7.8,
1.1 Hz, 1H), 7.57 (td, J = 7.6, 1.3 Hz, 1H), 7.44 (td, J = 7.7, 1.2 Hz, 1H), 7.38 – 7.34 (m, 2H), 7.32 (dd,
J = 7.7, 0.8 Hz, 1H), 7.27 – 7.21 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 173.2, 142.4, 139.6, 133.5,
132.4, 131.2, 131.0, 129.8, 129.0, 128.2, 127.6.
4'-bromo-[1,1'-biphenyl]-2-carboxylic acid (1e)2d: 1H NMR (400 MHz, CDCl3) δ 7.98 (dd, J = 7.8,
1.1 Hz, 1H), 7.57 (td, J = 7.5, 1.3 Hz, 1H), 7.53 – 7.49 (m, 2H), 7.44 (td, J = 7.7, 1.2 Hz, 1H), 7.32 (dd,
J = 7.6, 0.9 Hz, 1H), 7.23 – 7.15 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 173.0, 142.4, 140.0, 132.4,
131.2, 131.1, 131.0, 130.2, 128.9, 127.6, 121.7.
4'-acetyl-[1,1'-biphenyl]-2-carboxylic acid (1f)16:1H NMR (400 MHz, CDCl3) δ 8.00 (dd, J = 7.9, 1.1
Hz, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.60 (td, J = 7.6, 1.3 Hz, 1H), 7.47 (td, J = 7.7, 1.2 Hz, 1H), 7.42 (d,
J = 8.3 Hz, 2H), 7.34 (dd, J = 7.6, 0.8 Hz, 1H), 2.64 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 198.1,
172.5, 146.2, 142.5, 135.9, 132.4, 131.1, 131.0, 128.9, 128.8, 128.2, 127.9, 26.7.
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[1,1':4',1''-terphenyl]-2-carboxylic acid (1g): 1H NMR (400 MHz, CDCl3) δ 7.97 (dd, J = 7.7, 0.9 Hz,
1H), 7.68 – 7.52 (m, 5H), 7.49 – 7.38 (m, 6H), 7.38 – 7.31 (m, 1H). 13C NMR (101 MHz, CDCl3) δ
173.0, 143.0, 140.7, 140.2, 140.0, 132.2, 131.2, 130.8, 129.2, 128.9, 128.8, 127.3, 127.3, 127.1, 126.8.
HRMS (EI) calcd for C19H14O2 [M+] 274.0994, found 274.1000.
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4'-methoxy-[1,1'-biphenyl]-2-carboxylic acid (1h)16: 1H NMR (400 MHz, CDCl3) δ 7.92 (dd, J =
7.8, 1.1 Hz, 1H), 7.53 (td, J = 7.6, 1.4 Hz, 1H), 7.44 – 7.32 (m, 2H), 7.32 – 7.18 (m, 2H), 7.01 – 6.83
(m, 2H), 3.84 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 173.8, 159.1, 142.9, 133.3, 132.1, 131.2, 130.7,
129.6, 129.3, 126.8, 113.6, 55.2.
4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxylic acid (1i)2f: 1H NMR (400 MHz, CDCl3) δ 8.02 (dd,
J = 7.8, 1.1 Hz, 1H), 7.63 (d, J = 8.2 Hz, 2H), 7.59 (dd, J = 7.6, 1.3 Hz, 1H), 7.48 (td, J = 7.7, 1.2 Hz,
1H), 7.42 (d, J = 8.0 Hz, 2H), 7.32 (dd, J = 7.6, 0.8 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 172.7,
144.9, 142.3, 132.5, 131.2, 131.2, 129.5 (q, J = 32.4 Hz), 128.9, 128.8, 128.0, 124.9 (q, J = 3.7 Hz),
124.3 (q, J = 272.0 Hz).
4'-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-2-carboxylic acid (1j): 1H NMR (400 MHz, CDCl3) δ 7.95
(dd, J = 7.7, 0.9 Hz, 1H), 7.56 (td, J = 7.6, 1.2 Hz, 1H), 7.47 – 7.39 (m, 1H), 7.34 (d, J = 7.6 Hz, 1H),
7.29 (d, J = 8.7 Hz, 2H), 6.96 (d, J = 8.7 Hz, 2H), 4.38 (q, J = 8.1 Hz, 2H). 13C NMR (101 MHz,
CDCl3) δ 173.1, 156.8, 142.6, 135.3, 132.2, 131.3, 130.8, 129.9, 129.1, 127.2, 123.4 (q, J = 278.7 Hz),
114.5, 65.8 (q, J = 35.8 Hz). 19F NMR (376 MHz, CDCl3) δ ꢀ73.93 (s). HRMS (EI) calcd for
C15H11F3O3 [M+] 296.0660, found 296.0664.
4'-(difluoromethoxy)-[1,1'-biphenyl]-2-carboxylic acid (1k): 1H NMR (400 MHz, CDCl3) δ 7.98 (dd,
J = 7.8, 1.1 Hz, 1H), 7.57 (td, J = 7.6, 1.3 Hz, 1H), 7.44 (td, J = 7.7, 1.1 Hz, 1H), 7.37 – 7.28 (m, 3H),
7.13 (d, J = 8.5 Hz, 2H), 6.56 (t, J = 74.0 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 173.1, 150.7 (t, J =
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2.8 Hz), 142.4, 138.3, 132.4, 131.3, 131.0, 130.0, 129.0, 127.5, 118.9, 116.0 (t, J = 259.3 Hz). 19F
NMR (376 MHz, CDCl3) δ ꢀ80.62 (s). HRMS (EI) calcd for C14H10F2O3 [M+] 264.0598, found
264.0592.
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4'-(allyloxy)-[1,1'-biphenyl]-2-carboxylic acid (1l): H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 7.8
Hz, 1H), 7.53 (td, J = 7.5, 1.0 Hz, 1H), 7.37 (dd, J = 16.0, 7.9 Hz, 2H), 7.26 (d, J = 8.7 Hz, 2H), 6.93 (d,
J = 8.6 Hz, 2H), 6.08 (ddd, J = 22.5, 10.6, 5.3 Hz, 1H), 5.43 (dd, J = 17.3, 1.4 Hz, 1H), 5.30 (dd, J =
10.5, 1.1 Hz, 1H), 4.56 (d, J = 5.3 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 173.8, 158.1, 142.9, 133.5,
133.3, 132.1, 131.2, 130.7, 129.6, 129.3, 126.8, 117.8, 114.4, 68.8. HRMS (EI) calcd for C16H14O3 [M+]
254.0943, found 254.0948.
4'-(1-acetamidoethyl)-[1,1'-biphenyl]-2-carboxylic acid (1m): 1H NMR (400 MHz, DMSO) δ 12.78
(s, 1H), 8.35 (d, J = 8.2 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.56 (td, J = 7.5, 1.1 Hz, 1H), 7.43 (dd, J =
10.8, 4.2 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 4.96 (p, J
= 7.1 Hz, 1H), 1.86 (s, 3H), 1.36 (d, J = 7.0 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 170.2, 168.7,
144.1, 141.0, 139.5, 132.9, 131.2, 130.9, 129.4, 128.7, 127.6, 126.3, 47.9, 23.2, 22.9. HRMS (EI) calcd
for C17H17NO3 [M+] 283.1208, found 283.1210.
4'-(2-hydroxyethyl)-[1,1'-biphenyl]-2-carboxylic acid (2n): 1H NMR (400 MHz, DMSO) δ 12.75 (s,
1H), 7.69 (d, J = 7.5 Hz, 1H), 7.55 (t, J = 7.3 Hz, 1H), 7.43 (t, J = 7.4 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H),
7.25 (s, 4H), 4.70 (s, 1H), 3.65 (t, J = 6.9 Hz, 2H), 2.77 (t, J = 7.0 Hz, 2H). 13C NMR (101 MHz,
DMSO) δ 170.3, 141.2, 139.0, 138.8, 132.9, 131.2, 130.9, 129.4, 129.2, 128.6, 127.5, 62.5, 39.1.
HRMS (EI) calcd for C15H14O3 [M+] 242.0943, found 242.0948.
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6-methyl-[1,1'-biphenyl]-2-carboxylic acid (1o)2d:1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 7.3 Hz,
1H), 7.43 (d, J = 7.2 Hz, 1H), 7.41 – 7.28 (m, 4H), 7.18 – 7.10 (m, 2H), 2.07 (s, 3H). 13C NMR (101
MHz, CDCl3) δ 172.5, 142.5, 139.9, 137.5, 133.9, 130.0, 128.5, 128.0, 127.9, 127.1, 127.0, 20.8.
2-(naphthalen-2-yl)benzoic acid (1p)2d: 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.4 Hz, 1H), 7.87
– 7.81 (m, 2H), 7.81 – 7.75 (m, 2H), 7.64 – 7.56 (m, 1H), 7.52 – 7.47 (m, 2H), 7.46 – 7.39 (m, 3H). 13C
NMR (101 MHz, CDCl3) δ 172.5, 143.4, 138.7, 133.2, 132.5, 132.2, 131.5, 130.8, 129.2, 128.1, 127.7,
127.4, 127.3, 127.1, 126.9, 126.2, 126.0.
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3',5'-dimethyl-[1,1'-biphenyl]-2-carboxylic acid (1q)2f: 1H NMR (400 MHz, CDCl3) δ 7.91 (dd, J =
7.8, 1.0 Hz, 1H), 7.52 (td, J = 7.6, 1.3 Hz, 1H), 7.42 – 7.32 (m, 2H), 6.98 (s, 1H), 6.95 (s, 2H), 2.33 (s,
6H). 13C NMR (101 MHz, CDCl3) δ 173.8, 143.4, 140.8, 137.5, 131.9, 131.2, 130.5, 129.4, 129.1,
127.0, 126.3, 21.3.
3'-methoxy-[1,1'-biphenyl]-2-carboxylic acid (1r)2d: 1H NMR (400 MHz, CDCl3) δ 7.93 (dd, J = 7.8,
1.0 Hz, 1H), 7.55 (td, J = 7.6, 1.3 Hz, 1H), 7.42 (td, J = 7.6, 1.1 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.33
– 7.25 (m, 1H), 6.95 – 6.88 (m, 2H), 6.88 (s, 1H), 3.81 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 173.5,
159.3, 143.1, 142.4, 132.0, 131.1, 130.6, 129.4, 129.1, 127.3, 121.1, 114.1, 113.0, 55.2.
3'-methyl-[1,1'-biphenyl]-2-carboxylic acid (1s)2d: 1H NMR (400 MHz, CDCl3) δ 8.02 – 7.83 (m,
1H), 7.54 (td, J = 7.6, 1.3 Hz, 1H), 7.40 (td, J = 7.6, 1.1 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.30 – 7.25
(m, 1H), 7.20 – 7.04 (m, 3H), 2.38 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 173.5, 143.4, 140.9, 137.7,
132.0, 131.2, 130.6, 129.3, 129.1, 128.2, 128.0, 127.1, 125.7, 21.5.
4-chloro-[1,1'-biphenyl]-2-carboxylic acid (1t)2d: 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 2.2 Hz,
1H), 7.53 (dd, J = 8.3, 2.3 Hz, 1H), 7.43 – 7.34 (m, 3H), 7.33 – 7.27 (m, 3H). 13C NMR (101 MHz,
CDCl3) δ 172.2, 141.8, 139.8, 133.3, 132.6, 132.1, 130.6, 130.5, 128.4, 128.2, 127.7.
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4-methyl-[1,1'-biphenyl]-2-carboxylic acid (1u)2d: 1H NMR (400 MHz, CDCl3) δ 7.75 (s, 1H), 7.40 –
7.28 (m, 6H), 7.25 (d, J = 6.5 Hz, 1H), 2.41 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 173.6, 141.0, 140.5,
137.1, 132.8, 132.1, 131.1, 129.1, 128.5, 128.0, 127.1, 20.9.
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[1,1':4',1''-terphenyl]-2'-carboxylic acid (1v): 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.78 (d, J
= 7.9 Hz, 1H), 7.65 (d, J = 7.5 Hz, 2H), 7.54 – 7.42 (m, 3H), 7.42 – 7.32 (m, 6H). 13C NMR (101 MHz,
CDCl3) δ 173.3, 142.1, 140.7, 140.2, 139.5, 131.8, 130.5, 129.7, 129.3, 129.0, 128.5, 128.1, 127.9,
127.4, 127.1. HRMS (EI) calcd for C19H14O2 [M+] 274.0994, found 274.0998.
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4,5-dimethoxy-[1,1'-biphenyl]-2-carboxylic acid (1w): H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H),
7.42 – 7.33 (m, 3H), 7.33 – 7.28 (m, 2H), 6.77 (s, 1H), 3.94 (s, 3H), 3.91 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 172.5, 151.9, 147.7, 141.4, 138.7, 128.6, 127.9, 127.1, 120.3, 114.0, 113.6, 56.1, 56.1.
HRMS (EI) calcd for C15H14O4 [M+] 258.0892, found 258.0888.
[1,1':3',1''-terphenyl]-2'-carboxylic acid (1x)17: 1H NMR (400 MHz, CDCl3) δ 7.55 – 7.47 (m, 1H),
7.44 – 7.32 (m, 12H). 13C NMR (101 MHz, CDCl3) δ 174.0, 140.3, 140.2, 131.6, 129.6, 129.0, 128.4,
128.4, 127.6.
4,5-difluoro-[1,1'-biphenyl]-2-carboxylic acid (1y): 1H NMR (400 MHz, CDCl3) δ 7.80 (dd, J = 10.7,
8.1 Hz, 1H), 7.41 – 7.33 (m, 3H), 7.30 – 7.23 (m, 2H), 7.16 (dd, J = 10.7, 7.6 Hz, 1H). 13C NMR (101
MHz, CDCl3) δ 171.3, 152.2 (dd, J = 257.1, 12.6 Hz), 149.0 (dd, J = 250.5, 12.8 Hz), 141.7 (dd, J =
6.9, 3.9 Hz), 139.1, 128.3, 128.2, 128.0, 125.3 (dd, J = 5.2, 3.5 Hz), 120.4 (d, J = 17.7 Hz), 120.3 (dd, J
= 19.1, 1.8 Hz). 19F NMR (376 MHz, CDCl3) δ ꢀ130.43 (d, J = 21.8 Hz), ꢀ138.47 (d, J = 21.8 Hz).
HRMS (EI) calcd for C13H8F2O2 [M+] 234.0492, found 234.0496.
3-phenylthiophene-2-carboxylic acid (1z): 1H NMR (400 MHz, DMSO) δ 12.90 (s, 1H), 7.86 (d, J =
5.1 Hz, 1H), 7.46 (d, J = 6.6 Hz, 2H), 7.43 – 7.32 (m, 3H), 7.18 (d, J = 5.1 Hz, 1H). 13C NMR (101
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MHz, DMSO) δ 163.3, 147.6, 136.0, 132.2, 131.5, 129.7, 128.5, 128.2, 128.1.
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General Procedure for Silver-Catalyzed C(sp2)-H Functionalization/C-O Cyclization
Reaction
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To a 15 mL tube were sequentially added 1 (0.3 mmol, 1 equiv), AgNO3 (10.2 mg, 0.06 mmol,
0.02 equiv), (NH4)2S2O8 (205 mg, 0.9 mmol, 3 equiv), KOAc (88.3 mg, 0.9 mmol, 3 equiv), 3 mL
of CH2Cl2 and 3 mL H2O. The reaction mixture was then stirred at room temperature for the
appointed time. After completion, the reaction mixture was diluted with H2O, extracted with
CH2Cl2 (3 × 20 mL). The combined organic extracts were dried over MgSO4 and concentrated in
vacuo. Purification of the crude product by flash chromatography on silica gel using the indicated
solvent system afforded the desired product.
6H-benzo[c]chromen-6-one (2a)2d: According to the general procedure, the reaction mixture was
stirred at room temperature for 24 h. The product was isolated by flash chromatography (PE : EA = 20 :
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1, Rf = 0.4) as a white solid (55 mg, 93%). H NMR (400 MHz, CDCl3) δ 8.38 (dd, J = 7.9, 0.5 Hz,
1H), 8.10 (d, J = 8.1 Hz, 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.81 (td, J = 7.9, 1.1 Hz, 1H), 7.57 (t, J = 7.6
Hz, 1H), 7.51 – 7.42 (m, 1H), 7.40 – 7.29 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 161.2, 151.2, 134.8,
134.7, 130.5, 130.4, 128.9, 124.5, 122.7, 121.7, 121.2, 118.0, 117.7. GCMS (EI) m/z 196 (M)+.
3-methyl-6H-benzo[c]chromen-6-one (2b)2d: According to the general procedure, the reaction
mixture was stirred at room temperature for 24 h. The product was isolated by flash chromatography
(PE : EA = 20 : 1, Rf = 0.4) as a white solid (45 mg, 71%). 1H NMR (400 MHz, CDCl3) δ 8.37 (dd, J =
8.0, 1.0 Hz, 1H), 8.07 (d, J = 8.1 Hz, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.86 – 7.73 (m, 1H), 7.64 – 7.43 (m,
1H), 7.14 (d, J = 8.7 Hz, 2H), 2.45 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 161.4, 151.2, 141.3, 134.9,
134.8, 130.5, 128.4, 125.7, 122.5, 121.4, 120.8, 117.9, 115.4, 21.4. GCMS (EI) m/z 210 (M)+.
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3-fluoro-6H-benzo[c]chromen-6-one (2c)2d: According to the general procedure, the reaction mixture
was stirred at room temperature for 16 h. The product was isolated by flash chromatography (PE : EA =
20 : 1, Rf = 0.4) as a white solid (45 mg, 71%). 1H NMR (400 MHz, CDCl3) δ 8.34 (dd, J = 8.0, 1.0 Hz,
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1H), 8.00 (dd, J = 8.3, 5.6 Hz, 2H), 7.86 – 7.74 (m, 1H), 7.61 – 7.48 (m, 1H), 7.12 – 6.97 (m, 2H). 13
C
NMR (101 MHz, CDCl3) δ 163.4 (d, J = 251.3 Hz), 160.8, 152.1 (d, J = 12.3 Hz), 135.1, 134.2, 130.6,
128.7, 124.3 (d, J = 9.9 Hz), 121.5, 120.4, 114.6 (d, J = 3.2 Hz), 112.4 (d, J = 22.4 Hz), 105.0 (d, J =
25.3 Hz). 19F NMR (376 MHz, CDCl3) δ ꢀ108.36 (s). GCMS (EI) m/z 214 (M)+.
3-chloro-6H-benzo[c]chromen-6-one (2d)2d: According to the general procedure, the reaction mixture
was stirred at room temperature for 16 h. The product was isolated by flash chromatography (PE : EA =
20 : 1, Rf = 0.4) as a white solid (52 mg, 75%). 1H NMR (400 MHz, CDCl3) δ 8.32 (dd, J = 7.9, 1.0 Hz,
1H), 8.01 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.3 Hz, 1H), 7.87 – 7.72 (m, 1H), 7.64 – 7.46 (m, 1H), 7.32 –
7.24 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 160.5, 151.4, 135.8, 135.0, 133.8, 130.6, 129.1, 124.8,
123.7, 121.6, 120.7, 117.8, 116.6. GCMS (EI) m/z 230 (35M)+, 232 (37M)+.
3-bromo-6H-benzo[c]chromen-6-one (2e)2d: According to the general procedure, the reaction mixture
was stirred at room temperature for 16 h. The product was isolated by flash chromatography (PE : EA =
20 : 1, Rf = 0.4) as a white solid (73 mg, 88%). 1H NMR (400 MHz, CDCl3) δ 8.35 (dd, J = 7.9, 0.7 Hz,
1H), 8.04 (d, J = 8.1 Hz, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.85 – 7.78 (m, 1H), 7.63 – 7.56 (m, 1H), 7.48
(d, J = 1.9 Hz, 1H), 7.44 (dd, J = 8.5, 1.9 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 160.4, 151.4, 135.1,
133.9, 130.7, 129.3, 127.8, 123.9, 123.7, 121.6, 120.9, 120.8, 117.0. GCMS (EI) m/z 274 (79M)+, 276
(81M)+.
3-acetyl-6H-benzo[c]chromen-6-one (2f)2d: According to the general procedure, the reaction mixture
was stirred at room temperature for 24 h. The product was isolated by flash chromatography (PE : EA =
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10 : 1, Rf = 0.3) as a white solid (40 mg, 56%). 1H NMR (400 MHz, CDCl3) δ 8.43 (dd, J = 8.0, 1.0 Hz,
1H), 8.16 (t, J = 8.8 Hz, 2H), 7.97 – 7.81 (m, 3H), 7.73 – 7.57 (m, 1H), 2.67 (s, 3H). 13C NMR (101
MHz, CDCl3) δ 196.5, 160.6, 151.1, 138.3, 135.1, 133.6, 130.8, 130.1, 123.9, 123.2, 122.4, 122.0,
121.7, 117.9, 26.8. GCMS (EI) m/z 238 (M)+.
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3-phenyl-6H-benzo[c]chromen-6-one (2g): According to the general procedure, the reaction mixture
was stirred at room temperature for 48 h. The product was isolated by flash chromatography (PE : EA =
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20 : 1, , Rf = 0.5) as a white solid (54 mg, 67%). H NMR (400 MHz, CDCl3) δ 8.36 (dd, J = 7.9, 1.0
Hz, 1H), 8.06 (dd, J = 11.3, 8.1 Hz, 2H), 7.79 (td, J = 7.8, 1.4 Hz, 1H), 7.62 (dd, J = 5.2, 3.3 Hz, 2H),
7.56 – 7.50 (m, 3H), 7.50 – 7.43 (m, 2H), 7.43 – 7.35 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 161.2,
151.5, 143.4, 139.1, 134.8, 134.5, 130.5, 129.0, 128.7, 128.3, 127.0, 123.2, 123.1, 121.6, 121.0, 116.8,
115.7. HRMS (EI) calcd for C19H12O2 [M+] 272.0837, found 272.0832.
3-methoxy-6H-benzo[c]chromen-6-one (2h)2d: According to the general procedure, the reaction
mixture was stirred at room temperature for 8 h. The product was isolated by flash chromatography
(PE : EA = 20 : 1, Rf = 0.4) as a white solid (28 mg, 41%). 1H NMR (400 MHz, CDCl3) δ 8.32 (dd, J
= 8.0, 1.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.82 – 7.71 (m, 1H), 7.55 – 7.41
(m, 1H), 6.89 (dd, J = 8.8, 2.5 Hz, 1H), 6.82 (d, J = 2.5 Hz, 1H), 3.87 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 161.5, 161.5, 152.5, 135.1, 134.8, 130.5, 127.7, 123.7, 121.0, 119.9, 112.4, 111.1, 101.6, 55.7.
GCMS (EI) m/z 226 (M)+.
3-(trifluoromethyl)-6H-benzo[c]chromen-6-one (2i)2d: According to the general procedure, the
reaction mixture was stirred at room temperature for 8 h. The product was isolated by flash
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chromatography (PE : EA = 20 : 1, Rf = 0.5) as a white solid (26 mg, 33%). H NMR (400 MHz,
CDCl3) δ 8.42 (dd, J = 7.9, 1.0 Hz, 1H), 8.17 (t, J = 7.8 Hz, 2H), 7.89 (td, J = 7.8, 1.4 Hz, 1H), 7.74 –
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7.63 (m, 1H), 7.63 – 7.53 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 160.3, 150.9, 135.2, 133.3, 132.2 (q,
J = 33.5 Hz), 130.8, 130.2, 123.6, 123.3 (q, J = 272.5 Hz), 122.2, 121.6, 121.1 (q, J = 3.6 Hz), 121.1,
115.2 (q, J = 4.0 Hz). 19F NMR (376 MHz, CDCl3) δ ꢀ62.79.
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3-(2,2,2-trifluoroethoxy)-6H-benzo[c]chromen-6-one (2j): According to the general procedure, the
reaction mixture was stirred at room temperature for 16 h. The product was isolated by flash
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chromatography (PE : EA = 20 : 1, Rf = 0.5) as a white solid (67 mg, 76%). H NMR (400 MHz,
CDCl3) δ 8.31 (dd, J = 8.0, 1.0 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.93 (d, J = 8.9 Hz, 1H), 7.83 – 7.72
(m, 1H), 7.55 – 7.47 (m, 1H), 6.93 (dd, J = 8.8, 2.6 Hz, 1H), 6.83 (d, J = 2.6 Hz, 1H), 4.42 (q, J = 8.0
Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 161.1, 158.7, 152.3, 135.0, 134.5, 130.6, 128.3, 124.2, 123.1
(q, J = 278.0 Hz), 121.3, 112.8, 112.5, 102.9, 65.8 (q, J = 36.1 Hz). 19F NMR (376 MHz, CDCl3) δ
ꢀ73.70 (s). HRMS (EI) calcd for C15H9F3O3 [M+] 294.0504, found 294.0501.
3-(difluoromethoxy)-6H-benzo[c]chromen-6-one (2k): According to the general procedure, the
reaction mixture was then stirred at room temperature for 16 h. The product was isolated by flash
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chromatography (PE : EA = 10 : 1, Rf = 0.3) as a white solid (68 mg, 87%). H NMR (400 MHz,
CDCl3) δ 8.34 (d, J = 7.9 Hz, 1H), 8.17 – 7.92 (m, 2H), 7.82 (t, J = 7.7 Hz, 1H), 7.57 (t, J = 7.6 Hz,
1H), 7.10 (dd, J = 6.6, 2.2 Hz, 2H), 6.62 (t, J = 73.0 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 160.7,
152.2 (t, J = 2.9 Hz), 151.9, 135.1, 134.0, 130.7, 128.9, 124.2, 121.6, 120.6, 115.8, 115.4 (t, J = 262.0
Hz), 115.3, 108.3. 19F NMR (376 MHz, CDCl3) δ ꢀ81.76 (s). HRMS (EI) calcd for C14H8F2O3 [M+]
262.0442, found 262.0448.
3-(allyloxy)-6H-benzo[c]chromen-6-one (2l): According to the general procedure, the reaction
mixture was stirred at room temperature for 6 h. The product was isolated by flash chromatography
(PE : EA = 50 : 1, Rf = 0.4) as a white solid (34 mg, 45%). 1H NMR (400 MHz, CDCl3) δ 8.26 (dd, J =
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8.0, 1.5 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.84 (dd, J = 8.8, 2.1 Hz, 1H), 7.70 (dd, J = 10.8, 4.6 Hz,
1H), 7.41 (t, J = 7.6 Hz, 1H), 6.89 – 6.80 (m, 1H), 6.78 (t, J = 2.3 Hz, 1H), 5.99 (dtd, J = 15.8, 10.6, 5.3
Hz, 1H), 5.38 (dd, J = 17.3, 1.1 Hz, 1H), 5.27 (dd, J = 10.5, 1.0 Hz, 1H), 4.63 – 4.28 (m, 2H). 13C
NMR (101 MHz, CDCl3) δ 161.5, 160.4, 152.5, 135.1, 134.9, 132.4, 130.5, 127.7, 123.8, 121.1, 120.0,
118.4, 113.0, 111.3, 102.5, 69.2. HRMS (EI) calcd for C16H12O3 [M+] 252.0786, found 252.0782.
N-(1-(6-oxo-6H-benzo[c]chromen-3-yl)ethyl)acetamide (2m): According to the general procedure,
the reaction mixture was stirred at room temperature for 24 h. The product was isolated by flash
chromatography (PE : EA = 2 : 1, Rf = 0.5) as a white solid (76 mg, 90%). 1H NMR (400 MHz, CDCl3)
δ 8.34 (dd, J = 23.5, 7.8 Hz, 1H), 8.00 (t, J = 12.6 Hz, 1H), 7.86 (t, J = 12.9 Hz, 1H), 7.54 (t, J = 7.6 Hz,
1H), 7.32 – 7.23 (m, 2H), 6.82 (d, J = 6.8 Hz, 1H), 5.18 (p, J = 6.8 Hz, 1H), 2.09 (s, 3H), 1.54 (d, J =
6.9 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 170.0, 161.3, 151.3, 146.6, 134.9, 134.5, 130.4, 128.8,
123.1, 123.0, 121.7, 120.8, 116.8, 114.8, 48.6, 23.2, 21.7. HRMS (EI) calcd for C17H15NO3 [M+]
281.1052, found 281.1056.
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3-(2-hydroxyethyl)-6H-benzo[c]chromen-6-one (2n): According to the general procedure, the
reaction mixture was stirred at room temperature for 24 h. The product was isolated by flash
chromatography (PE : EA = 4 : 1, Rf = 0.6) as a white solid (47 mg, 65%). 1H NMR (400 MHz, CDCl3)
δ 8.33 (d, J = 7.9 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.77 (t, J = 7.6 Hz, 1H),
7.53 (t, J = 7.6 Hz, 1H), 7.21 – 7.19 (m, 2H), 3.95 (t, J = 6.4 Hz, 2H), 2.96 (t, J = 6.4 Hz, 2H). 13C
NMR (101 MHz, CDCl3) δ 161.3, 151.3, 142.2, 134.8, 134.7, 130.5, 128.6, 125.5, 122.8, 121.5, 120.8,
117.9, 116.3, 63.2, 38.9. HRMS (EI) calcd for C15H12O3 [M+] 240.0786, found 240.0783.
10-methyl-6H-benzo[c]chromen-6-one (2o)2d: According to the general procedure, the reaction
mixture was stirred at room temperature for 24 h. The product was isolated by flash chromatography
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(PE : EA = 20 : 1, Rf = 0.4) as a white solid (39 mg, 62%). 1H NMR (400 MHz, CDCl3) δ 8.32 (d, J =
7.7 Hz, 1H), 8.25 (d, J = 8.2 Hz, 1H), 7.61 (d, J = 7.4 Hz, 1H), 7.44 (ddd, J = 7.6, 5.7, 2.8 Hz, 2H),
7.39 – 7.33 (m, 1H), 7.33 – 7.27 (m, 1H), 2.85 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 161.6, 151.1,
139.0, 135.0, 133.4, 129.6, 129.0, 128.2, 127.1, 124.0, 122.6, 119.5, 117.8, 25.3. GCMS (EI) m/z 210
(M)+.
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6H-dibenzo[c,h]chromen-6-one (2p)2f: According to the general procedure, the reaction mixture was
stirred at room temperature for 24 h. The product was isolated by flash chromatography (PE : EA = 20 :
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1, Rf = 0.5) as a light yellow solid (47 mg, 64%). H NMR (400 MHz, CDCl3) δ 8.51 – 8.41 (m, 1H),
8.35 (dd, J = 7.9, 1.0 Hz, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.82 – 7.73 (m, 2H),
7.63 (d, J = 8.7 Hz, 1H), 7.58 – 7.48 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 161.1, 147.0, 135.1,
134.8, 134.1, 130.4, 128.4, 127.7, 127.5, 126.9, 124.4, 123.6, 122.1, 121.9, 120.9, 119.0, 112.8. GCMS
(EI) m/z 246 (M)+.
2,4-dimethyl-6H-benzo[c]chromen-6-one (2q)2f: According to the general procedure, the reaction
mixture was stirred at room temperature for 18 h. The product was isolated by flash chromatography
(PE : EA = 20 : 1, Rf = 0.5) as a white solid (51 mg, 76%). 1H NMR (400 MHz, CDCl3) δ 8.32 (d, J =
7.9 Hz, 1H), 7.97 (d, J = 8.1 Hz, 1H), 7.80 – 7.56 (m, 1H), 7.54 (s, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.05
(s, 1H), 2.38 (s, 3H), 2.36 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 161.3, 147.5, 135.0, 134.5, 133.3,
132.7, 130.3, 128.3, 126.4, 121.7, 120.9, 120.2, 117.1, 21.0, 15.8. GCMS (EI) m/z 224 (M)+.
2-methoxy-6H-benzo[c]chromen-6-one (2r)2d: According to the general procedure, the reaction
mixture was stirred at room temperature for 24 h. The product was isolated by flash chromatography
(PE : EA = 50 : 1, Rf = 0.3) as a white solid (50 mg, 74%). 1H NMR (400 MHz, CDCl3) δ 8.36 (dd, J =
7.9, 1.1 Hz, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.79 (td, J = 7.9, 1.4 Hz, 1H), 7.60 – 7.51 (m, 1H), 7.42 (d, J
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= 2.9 Hz, 1H), 7.29 – 7.20 (m, 1H), 7.01 (dd, J = 9.0, 2.9 Hz, 1H), 3.89 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 161.3, 156.3, 145.5, 134.7, 134.5, 130.6, 128.9, 121.7, 121.2, 118.6, 118.4, 117.1, 106.2, 55.8.
GCMS (EI) m/z 226 (M)+.
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Mixture isomers of 2s and 2s’: According to the general procedure, the reaction mixture was stirred at
room temperature for 10 h. The mixture product were isolated by flash chromatography (PE : EA = 20 :
1, Rf = 0.4) as a white solid (52 mg, 82%). 1H NMR (400 MHz, CDCl3) δ 8.40 – 8.25 (m, two isomers,
2H), 8.10 – 7.95 (m, two isomers, 2H), 7.82 (d, J = 7.9 Hz, 1H), 7.77 (dd, J = 11.8, 4.6 Hz, two isomers,
3H), 7.52 (t, J = 7.6 Hz, two isomers, 2H), 7.33 – 7.09 (m, two isomers, 4H), 2.45 (s, one isomer, 3H),
2.42 (s, the other isomer, 3H). 13C NMR (101 MHz, CDCl3) δ 161.3, 161.2, 149.5, 149.2, 135.0, 134.7,
134.7, 134.0, 131.7, 131.3, 130.4, 130.3, 128.6, 128.6, 126.9, 123.9, 122.7, 121.8, 121.5, 121.1, 120.9,
120.3, 117.7, 117.5, 117.4, 21.1, 15.9. GCMS (EI) m/z 210 (M)+.
8-chloro-6H-benzo[c]chromen-6-one (2t)2d: According to the general procedure, the reaction mixture
was stirred at room temperature for 24 h. The product was isolated by flash chromatography (PE : EA =
20 : 1, Rf = 0.4) as a white solid (34 mg, 50%). 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 2.3 Hz, 1H),
8.02 (d, J = 8.6 Hz, 1H), 8.00 – 7.92 (m, 1H), 7.74 (dd, J = 8.6, 2.3 Hz, 1H), 7.54 – 7.43 (m, 1H), 7.34
(dd, J = 12.0, 4.5 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 159.9, 151.0, 135.1, 134.9, 133.1, 130.8,
129.9, 124.8, 123.4, 122.7, 122.4, 117.8, 117.2. GCMS (EI) m/z 230 (35M)+, 232 (37M)+.
8-methyl-6H-benzo[c]chromen-6-one (2u)2d: According to the general procedure, the reaction
mixture was stirred at room temperature for 24 h. The product was isolated by flash chromatography
(PE : EA = 20 : 1, Rf = 0.5) as a white solid (49 mg, 78%). 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H),
7.98 – 7.93 (m, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.56 (dd, J = 8.2, 1.5 Hz, 1H), 7.47 – 7.35 (m, 1H), 7.34
– 7.22 (m, 2H), 2.44 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 161.3, 150.9, 139.1, 136.0, 132.1, 130.2,
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8-phenyl-6H-benzo[c]chromen-6-one (2v): According to the general procedure, the reaction mixture
was stirred at room temperature for 48 h. The product was isolated by flash chromatography (PE : EA =
20 : 1, Rf = 0.4) as a white solid (43 mg, 53%). 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 2.0 Hz, 1H),
8.17 (d, J = 8.4 Hz, 1H), 8.10 – 7.99 (m, 2H), 7.75 – 7.64 (m, 2H), 7.57 – 7.45 (m, 3H), 7.45 – 7.29 (m,
3H). 13C NMR (101 MHz, CDCl3) δ 161.3, 151.2, 141.7, 138.9, 133.5, 133.4, 130.4, 129.1, 128.5,
128.3, 127.0, 124.6, 122.8, 122.4, 121.6, 117.9, 117.8. GCMS (EI) m/z 272 (M)+. HRMS (EI) calcd for
C19H12O2 [M+] 272.0837, found 272.0832.
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8,9-dimethoxy-6H-benzo[c]chromen-6-one (2w)18: According to the general procedure, the reaction
mixture was stirred at room temperature for 12 h. The product was isolated by flash chromatography
(PE : EA = 20 : 1, Rf = 0.3) as a white solid (56 mg, 73%). 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J =
8.0 Hz, 1H), 7.61 (s, 1H), 7.38 (td, J = 7.9, 1.4 Hz, 1H), 7.32 (s, 1H), 7.31 – 7.21 (m, 2H), 4.07 (s, 3H),
3.95 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 161.0, 154.9, 150.8, 149.9, 129.7, 129.5, 124.3, 122.1,
117.9, 117.5, 114.3, 110.2, 102.5, 56.3, 56.2. GCMS (EI) m/z 256 (M)+.
7-phenyl-6H-benzo[c]chromen-6-one (2x)19: According to the general procedure, the reaction
mixture was stirred at room temperature for 48 h. The product was isolated by flash chromatography
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(PE : EA = 50 : 1, Rf = 0.4) as a white solid (0.2 mmol scale, 22 mg, 42%). H NMR (400 MHz,
CDCl3) δ 8.18 (d, J = 8.1 Hz, 1H), 8.11 (dd, J = 8.2, 1.1 Hz, 1H), 7.81 (t, J = 7.8 Hz, 1H), 7.53 – 7.39
(m, 5H), 7.39 – 7.29 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 159.2, 151.5, 146.9, 141.9, 136.2, 133.6,
132.4, 130.5, 128.2, 127.8, 127.3, 124.3, 123.1, 121.2, 118.7, 118.1, 117.5. GCMS (EI) m/z 271 (M)+.
8,9-difluoro-6H-benzo[c]chromen-6-one (2y)20: According to the general procedure, the reaction
mixture was stirred at room temperature for 24 h. The product was isolated by flash chromatography
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(PE : EA = 50 : 1, Rf = 0.4) as a white solid (43 mg, 63%). 1H NMR (400 MHz, CDCl3) δ 8.18 (dd, J =
9.9, 8.0 Hz, 1H), 7.97 – 7.80 (m, 2H), 7.53 (td, J = 7.6, 1.4 Hz, 1H), 7.37 (ddd, J = 6.1, 3.6, 1.2 Hz,
2H). 13C NMR (101 MHz, CDCl3) δ 159.4 (d, J = 1.8 Hz), 155.4 (dd, J = 259.7, 13.8 Hz), 151.3, 150.6
(dd, J = 254.2, 13.7 Hz), 133.1 (dd, J = 8.2, 3.4 Hz), 131.2, 125.0, 122.8, 119.2 (dd, J = 18.9, 2.4 Hz),
118.4 (dd, J = 6.2, 2.9 Hz), 118.0, 116.7 (dd, J = 2.2, 1.7 Hz), 110.7 (d, J = 19.4 Hz). 19F NMR (376
MHz, CDCl3) δ ꢀ124.86 (d, J = 21.5 Hz), ꢀ133.84 (d, J = 21.4 Hz). GCMS (EI) m/z 232 (M)+.
4H-thieno[2,3-c]chromen-4-one (2z)3o: According to the general procedure, the reaction mixture was
stirred at room temperature for 12 h. The product was isolated by flash chromatography (PE : EA = 10 :
1, Rf = 0.3) as a yellow solid (0.2 mmol scale, 16 mg, 40%).1H NMR (400 MHz, CDCl3) δ 7.93 (d, J =
5.2 Hz, 1H), 7.84 (dd, J = 7.8, 1.4 Hz, 1H), 7.65 (d, J = 5.2 Hz, 1H), 7.54 – 7.47 (m, 1H), 7.44 (dd, J =
8.3, 1.0 Hz, 1H), 7.38 – 7.32 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 157.2, 152.6, 145.0 136.9, 130.2,
124.6, 124.4, 123.8, 122.4, 117.5, 117.4.
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Gram Scale Reaction and Further Conversion of Lactone
To a 500 mL flask were sequentially added 1a (3.96 g, 20 mmol), AgNO3 (338 mg, 2 mmol, 0.1 equiv),
(NH4)2S2O8 (13.6 g, 60 mmol, 3 equiv), KOAc (5.88 g, 60 mmol, 3 equiv), CH2Cl2 (200 mL) and H2O
(200 mL). The reaction mixture was then stirred at room temperature for 24 h. The product was
isolated by flash chromatography (PE : EA = 20 : 1, Rf = 0.4) as a white solid (3.5 g, 89% yield).
To a 25 mL flask were added the lactone 2a (196.2 mg, 0.25 mmol) and LiOH•H2O (1.0 g, 24 mmol,
24 equiv). To this mixture was then added MeOH (16 mL), THF (8 mL), and H2O (4 mL). The reaction
mixture was then stirred for 24 h at room temperature and followed the course of the reaction by TLC
until completion. The MeOH and THF was then removed in vacuo, and the resulting residue was
diluted with H2O (15 mL), ice and EtOAc (20 mL). After acidification with 2 M HCl (pH 4ꢀ5), the
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solution was extracted with EtOAc for three times. The combined organic extract was washed with
brine, dried over MgSO4 and concentrated in vacuo. The crude was washed with EtOAc furnishing the
final hydroxyacids 3 as a white solid (184 mg, 86% yield).
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2'-hydroxy-[1,1'-biphenyl]-2-carboxylic acid (3)2e: H NMR (400 MHz, CDCl3) δ 8.42 (dd, J = 7.9,
0.9 Hz, 1H), 8.14 (d, J = 8.1 Hz, 1H), 8.08 (dd, J = 7.9, 1.3 Hz, 1H), 7.89 – 7.78 (m, 1H), 7.66 – 7.56
(m, 1H), 7.55 – 7.44 (m, 1H), 7.41 – 7.32 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 161.2, 151.3, 134.9,
134.8, 130.6, 130.5, 128.9, 124.6, 122.8, 121.7, 121.3, 118.1, 117.8.
A cooled solution of lactone 2a (392.4 mg, 2 mmol) in a mixture of BF3•Et2O (5 mL) and THF (10 mL)
was added over 15 min to a suspension of NaBH4 (250 mg, 6.6 mmol) in THF (5 mL) under nitrogen
while maintaining the reaction temperature below 10 °C. The reaction mixture was then raised within
30 min to the reflux temperature, kept under reflux for 1 h, and then cooled to ꢀ3 °C. 2 N cold HCl aq.
(8 mL) was then cautiously added and the temperature was allowed to increase to 25 °C. Water (40 mL)
was added and the reaction mixture was extracted with CHCl3 (3 × 50 mL). The combined extracts
were evaporated and the oily residue was heated at 80 °C with 2N NaOH aq. (80 mL) for 20 min. The
resulting mixture was cooled and extracted with ether (4 × 30 mL). The ether extracts were combined,
dried over Na2SO4, and concentrated in vacuo. The product was isolated by flash chromatography (PE :
EA = 20 : 1, Rf = 0.6) as a colorless liquid (284 mg, 78% yield).
6H-benzo[c]chromene (4)21: 1H NMR (400 MHz, CDCl3) δ 7.71 (dd, J = 7.7, 1.5 Hz, 1H), 7.67 (d, J =
7.7 Hz, 1H), 7.34 (dd, J = 11.1, 4.0 Hz, 1H), 7.30 – 7.18 (m, 2H), 7.11 (d, J = 7.5 Hz, 1H), 7.03 (td, J =
7.6, 1.2 Hz, 1H), 6.98 (dd, J = 8.1, 1.0 Hz, 1H), 5.09 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 154.7,
131.4, 130.1, 129.4, 128.4, 127.6, 124.6, 123.3, 122.9, 122.1, 122.0, 117.4, 68.4.
Chemoselectivity Profile in C-H Functionalization/C-O Cyclization
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To a 15 mL tube were sequentially added 5 (70.2 mg, 0.3 mmol), AgNO3 (10.2 mg, 0.06 mmol, 0.2
equiv), (NH4)2S2O8 (205 mg, 0.9 mmol, 3 equiv), KOAc (88.3 mg, 0.9 mmol, 3 equiv), 3 mL of CH2Cl2
and 3 mL H2O. The reaction mixture was then stirred at room temperature for 3 h. The product was
isolated by flash chromatography (PE : EA = 5 : 1, Rf = 0.5) as a white solid (43 mg, 72%).
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3-(2-hydroxy-2-methylpropyl)-6H-benzo[c]chromen-6-one (6): H NMR (400 MHz, CDCl3) δ 8.37
(d, J = 7.9 Hz, 1H), 8.07 (d, J = 8.1 Hz, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.85 – 7.70 (m, 1H), 7.56 (t, J =
7.6 Hz, 1H), 7.26 – 7.18 (m, 2H), 2.86 (s, 2H), 1.28 (s, 11H). 13C NMR (101 MHz, CDCl3) δ 161.3,
151.0, 141.3, 134.9, 134.8, 130.6, 128.6, 127.0, 122.4, 121.5, 121.0, 119.3, 116.3, 70.9, 49.4, 29.4.
HRMS (EI) calcd for C17H16O3[M+] 268.1099, found 268.1095.
In a 15 mL sealed tube, 2.0 mL hexafluorobenzene was added to a mixture of alcohol substrate 6 (53.6
mg, 0.2 mmol, 1.0 equiv), Pd(OAc)2 (2.3 mg, 0.01 mmol, 0.05 equiv, 5 mol%), Li2CO3 (22.2 mg, 0.3
mmol, 1.5 equiv), and Iodobenzene diacetate (96.6 mg, 0.3 mmol, 1.5 equiv) under air. The tube was
sealed with a Teflon lined cap and the reaction mixture was stirred at 100 °C for 48 h. After cooling to
room temperature, the reaction mixture was diluted with diethyl ether (15 mL), filtered through celite,
washed with diethyl ether (10 mL × 2), concentrated under vacuum carefully and the residue was
purified by flash chromatography (PE : EA = 50 : 1, Rf = 0.6), giving the corresponding product 7 as a
white solid (34 mg, 64%).
9,9-dimethyl-8,9-dihydro-5H-benzo[c]furo[2,3-g]chromen-5-one (7): 1H NMR (400 MHz, CDCl3) δ
8.37 (dd, J = 7.9, 0.9 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.83 – 7.71 (m, 1H), 7.62 – 7.48 (m, 1H), 7.29
(s, 1H), 7.15 (s, 1H), 3.10 (s, 2H), 1.52 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 161.6, 156.0, 145.8,
135.1, 134.7, 131.3, 130.5, 128.5, 121.6, 120.7, 117.4, 114.6, 101.5, 87.8, 43.0, 28.1. HRMS (EI) calcd
for C17H14O3[M+] 266.0943, found 266.0945.
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Intermolecular Kinetic Isotope Effect (KIE)
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A 15 mL tube equipped with a magnetic stirrer was charged with 1a (0.15 mmol), [D5]1a (0.15 mmol),
AgNO3 (20 mol %), KOAc (3 equiv), (NH4)2S2O8 (3 equiv), and CH2Cl2 (3 mL), H2O (3 mL). The
mixture was stirred at room temperature for 30 min. The reaction mixture was purified by flash
chromatography to give the desired product. This KIE value was determined by 1H NMR analysis (KIE
≈ 1.27) was obtained.
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ASSOCIATED CONTENT
Supporting Information.
The supplementary crystallographic data and (CIF File) for the compound has been provided in
supporting information. CCDC 1038197 contains supplementary crystallographic data for the
structure 2j. These data can be obtained free of charge from the Cambridge Crystallographic Data
1
Centre via www.ccdc.cam.ac.uk/data_request/cif. Optimization data, H and 13C NMR spectra.
This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Email: hjxu@hfut.edu.cn
Notes
We declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge financial support from the National Natural Science Foundation of
China (Nos. 21472033, 21402036 and 21272050), the program for New Century Excellent Talents
in University of the Chinese Ministry of Education (NCETꢀ11ꢀ0627), and the project funded by
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China Postdoctoral Science (2014M551793).
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