Synthesis of Cyclohexane-Fused Isocoumarins via Cationic Palladium(II)-Catalyzed Cascade Cyclization Reaction of Alkyne-Tethered Carbonyl Compounds Initiated by Intramolecular Oxypalladation of Ester-Substituted Aryl Alkynes

Article abstract of DOI:10.1021/acs.joc.6b00128

A cationic Pd(II)-catalyzed cascade cyclization reaction of alkyne-tethered carbonyl compounds was developed. This reaction is initiated by intramolecular oxypalladation of alkynes with an ester group followed by 1,2-addition of the formed C-Pd(II) bond to the carbonyl group, providing a highly efficient method for the synthesis of cyclohexane-fused isocoumarins.

Full text of DOI:10.1021/acs.joc.6b00128

Note
pubs.acs.org/joc
Synthesis of Cyclohexane-Fused Isocoumarins via Cationic
Palladium(II)-Catalyzed Cascade Cyclization Reaction of Alkyne-
Tethered Carbonyl Compounds Initiated by Intramolecular
Oxypalladation of Ester-Substituted Aryl Alkynes
Jianbo Zhang, Xiuling Han,* and Xiyan Lu*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: A cationic Pd(II)-catalyzed cascade cyclization reaction of
alkyne-tethered carbonyl compounds was developed. This reaction is
initiated by intramolecular oxypalladation of alkynes with an ester group
followed by 1,2-addition of the formed C−Pd(II) bond to the carbonyl
group, providing a highly efficient method for the synthesis of cyclohexane-
fused isocoumarins.
Scheme 1. Pd-Catalyzed Cascade Reactions of 2-
Alkynylbenzoates
ransition metal-catalyzed cascade reactions have drawn
Tconsiderable interest due to their high efficiency and
diversity in constructing complex molecules.1 Palladium-
catalyzed cascade reactions, as essential tools for the formation
of carbo- and heterocyclic compounds, have particularly
experienced tremendous development based on fundamental
mechanistic insight into elemental reactions.2
Isocoumarins not only extensively exist in natural products
exhibiting a wide range of biological and pharmacological
activities but also serve as important intermediates in the
synthesis of a variety of heterocyclic compounds.3 Traditional
methods and transition metal-catalyzed reactions to approach
this structure have been well-established.4 However, palladium-
catalyzed reactions are rarely reported in the synthesis of
isocoumarins.5 Recently, our group5e and Li5f reported
palladium-catalyzed cascade reactions of 2-alkynylbenzoates
with electron-deficient alkenes to deliver substituted isocou-
marins conveniently (Scheme 1, eqs 1 and 2). These two
reactions were initiated by oxypalladation of the alkyne with the
intramolecular ester group and quenched by protonolysis and
β-H elimination of the carbon−palladium bond.
In our previous work, a series of palladium(II)-catalyzed
cascade reactions initiated by nucleopalladation of alkynes and
quenched by 1,2-addition to a carbonyl or nitrile group to
afford cyclic compounds have been successfully established.6
Inspired by these works, palladium(II)-catalyzed intramolecular
cascade cyclization of alkyne-tethered carbonyl compounds
bearing an aryl ester to synthesize cycloalkane-fused iso-
coumarins was proposed (Scheme 1, eq 3). In the literature,
only a few examples of an approach to such compounds have
been reported.5g,h
product 2a was obtained with a moderate yield of inseparable
byproduct 3a (Table 1, entries 1 and 2). Without the catalyst
and ligand, only 3a was isolated in 53% yield in the presence of
acetic acid (Table 1, entry 3). In the absence of acetic acid, the
reaction was totally suppressed (Table 1, entry 4). From the
above results, it can be seen that Pd(OAc)2 was not effective
enough for this cascade cyclization and that a highly active
Initially, the optimization of reaction conditions was carried
out by using 1a as the substrate under the catalysis of
Pd(OAc)2/bpy (Table 1, entry 1). A small amount of desired
Received: January 19, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.6b00128
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
a
of 4 Å effectively improved the yield of desired product 2a by
minimizing the formation of byproduct 3a (Table 1, entry 17).
The same effect could also be observed in THF or DCE for this
new reaction; however, the result is not as good as with dioxane
(Table 1, entries 18 and 19).
Table 1. Optimization of the Reaction Conditions
Having established the optimal conditions, our attention
turned to an evaluation of the scope and limitations of this
reaction. The results showed that substrates with an electron-
donating group on the benzene ring gave good yields of
cyclohexane-fused isocoumarins 2 and that only a very minor
amount of the byproducts 3 were produced (Scheme 2, 2b−
2d). Substrates with bromo- or chloro- on the benzene ring can
also give corresponding products in moderate yields, but the
yield of fluorine-substituted product 2e decreased dramatically
temp
yield (%)
b
entry
catalyst (3 mol %)
Pd(OAc)2/bpy
solvent
(°C)
(2a/3a)
c
1
HOAc/dioxane
(1/4)
rt
54 (∼1/14)
72 (∼1/8)
53 (3a)
c
2
Pd(OAc)2/bpy
HOAc/dioxane
(1/4)
80
80
3
HOAc/dioxane
(1/4)
c
a b
,
4
Pd(OAc)2/bpy
dioxane
dioxane
80
80
no reaction
Scheme 2. Substrate Scope of the Reaction
5
[(bpy)Pd(H2O)2]
(OTf)2
53 (∼1/20)
d
6
[(dppp)Pd(H2O)2]
(BF4)2
dioxane
dioxane
dioxane
MeCN
DCE
80
80
21 (∼9/1)
76 (∼8/1)
45 (∼1/6)
81 (∼1/1)
76 (∼4/3)
88 (∼1/2)
89 (∼4/1)
66 (∼2/1)
Pd black
7
[(dppp)Pd(H2O)2]
(OTf)2
8
[(rac-binap)
Pd(H2O)2](OTf)2
80
9
[(dppp)Pd(H2O)2]
(OTf)2
80
10
11
12
13
14
15
16
[(dppp)Pd(H2O)2]
(OTf)2
80
[(dppp)Pd(H2O)2]
(OTf)2
C6H5CF3
THF
80
[(dppp)Pd(H2O)2]
(OTf)2
80
[(dppp)Pd(H2O)2]
(OTf)2
DME
80
[(dppp)Pd(H2O)2]
(OTf)2
DMF
80
[(dppp)Pd(H2O)2]
(OTf)2
dioxane
dioxane
dioxane
THF
60
89 (∼2/1)
86 (∼8/1)
78 (>20/1)
82 (∼11/1)
90 (∼8/1)
[(dppp)Pd(H2O)2]
(OTf)2
100
100
100
100
e
17
[(dppp)Pd(H2O)2]
(OTf)2
e
18
[(dppp)Pd(H2O)2]
(OTf)2
e
19
[(dppp)Pd(H2O)2]
(OTf)2
DCE
a
Reaction conditions: 1a (0.1 mmol, 1.0 equiv) and catalyst (3 mol %)
were dissolved in solvents (1 mL) as shown in the table; the mixture
was stirred at 80 °C until the consumption of 1a as monitored by
b
TLC. Isolated yield; the ratio in the parentheses of product (2a/3a)
was determined by H NMR. Pd(OAc)2 (5 mol %) and bpy (6 mol
%) were used. Recovered 62% of 1a. Added MS of 4 Å (20 w/w %).
c
1
d
e
palladium catalyst might be needed. In our previous work, it
was found that cationic palladium complexes had better
catalytic activity than neutral ones, especially for the addition
reactions to carbonyl groups.7,8 Therefore, cationic palladium
complexes were then tested.
The study revealed that [(dppp)Pd(H2O)2](OTf)2 proved
to be optimal to provide 76% total yield of the products (2a/3a
= 8/1) (Table 1, entries 5−8) in dioxane. Subsequently, the
effect of solvent and temperature were examined. Except DMF,
moderate to good yields of the two products were obtained
with different solvents, but the 2a/3a ratio decreased
significantly (Table 1, entries 9−14). Reducing or raising the
temperature did not improve the reaction (Table 1, entries 15
and 16). Further investigation showed that the addition of MS
a
Reaction conditions: 1 (0.2 mmol, 1.0 equiv), [(dppp)Pd(H2O)2]-
(OTf)2 (3 mol %) and MS of 4 Å (20%, w/w) were dissolved in
dioxane (2 mL); the mixture was stirred at 100 °C until the
b
c
consumption of 1 as monitored by TLC. Isolated yield. Trace
amount of inseparable 3 was contained in the product. Reaction
performed at 80 °C. Reaction performed at room temperature.
d
e
B
DOI: 10.1021/acs.joc.6b00128
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The Journal of Organic Chemistry
Note
(Scheme 2, 2e−2g). Then, the influence of different kinds of
carbonyl groups was investigated. Compared to electron-
donating group substituted aryl ketone 1h, electron-with-
drawing group substituted aryl ketone or 2-naphthyl ketone
afforded a better result (Scheme 2, 2h−2k). Alkyl ketones and
aldehydes were also suitable for this cascade cyclization reaction
under milder reaction conditions (Scheme 2, 2l and 2m).
Unfortunately, when we attempted to synthesize the cyclo-
pentane- or cycloheptane-fused isocoumarins using this
procedure, the addition of the newly formed carbon−palladium
bond to the carbonyl group did not occur at all, and only
products 3n and 3o were observed. However, the reaction of
phenyl-substituted substrate 1p can proceed smoothly, leading
to the double ring fused isocoumarin 2p in 72% yield under the
catalysis of [(rac-binap)Pd(H2O)2](OTf)2 (Scheme 3).
atom, which increases the polarity of the C−Pd bond. In
contrast to the neutral palladium species (e. g., Pd(OAc)2), the
success of the addition of the C−Pd bond to the ketone in
most of our reactions might be due to the high Lewis acidity of
cationic palladium catalyst, which can activate the carbonyl
group.7 As for similar reactions quenched by conjugate addition
in eq 1, Pd(OAc)2 can catalyze the process successfully instead,
indicating that neutral palladium species may coordinate with
the carbon−carbon double bond to undergo the subsequent
addition.
In conclusion, we have accomplished a cationic palladium-
catalyzed intramolecular cascade cyclization reaction of an
alkyne-tethered carbonyl compound initiated by oxypalladation
of the ester group with alkyne. This procedure provides a
convenient and efficient method for the synthesis of cyclo-
hexane-fused isocoumarins. A cationic palladium catalyst was
the key for the success of this reaction.
Scheme 3. Reaction of Substrate 1p
EXPERIMENTAL SECTION
General Information. All reactions were performed under
nitrogen. All solvents were dried and distilled using standard
procedures. Unless otherwise noted, reagents were obtained from
■
1
commercial sources and used without further purification. H NMR
and 13C NMR were recorded in deuterated chloroform (CDCl3).
Coupling constants are recorded in hertz, and chemical shifts are
recorded as δ values in ppm. The following abbreviations are used to
describe multiplicities: s = singlet, d = doublet, dd = double doublet, t
= triplet, and m = multiplet. High-resolution mass spectra were carried
out on a mass spectrometer with a TOF analyzer (ESI, EI). Infrared
spectra were recorded on an FT-IR spectrometer. Melting points were
determined by using a local hot-stage melting point apparatus and are
uncorrected. For column chromatography, silica gel of 200−300 mesh
size was used.
A proposed mechanism for the reaction is outlined in
Scheme 4. First, the active cationic palladium(II) complex I was
Scheme 4. Proposed Mechanism
General Procedure for the Preparation of Substrates 1a−1l,
1o, and 1p. A solution of tert-butyl 2-iodobenzoate11 (2 mmol),
terminal alkyne12 (1.2 equiv), and Pd(PPh3)2C12 (70 mg, 0.05 equiv)
in Et3N (10 mL) was stirred at room temperature for 5 min; then, CuI
(19 mg, 0.05 equiv) was added, and the mixture was stirred at 70 °C
overnight. After completion of the reaction as monitered by TLC, the
suspension was filtered, and the filtrate was purified by silica gel
column chromatography (ethyl acetate/petroleum ether, 1/12) to
furnish the products.
Diethyl 2-(3-(2-(tert-Butoxycarbonyl)phenyl)prop-2-yn-1-yl)-2-(2-
oxo-2-phenylethyl)malonate (1a). Yellow oil (701 mg, 71%); 1H
NMR (400 MHz, CDCl3) δ 8.08−8.06 (m, 2H), 7.80 (dd, J = 7.8, 0.6
Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.45 (t, J = 8.2 Hz, 2H), 7.40−7.33
(m, 2H), 7.31−7.27 (m, 1H), 4.25 (q, J = 7.1 Hz, 4H), 4.10 (s, 2H),
3.41 (s, 2H), 1.51 (s, 9H), 1.25 (t, J = 7.0 Hz, 6H); 13C NMR (100
MHz, CDCl3) δ 197.2, 169.4, 165.2, 136.5, 134.2, 133.6, 133.3, 130.9,
129.9, 128.5, 128.2, 127.5, 123.2, 89.8, 82.6, 81.2, 61.9, 55.1, 41.1, 28.0,
24.6, 13.9; IR (KBr) ν 2976, 2928, 2237, 1730, 1712, 1684, 1597,
1448, 1366, 1292, 1248, 1188, 1137, 1085, 1002, 848, 761, 688 cm−1;
MS (m/z, ESI) 510 [M + NH4]+; HRMS (ESI) calcd for C29H36NO7
[M + NH4]+ 510.2486, found 510.2474.
Diethyl 2-(3-(2-(tert-Butoxycarbonyl)-4-methylphenyl)prop-2-yn-
1-yl)-2-(2-oxo-2-phenylethyl)malonate (1b). Yellow solid (666 mg,
65%); mp 73−74 °C; 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 7.6
Hz, 2H), 7.59−7.54 (m, 2H), 7.45 (t, J = 7.6 Hz, 2H), 7.28−7.25 (m,
1H), 7.15 (d, J = 8.0 Hz, 1H), 4.24 (q, J = 7.6 Hz, 4H), 4.08 (s, 2H),
3.38 (s, 2H), 2.34 (s, 3H), 1.50 (s, 9H), 1.24 (t, J = 7.6 Hz, 6H); 13C
NMR (100 MHz, CDCl3) δ 197.2, 169.5, 165.4, 137.7, 136.5, 134.2,
133.5, 133.3, 131.8, 130.4, 128.5, 128.2, 120.2, 88.7, 82.6, 81.2, 61.9,
55.1, 41.2, 28.1, 24.6, 21.2, 14.0; IR (KBr) ν 2972, 2928, 1732, 1712,
1683, 1597, 1449, 1358, 1300, 1258, 1183, 1160, 1081, 1046, 999, 850,
748, 687 cm−1; MS (m/z, ESI) 524 [M + NH4]+; HRMS (ESI) calcd
for C30H38NO7 [M + NH4]+ 524.2643, found 524.2644.
formed;9 then, intramolecular oxypalladation of the ester group
to alkyne with a loss of isobutene led to intermediate II.10
When cationic palladium catalyst was used, a C−Pd bond
added easily to intramolecular ketone followed by protonolysis
to give product 2 and regenerated the active cationic
palladium(II) species to complete the catalytic cycle. The
ready protonolysis of the C−Pd bond of vinylpalladium species
II in some cases to give product 3 in the reaction might be due
to the electronic effect of the lone pair electrons on the oxygen
Diethyl 2-(3-(6-(tert-Butoxycarbonyl)benzo[d][1,3]dioxol-5-yl)-
prop-2-yn-1-yl)-2-(2-oxo-2-phenylethyl)malonate (1c). Yellow oil
C
DOI: 10.1021/acs.joc.6b00128
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The Journal of Organic Chemistry
Note
1
(924 mg, 87%); H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 7.2 Hz,
13.9; IR (KBr) ν 2978, 2932, 1735, 1717, 1676, 1599, 1575, 1366,
1284, 1252, 1169, 1133, 1031, 832, 758 cm−1; MS (m/z, ESI) 523 [M
+ H]+; HRMS (ESI) calcd for C30H35O8 [M + H]+ 523.2326, found
523.2323.
2H), 7.56 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.26 (s, 1H),
6.78 (s, 1H), 6.00 (s, 2H), 4.24 (q, J = 7.2 Hz, 4H), 4.09 (s, 2H), 3.38
(s, 2H), 1.49 (s, 9H), 1.24 (t, J = 7.0 Hz, 6H); 13C NMR (100 M,
CDCl3) δ 197.2, 169.4, 164.2, 149.7, 147.2, 136.5, 133.2, 128.5, 128.2,
128.1, 118.5, 113.4, 109.9, 102.0, 88.6, 82.5, 81.0, 61.9, 55.1, 41.1, 28.0,
24.6, 13.9; IR (KBr) ν 2979, 2931, 1736, 1719, 1687, 1600, 1504,
1370, 1249, 1183, 1124, 1034, 1002, 932, 857, 749, 689 cm−1; MS (m/
z, ESI) 554 [M + NH4]+; HRMS (ESI) calcd for C30H36NO9 [M +
NH4]+ 554.2385, found 554.2382.
Diethyl 2-(3-(2-(tert-Butoxycarbonyl)-4-methoxyphenyl)prop-2-
yn-1-yl)-2-(2-oxo-2-phenylethyl)malonate (1d). Yellow oil (758
mg, 73%); 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 7.2 Hz,
2H), 7.56 (t, J = 7.2 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.32−7.28 (m,
2H), 6.90 (dd, J = 2.8, 8.4 Hz, 1H), 4.25 (q, J = 7.1 Hz, 4H), 4.09 (s,
2H), 3.80 (s, 3H), 3.39 (s, 2H), 1.50 (s, 9H), 1.25 (t, J = 7.0 Hz, 6H);
13C NMR (100 MHz, CDCl3) δ 197.1, 169.4, 165.0, 158.6, 136.4,
135.5, 134.9, 133.2, 128.4, 128.1, 117.1, 115.3, 114.7, 87.6, 82.3, 81.3,
61.8, 55.3, 55.0, 41.1, 27.9, 24.5, 13.9; IR (KBr) ν 2979, 2934, 2255,
1735, 1721, 1687, 1603, 1563, 1496, 1448, 1366, 1291, 1250, 1183,
1165, 1075, 1039, 1002, 911, 849, 730, 689 cm−1; MS (m/z, ESI) 540
[M + NH4]+; HRMS (ESI) calcd for C30H38NO8 [M + NH4]+
540.2592, found 540.2592.
Diethyl 2-(3-(2-(tert-Butoxycarbonyl)-4-fluorophenyl)prop-2-yn-
1-yl)-2-(2-oxo-2-phenylethyl)malonate (1e). Yellow oil (608 mg,
60%); H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 7.6 Hz, 2H), 7.57
Diethyl 2-(3-(2-(tert-Butoxycarbonyl)phenyl)prop-2-yn-1-yl)-2-(2-
(4-chlorophenyl)-2-oxoethyl)malonate (1i). Yellow oil (520 mg,
1
45%); H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.4 Hz, 2H), 7.80
(d, J = 8.0 Hz, 1H), 7.43−7.27 (m, 5H), 4.24 (q, J = 6.9 Hz, 4H), 4.08
(s, 2H), 3.39 (s, 2H), 1.51 (s, 9H), 1.25 (t, J = 7.0, 6H); 13C NMR
(100 MHz, CDCl3) δ 196.1, 169.3, 165.1, 139.7, 134.9, 134.2, 133.6,
131.0, 130.0, 129.7, 128.8, 127.5, 123.2, 89.7, 82.6, 81.2, 62.0, 55.1,
41.1, 28.0, 24.6, 14.0; IR (KBr) ν 3475, 3377, 2978, 2925, 2221, 1732,
1686, 1591, 1448, 1365, 1286, 1249, 1183, 1136, 1085, 1067, 1047,
999, 861, 758, 692 cm−1; MS (m/z, ESI) 544 [M + NH4]+; HRMS
(ESI) calcd for C29H35ClNO7 [M + NH4]+ 544.2097, found 544.2094.
Diethyl 2-(3-(2-(tert-Butoxycarbonyl)phenyl)prop-2-yn-1-yl)-2-(2-
(4-nitrophenyl)-2-oxoethyl)malonate (1j). Yellow solid (512 mg,
1
48%); mp 101−102 °C; H NMR (400 MHz, CDCl3) δ 8.31−8.25
(m, 4H), 7.81 (dd, J = 8.2, 1.0 Hz, 1H), 7.42−7.35 (m, 2H), 7.30 (td, J
= 7.5, 1.7 Hz, 1H), 4.29−4.23 (m, 4H), 4.18 (s, 2H), 3.40 (s, 2H),
1.52 (s, 9H), 1.26 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ
196.1, 169.2, 165.0, 150.4, 141.0, 134.2, 133.6, 131.1, 130.0, 129.4,
127.6, 123.7, 123.1, 89.5, 82.8, 81.2, 62.1, 55.2, 41.7, 28.0, 24.7, 14.0;
IR (KBr) ν 2977, 2914, 1733, 1709, 1691, 1602, 1529, 1446, 1345,
1285, 1250, 1184, 1138, 1085, 1069, 1004, 892, 781, 700 cm−1; MS
(m/z, ESI) 555 [M + NH4]+; HRMS (ESI) calcd for C29H35N2O9 [M
+ NH4)+ 555.2337, found 555.2334.
1
(t, J = 7.4, 1H), 7.51−7.43 (m, 3H), 7.36 (dd, J = 4.8, 9.2 Hz, 1H),
7.06 (td, J = 8.2, 2.4 Hz, 1H), 4.25 (q, J = 7.1 Hz, 4H), 4.09 (s, 2H),
3.40 (s, 2H), 1.50 (s, 9H), 1.25 (t, J = 7.0 Hz, 6H); 13C NMR (100
Diethyl 2-(3-(2-(tert-Butoxycarbonyl)phenyl)prop-2-yn-1-yl)-2-(2-
(naphthalen-2-yl)-2-oxoethyl)malonate (1k). Yellow oil (659 mg,
62%); 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.08 (dd, J = 8.8,
1.6 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.89−7.84 (m, 2H), 7.78 (dd, J
= 7.8, 1.4 Hz, 1H), 7.61−7.50 (m, 2H), 7.38 (dd, J = 7.8, 1.0 Hz, 1H),
7.34−7.24 (m, 2H), 4.28 (q, J = 7.1 Hz, 4H), 4.23 (s, 2H), 3.46 (s,
2H), 1.45 (s, 9H), 1.26 (t, J = 7.0 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 197.1, 169.5, 165.2, 135.7, 134.2, 133.9, 133.7, 132.4, 130.9,
130.2, 129.9, 129.6, 128.5, 128.3, 127.7, 127.5, 126.6, 123.7, 123.1,
89.8, 82.6, 81.2, 62.0, 55.2, 41.1, 28.0, 24.6, 14.0; IR (KBr) ν 3061,
2978, 2931, 2238, 1735, 1718, 1680, 1469, 1366, 1281, 1255, 1180,
1132, 1083, 856, 818, 756 cm−1; MS (m/z, ESI) 560 [M + NH4]+;
HRMS (ESI) calcd for C33H38NO7 [M + NH4]+ 560.2643, found
560.2641.
MHz, CDCl3) δ 197.1, 169.4, 163.8 (d, JCF = 2.6 Hz), 161.3 (d, JCF
=
248.8 Hz), 136.5, 136.0 (d, JCF = 7.8 Hz), 135.5 (d, JCF = 7.4 Hz),
133.3, 128.5, 128.2, 119.4 (d, JCF = 3.8 Hz), 118.4 (d, JCF = 21.9 Hz),
117.0 (d, JCF = 23.8 Hz), 89.6 (d, JCF = 1.8 Hz), 81.8, 81.5, 61.9, 55.0,
41.1, 27.9, 24.5, 13.9; IR (KBr) ν 2980, 2933, 2226, 1724, 1686, 1600,
1491, 1449, 1367, 1304, 1249, 1184, 1159, 1067, 1002, 942, 831, 749,
689 cm−1; MS (m/z, ESI) 528 [M + NH4]+; HRMS (ESI) calcd for
C29H35FNO7 [M + NH4]+ 528.2392, found 528.2388.
Diethyl 2-(3-(2-(tert-Butoxycarbonyl)-4-chlorophenyl)prop-2-yn-
1-yl)-2-(2-oxo-2-phenylethyl)malonate (1f). Yellow solid (281 mg,
27%); mp 59−60 °C; 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 7.6
Hz, 2H), 7.76 (s, 1H), 7.57 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.6 Hz,
2H), 7.31 (s, 2H), 4.25 (q, J = 7.1 Hz, 4H), 4.08 (s, 2H), 3.41 (s, 2H),
1.50 (s, 9H), 1.24 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ
197.1, 169.3, 163.8, 136.5, 135.4, 135.0, 133.4, 133.3, 131.1, 130.0,
128.5, 128.2, 121.8, 91.1, 81.9, 81.6, 61.9, 55.0, 41.1, 28.0, 24.6, 14.0;
IR (KBr) ν 2970, 2928, 1731, 1715, 1686, 1596, 1476, 1356, 1295,
1250, 1185, 1166, 1142, 1094, 1047, 999, 836, 746, 687 cm−1; MS (m/
z, ESI) 544 [M + NH4]+; HRMS (ESI) calcd for C29H35ClNO7 [M +
NH4]+ 544.2097, found 544.2095.
tert-Butyl 2-(6-Oxohept-1-yn-1-yl)benzoate (1l). Yellow oil (378
1
mg, 66%); H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 7.2 Hz, 1H),
7.48−7.45 (m, 1H), 7.38 (t, J = 7.4 Hz, 1H), 7.32−7.27 (m, 1H), 2.72
(t, J = 7.4 Hz, 2H), 2.52 (t, J = 6.8 Hz, 2H), 2.18 (s, 3H), 1.93−1.85
(m, 2H), 1.60 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 208.6, 165.8,
134.0, 133.9, 130.8, 129.8, 127.2, 123.5, 94.0, 81.3, 80.2, 42.1, 30.0,
28.1, 22.4, 19.0; IR (KBr) ν 3413, 3065, 2977, 2932, 2234, 1710, 1596,
1567, 1445, 1367, 1252, 1183, 1171, 1131, 1082, 1038, 954, 847, 757,
699 cm−1; MS (m/z, ESI) 304 [M + NH4)+; HRMS (ESI) calcd for
C18H26NO3 [M + NH4]+ 304.1907, found 304.1909.
Diethyl 2-(3-(4-Bromo-2-(tert-butoxycarbonyl)phenyl)prop-2-yn-
1-yl)-2-(2-oxo-2-phenylethyl)malonate (1g). Yellow solid (910 mg,
82%); mp 62−63 °C; H NMR(400 MHz, CDCl3) δ 8.06 (d, J = 7.6
1
Diethyl 2-(3-(2-(tert-Butoxycarbonyl)phenyl)prop-2-yn-1-yl)-2-(3-
1
oxo-3-phenylpropyl)malonate (1o). Yellow oil (617 mg, 52%); H
Hz, 2H), 7.92 (d, J = 2.0 Hz, 1H), 7.57 (t, J = 7.4 Hz, 1H), 7.48−7.43
(m, 3H), 7.24 (d, J = 8.4 Hz, 1H), 4.24 (q, J = 7.2 Hz, 4H), 4.09 (s,
2H), 3.40 (s, 2H), 1.50 (s, 9H), 1.24 (t, J = 7.2 Hz, 6H); 13C NMR
(100 MHz, CDCl3) δ 197.1, 169.3, 163.7, 136.4, 135.5, 135.1, 134.0,
133.3, 132.9, 128.5, 128.2, 122.2, 121.4, 91.3, 81.9, 81.7, 61.9, 55.0,
41.1, 28.0, 24.6, 13.9; IR (KBr) ν 2972, 2927, 2236, 1730, 1684, 1597,
1580, 1472, 1448, 1367, 1293, 1249, 1184, 1164, 1143, 1092, 1046,
999, 833, 760, 747, 688 cm−1; MS (m/z, ESI) 588 [M + NH4]+;
HRMS (ESI) calcd for C29H35BrNO7 [M + NH4]+ 588.1591, found
588.1588.
NMR (400 MHz, CDCl3) δ 7.98−7.96 (m, 2H), 7.82 (dd, J = 7.8, 1.0
Hz, 1H), 7.54−7.50 (m, 1H), 7.45−7.34 (m, 4H), 7.31 (dd, J = 7.4,
1.4 Hz, 1H), 4.28−4.19 (m, 4H), 3.19 (s, 2H), 3.14 (t, J = 8.0 Hz,
2H), 2.61 (t, J = 8.0 Hz, 2H), 1.54 (s, 9H), 1.25 (t, J = 7.2 Hz, 6H);
13C NMR (100 MHz, CDCl3) δ 198.7, 170.1, 165.2, 136.6, 134.5,
133.6, 132.9, 131.0, 129.9, 128.5, 128.0, 127.5, 123.1, 89.0, 82.7, 81.3,
61.7, 56.5, 33.8, 28.1, 27.2, 24.9, 14.0; IR (KBr) ν 3064, 2980, 2934,
2230, 1727, 1687, 1597, 1481, 1447, 1368, 1299, 1253, 1132, 1080,
1039, 849, 758, 692 cm−1; MS (m/z, ESI) 524 [M + NH4]+; HRMS
(ESI) calcd for C30H38NO7 [M + NH4]+ 524.2643, found 524.2641.
tert-Butyl 2-((2-Formylphenyl)ethynyl)benzoate (1p). Yellow solid
(581 mg, 95%); mp 66−67 °C; 1H NMR (400 MHz, CDCl3) δ 10.75
(s, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.67 (t, J =
8.0 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.51−7.39 (m, 3H), 1.60 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 192.4, 165.1, 136.1, 134.0,
133.8, 133.6, 133.1, 131.2, 130.2, 128.6, 128.5, 127.0, 126.9, 122.3,
95.0, 89.3, 81.7, 28.1; IR (KBr) ν 3066, 2979, 2930, 1712, 1688, 1590,
Diethyl 2-(3-(2-(tert-Butoxycarbonyl)phenyl)prop-2-yn-1-yl)-2-(2-
(4-methoxyphenyl)-2-oxoethyl)malonate (1h). Yellow oil (810 mg,
78%); H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 9.2 Hz, 2H), 7.80
(dd, J = 7.8, 0.6 Hz, 1H), 7.40−7.28 (m, 3H), 6.92 (d, J = 8.8 Hz, 2H),
4.24 (q, J = 6.8 Hz, 4H), 4.03 (s, 2H), 3.86 (s, 3H), 3.39 (s, 2H), 1.52
(s, 9H), 1.25 (t, J = 7.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ
195.6, 169.5, 165.2, 163.6, 134.3, 133.6, 130.9, 130.5, 129.9, 129.6,
127.5, 123.2, 113.6, 89.9, 82.5, 81.3, 61.9, 55.4, 55.1, 40.7, 28.0, 24.6,
1
D
DOI: 10.1021/acs.joc.6b00128
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1485, 1365, 1297, 1277, 1254, 1163, 1090, 877, 758, 698, 637 cm−1;
MS (m/z, ESI) 324 [M + NH4]+; HRMS (ESI) calcd for C20H22NO3
[M + NH4]+ 324.1594, found 324.1594.
128.1, 128.0, 125.2, 120.3, 106.4, 62.1, 54.7, 40.8, 36.6, 13.9; IR (KBr)
ν 2982, 2934, 1728, 1685, 1657, 1599, 1448, 1357, 1283, 1184, 1041,
1021, 914, 858, 754, 730, 688 cm−1; MS (m/z, ESI) 454 [M + NH4]+;
HRMS (ESI) calcd for C25H28NO7 [M + NH4]+ 454.1860, found
454.1865.
General Procedure for the Preparation of Substrates 1m
and 1n. A solution of tert-butyl 2-iodobenzoate (1.5 g, 1 equiv),
alkyn-1-ol (5 mmol, 1 equiv), and Pd(PPh3)4 (56 mg, 0.01 equiv) in
Et3N (25 mL) was stirred at room temperature for 5 min; then, CuI
(20 mg, 0.02 equiv) was added. The mixture was stirred at room
temperature overnight. The suspension was filtered, and the filtrate
was concentrated and oxidized with PCC (1.2 equiv) and Celite in
DCM (20 mL). The suspension was filtered, and the filtrate was
purified by silica gel column chromatography (ethyl acetate/petroleum
ether, 1/12) to furnish the products.
Diethyl 1-Hydroxy-8-methyl-6-oxo-1-phenyl-1,2,4,6-tetrahydro-
3H-benzo[c]chromene-3,3-dicarboxylate (2b). White solid (90 mg,
99%); mp 195−196 °C; 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H),
7.42 (br s, 2H), 7.31−7.27 (m, 3H), 7.23−7.18 (m, 2H), 5.17 (s, 1H),
4.34−4.07 (m, 4H), 3.38 (d, J = 17.6 Hz, 1H), 3.28 (dd, J = 18.0, 2.0
Hz, 1H), 2.94 (dd, J = 14.8, 2.4 Hz, 1H), 2.33 (s, 3H), 2.25 (d, J = 15.2
Hz, 1H), 1.28−1.22 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 172.5,
169.4, 162.0, 149.3, 147.2, 137.6, 135.2, 132.7, 129.1, 128.5, 127.0,
126.8, 125.0, 121.4, 114.3, 73.1, 62.7, 62.2, 53.0, 47.5, 33.5, 21.0, 13.8,
13.7; IR (KBr) ν 3479, 2982, 1750, 1724, 1643, 1502, 1446, 1368,
1266, 1244, 1200, 1161, 1091, 1074, 1050, 997, 869, 832, 768, 707
cm−1; MS (m/z, ESI) 451 [M + H]+; HRMS (ESI) calcd for C26H27O7
[M + H]+ 451.1751, found 451.1759.
tert-Butyl 2-(6-Oxohex-1-yn-1-yl)benzoate (1m). Yellow oil (1.04
1
g, 78%); H NMR (400 MHz, CDCl3) δ 9.84 (s, 1H), 7.81−7.79 (m,
1H), 7.47 (dd, J = 7.6, 0.8 Hz, 1H), 7.38 (td, J = 7.6, 1.5 Hz, 1H),
7.32−7.28 (m, 1H), 2.72 (dd, J = 7.2, 1.2 Hz, 2H), 2.55 (t, J = 6.8 Hz,
2H), 1.99−1.92 (m, 2H), 1.60 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 202.0, 165.7, 134.0, 133.9, 130.8, 129.7, 127.3, 123.4, 93.5, 81.3, 80.4,
42.7, 28.1, 21.0, 19.1; IR (KBr) ν 2978, 2934, 2254, 1704, 1596, 1481,
1447, 1368, 1306, 1253, 1170, 1133, 1083, 910, 846, 758, 730, 648
cm−1; MS (70 eV, EI) m/z (%) 246, 230, 214, 186, 173, 172, 160, 149,
115, 105, 76, 57; HRMS (EI) calcd for C13H11O3 [M-C4H9]+
215.0708, found 215.0713.
Diethyl 1-Hydroxy-6-oxo-1-phenyl-1,2,4,6-tetrahydro-3H-[1,3]-
dioxolo[4′,5′4,5]benzo[1,2-c]chromene-3,3-dicarboxylate (2c).
1
White solid (89 mg, 93%); mp 193−194 °C; H NMR (400 MHz,
CDCl3) δ 7.55 (s, 1H), 7.40 (br s, 2H), 7.31−7.28 (m, 2H), 7.24−7.20
(m, 1H), 6.90 (s, 1H), 5.92 (dd, J = 11.8, 1.0 Hz, 2H), 5.29 (s, 1H),
4.34−4.06 (m, 4H), 3.37 (d, J = 18.0 Hz, 1H), 3.26 (dd, J = 18.0, 2.0
Hz, 1H), 2.93 (dd, J = 15.2, 2.4 Hz, 1H), 2.23 (d, J = 15.2 Hz, 1H),
1.28−1.21 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 172.5, 169.3,
161.4, 152.8, 149.2, 147.4, 146.8, 133.1, 128.5, 127.1, 124.9, 116.2,
114.2, 107.0, 106.1, 101.9, 73.1, 62.8, 62.2, 52.9, 47.6, 33.4, 13.8, 13.7;
IR (KBr) ν 3413, 3059, 2982, 2918, 1729, 1704, 1650, 1623, 1478,
1448, 1410, 1368, 1306, 1246, 1201, 1184, 1166, 1075, 1055, 1033,
1004, 912, 862, 830, 768, 702 cm−1; MS (m/z, ESI) 481 [M + H]+;
HRMS (ESI) calcd for C26H25O9 [M + H]+ 481.1493, found 481.1499.
Diethyl 1-Hydroxy-8-methoxy-6-oxo-1-phenyl-1,2,4,6-tetrahy-
dro-3H-benzo[c]chromene-3,3-dicarboxylate (2d). White solid (75
mg, 83%); mp 143−144 °C; 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J
= 2.8 Hz, 1H), 7.46−7.34 (m, 3H), 7.30−7.26 (m, 2H), 7.23−7.19 (m,
1H), 6.95 (dd, J = 9.0, 2.6 Hz, 1H), 5.22 (s, 1H), 4.34−4.07 (m, 4H),
3.80 (s, 3H), 3.38 (d, J = 17.6 Hz, 1H), 3.28 (dd, J = 17.6, 2.0 Hz, 1H),
2.94 (dd, J = 14.8, 2.0 Hz, 1H), 2.25 (d, J = 14.8 Hz, 1H), 1.28−1.21
(m, 6H); 13C NMR (100 MHz, CDCl3) δ 172.5, 169.4, 162.0, 158.6,
148.0, 147.1, 128.9, 128.5, 128.4, 127.1, 125.0, 123.3, 122.8, 114.2,
109.9, 73.1, 62.7, 62.2, 55.4, 53.0, 47.5, 33.3, 13.8, 13.7; IR (KBr) ν
3455, 2958, 2919, 2850, 1725, 1698, 1643, 1496, 1445, 1357, 1327,
1311, 1285, 1242, 1204, 1180, 1085, 1071, 1045, 1022, 1006, 896, 846,
788, 765, 701 cm−1; MS (m/z, ESI) 467 [M + H]+; HRMS (ESI) calcd
for C26H27O8 [M + H]+ 467.1700, found 467.1692.
tert-Butyl 2-(5-Oxopent-1-yn-1-yl)benzoate (1n). Yellow oil (701
1
mg, 55%); H NMR (400 MHz, CDCl3) δ 9.87 (s, 1H), 7.80 (d, J =
7.6 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.38 (td, J = 7.6, 1.1 Hz, 1H),
7.32−7.28 (m, 1H), 2.79 (s, 4H), 1.60 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 200.6, 165.7, 134.0, 133.9, 130.8, 129.8, 127.4, 123.1, 92.4,
81.4, 80.3, 42.4, 28.1, 13.0; IR (KBr) ν 2978, 2932, 2725, 2233, 1786,
1706, 1597, 1481, 1445, 1367, 1304, 1253, 1170, 1130, 1082, 1040,
908, 846, 757 cm−1; MS (m/z, ESI) 276 [M + NH4]+; HRMS (ESI)
calcd for C16H22NO3 [M + NH4]+ 276.1594, found 276.1591.
General Procedure of the Cationic Palladium(II)-Catalyzed
Cascade Cyclization Reaction of Alkyne-Tethered Carbonyl
Compounds. A suspension of [(dppp)Pd(H2O)2](OTf)2 (5.3 mg, 3
mol %) and MS of 4 Å (20 w/w %) in dioxane (2 mL) was stirred at
room temperature for 5 min under N2; then, substrate 1 (0.2 mmol, 1
equiv) was added and stirred at 100 °C. After completion, the reaction
mixture was purified by flash chromatography, eluting with ethyl
acetate and petroleum ether (1/7) to afford the products. Compounds
2i−2k and 2o can be isolated from 3i−3k and 3o by the above
chromatography. Compounds 2a−2d, 2f−2h, 2l, 2m, and 2p cannot
be separated from byproducts 3a−3d, 3f−3h, 3l, 3m, and 3p by this
method, and mixtures were obtained. Suspending the above mixture of
2 and 3 in petroleum ether (PE) and then filtering can give pure
products 2a−2d, 2f−2h, 2l, 2m, and 2p eventually (products 3 can
dissolve in PE but 2 cannot). Product 2e was isolated by
chromatography again using PE/benzene/Et3N (20/5/2) as the
eluent.
Diethyl 1-Hydroxy-6-oxo-1-phenyl-1,2,4,6-tetrahydro-3H-benzo-
[c]chromene-3,3-dicarboxylate (2a). Yellow solid (67 mg, 75%); mp
139−140 °C; 1H NMR (400 MHz, CDCl3) δ 8.25 (dd, J = 7.6, 1.6 Hz,
1H), 7.43−7.28 (m, 7H), 7.22 (t, J = 7.2 Hz, 1H), 5.24 (s, 1H), 4.35−
4.10 (m, 4H), 3.39 (d, J = 18.0 Hz, 1H), 3.30 (dd, J = 18.0, 2.4 Hz,
1H), 2.95 (dd, J = 15.2, 2.0 Hz, 1H), 2.24 (d, J = 14.8 Hz, 1H), 1.29−
1.22 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 172.6, 169.4, 161.9,
150.2, 147.2, 135.3, 133.9, 129.5, 128.6, 127.5, 127.2, 126.9, 125.0,
121.6, 114.4, 73.2, 62.8, 62.3, 53.1, 47.6, 33.6, 13.9, 13.8; IR (KBr) ν
3488, 2995, 2923, 2852, 1743, 1713, 1641, 1487, 1448, 1370, 1272,
1244, 1218, 1186, 1163, 1091, 1073, 1033, 999, 865, 771, 696 cm−1;
MS (m/z, ESI) 437 [M + H]+; HRMS (ESI) calcd for C25H25O7 [M +
H]+ 437.1595, found 437.1592.
Diethyl 8-Fluoro-1-hydroxy-6-oxo-1-phenyl-1,2,4,6-tetrahydro-
3H-benzo[c]chromene-3,3-dicarboxylate (2e). White solid (36 mg,
41%); mp 151−152 °C; 1H NMR (400 MHz, CDCl3) δ 7.88 (dd, J =
8.2, 2.8 Hz, 1H), 7.47 (dd, J = 9.0, 5.4 Hz, 1H), 7.40 (br s, 2H), 7.30
(t, J = 7.4 Hz, 2H), 7.23 (t, J = 7.2 Hz, 1H), 7.10 (td, J = 8.6, 2.8 Hz,
1H), 5.36 (s, 1H), 4.36−4.09 (m, 4H), 3.40 (d, J = 18.0 Hz, 1H), 3.28
(dd, J = 17.6, 2.6 Hz, 1H), 2.95 (dd, J = 15.2, 2.4 Hz, 1H), 2.24 (d, J =
15.2 Hz, 1H), 1.29−1.22 (m, 6H); 13C NMR (100 MHz, CDCl3) δ
172.7, 169.3, 161.2 (d, JCF = 248.6 Hz), 161.0 (d, JCF = 3.4 Hz), 154.5,
149.4 (d, JCF = 2.3 Hz), 146.9, 131.9 (d, JCF = 2.7 Hz), 129.7 (d, JCF
7.5 Hz), 128.7, 127.3, 125.0, 123.4 (d, JCF = 8.0 Hz), 122.2 (d, JCF
=
=
22.4 Hz), 114.8 (d, JCF = 22.7 Hz), 114.1 (d, JCF = 1.1 Hz), 63.0, 62.4,
53.1, 47.5, 33.5, 13.9, 13.8; IR (KBr) ν 3478, 3070, 2983, 2923, 1749,
1723, 1648, 1494, 1447, 1368, 1306, 1263, 1240, 1203, 1166, 1093,
1067, 1000, 901, 875, 834, 767, 701 cm−1; MS (m/z, ESI) 472 [M +
NH4]+; HRMS (ESI) calcd for C25H27FNO7 [M + NH4]+ 472.1766,
found 472.1767.
Diethyl 2-((1-Oxo-1H-isochromen-3-yl)methyl))-2-(2-oxo-2-
phenylethyl)malonate (3a). Yellow oil; 1H NMR (400 MHz,
CDCl3) δ 8.20 (d, J = 8.4 Hz, 1H), 7.98−7.95 (m, 2H), 7.63 (td, J
= 7.6, 1.2 Hz, 1H), 7.60−7.55 (m, 1H), 7.45 (t, J = 7.6 Hz, 3H), 7.22
(d, J = 7.6 Hz, 1H), 6.19 (s, 1H), 4.33−4.24 (m, 4H), 3.81 (s, 2H),
3.48 (s, 2H), 1.28 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ
197.0, 169.5, 161.7, 153.4, 136.6, 136.3, 134.7, 133.5, 129.4, 128.6,
Diethyl 8-Chloro-1-hydroxy-6-oxo-1-phenyl-1,2,4,6-tetrahydro-
3H-benzo[c]chromene-3,3-dicarboxylate (2f). White solid (75 mg,
1
79%); mp 201−202 °C; H NMR (400 MHz, CDCl3) δ 8.19 (d, J =
2.4 Hz, 1H), 7.42−7.21 (m, 7H), 5.33 (s, 1H), 4.36−4.08 (m, 4H),
3.40 (d, J = 18.0 Hz, 1H), 3.28 (dd, J = 18.0, 1.6 Hz, 1H), 2.95 (dd, J =
15.2, 2.0 Hz, 1H), 2.25 (d, J = 15.2 Hz, 1H), 1.29−1.22 (m, 6H); 13C
NMR (100 MHz, CDCl3) δ 172.5, 169.2, 160.7, 150.3, 146.8, 134.2,
E
DOI: 10.1021/acs.joc.6b00128
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
133.8, 133.4, 128.7, 128.6, 127.3, 124.9, 122.9, 114.1, 73.0, 62.9, 62.4,
53.0, 47.4, 33.5, 13.9, 13.7; IR (KBr) ν 3485, 2989, 1749, 1722, 1644,
1480, 1445, 1369, 1338, 1265, 1230, 1218, 1162, 1095, 1073, 1050,
900, 882, 861, 830, 768, 705 cm−1; MS (m/z, ESI) 488 [M + NH4]+;
HRMS (ESI) calcd for C25H27ClNO7 [M + NH4]+ 488.1471, found
488.1487.
123.1, 121.5, 114.2, 73.4, 62.8, 62.3, 53.0, 47.4, 33.6, 13.8, 13.7; IR
(KBr) ν 3506, 2988, 1743, 1717, 1643, 1488, 1469, 1369, 1266, 1218,
1186, 1159, 1086, 1033, 999, 824, 751, 693 cm−1; MS (m/z, ESI) 487
[M + H]+; HRMS (ESI) calcd for C29H27O7 [M + H]+ 487.1751,
found 487.1758.
1-Hydroxy-1-methyl-1,2,3,4-tetrahydro-6H-benzo[c]chromen-6-
one (2l). White solid (36 mg, 85%); mp 127−128 °C; 1H NMR (400
MHz, CDCl3) δ 8.39 (d, J = 8.4 Hz, 1H), 8.18 (d, J = 7.6 Hz, 1H),
7.66 (t, J = 7.8 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 2.66−2.58 (m, 1H),
2.53−2.49 (m, 1H), 2.24 (br s, 1H), 2.06−2.03 (m, 1H), 1.96−1.90
(m, 2H), 1.85−1.78 (m, 1H), 1.68 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 162.4, 152.9, 136.0, 134.0, 129.7, 127.1, 126.2, 121.0, 115.8,
71.6, 41.9, 28.3, 27.7, 18.7; IR (KBr) ν 3467, 2981, 2940, 2866, 1695,
1630, 1600, 1558, 1478, 1454, 1389, 1364, 1311, 1248, 1188, 1141,
1089, 1031, 996, 927, 811, 770, 701 cm−1; MS (70 eV, EI) m/z (%)
230 [M]+, 215, 197, 184, 174, 159, 141, 128, 115, 103, 89, 77, 63, 43,
41; Anal. Calcd (%) for C14H14O3 C 73.03, H 6.13; found C 72.77, H
6.20.
Diethyl 8-Bromo-1-hydroxy-6-oxo-1-phenyl-1,2,4,6-tetrahydro-
3H-benzo[c]chromene-3,3-dicarboxylate (2g). White solid (79 mg,
1
77%); mp 217−218 °C; H NMR (400 MHz, CDCl3) δ 8.35 (d, J =
1.6 Hz, 1H), 7.47−7.27 (m, 6H), 7.24−7.21 (m, 1H), 5.33 (s, 1H),
4.34−4.10 (m, 4H), 3.38 (d, J = 18.0 Hz, 1H), 3.27 (dd, J = 18.0, 2.0
Hz, 1H), 2.94 (dd, J = 15.2, 1.6 Hz, 1H), 2.24 (d, J = 15.2 Hz, 1H),
1.29−1.22 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 172.6, 169.2,
160.6, 150.5, 146.8, 137.0, 134.1, 131.8, 128.8, 128.6, 127.3, 124.9,
123.1, 121.3, 114.2, 73.0, 63.0, 62.4, 53.0, 47.4, 33.6, 13.9, 13.8; IR
(KBr) ν 3489, 2982, 1748, 1722, 1643, 1476, 1446, 1368, 1264, 1228,
1216, 1160, 1094, 1070, 1047, 996, 862, 833, 768, 707 cm−1; MS (m/z,
ESI) 532 [M + NH4]+; HRMS (ESI) calcd for C25H27BrNO7 [M +
NH4]+ 532.0965, found 532.0975.
1-Hydroxy-1,2,3,4-tetrahydro-6H-benzo[c]chromen-6-one (2m).
Diethyl 1-Hydroxy-1-(4-methoxyphenyl)-6-oxo-1,2,4,6-tetrahy-
dro-3H-benzo[c]chromene-3,3-dicarboxylate (2h). Yellow solid (47
mg, 54%); mp 113−114 °C; 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J
= 7.6 Hz, 1H), 7.47−7.32 (m, 5H), 6.81 (d, J = 8.4 Hz, 2H), 5.15 (s,
1H), 4.34−4.08 (m, 4H), 3.76 (s, 3H), 3.38 (d, J = 18.0 Hz, 1H), 3.27
(dd, J = 17.8, 2.2 Hz, 1H), 2.93 (dd, J = 15.2, 2.0 Hz, 1H), 2.24 (d, J =
15.2 Hz, 1H), 1.28−1.22 (m, 6H); 13C NMR (100 MHz, CDCl3) δ
172.5, 169.4, 161.9, 158.5, 150.1, 139.2, 135.3, 133.9, 129.4, 127.4,
127.0, 126.2, 121.5, 114.4, 113.8, 72.9, 62.8, 62.3, 55.2, 53.0, 47.7, 33.6,
13.9, 13.8; IR (KBr) ν 3484, 3437, 3065, 2930, 2851, 1728, 1699,
1643, 1600, 1508, 1477, 1370, 1263, 1244, 1208, 1182, 1082, 1064,
1037, 992, 830, 774, 704 cm−1; MS (70 eV, EI) m/z (%) 466 [M]+,
448, 421, 375, 347, 331, 303, 213, 135, 107, 92, 77; HRMS (EI) calcd
for C26H26O8 [M]+ 466.1628, found 466.1634.
1
White solid (30 mg, 69%); mp 133−134 °C; H NMR (400 MHz,
CDCl3) δ 8.27 (d, J = 8.0 Hz, 1H), 7.80−7.74 (m, 2H), 7.50−7.45 (m,
1H), 5.05−5.04 (m, 1H), 2.62−2.58 (m, 2H), 2.14−2.03 (m, 2H),
1.95−1.80 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 162.3, 155.1,
136.8, 134.9, 129.6, 127.4, 122.4, 120.4, 111.7, 62.9, 31.2, 27.5, 16.4; IR
(KBr) ν 3460, 2954, 2931, 2875, 1693, 1648, 1600, 1484, 1395, 1366,
1306, 1272, 1190, 1145, 1077, 998, 940, 801, 731, 694 cm−1; MS (m/z,
ESI) 217 [M + H]+; HRMS (ESI) calcd for C13H13O3 [M + H]+
217.0859, found 217.0860.
3-(1-Oxo-1H-isochromen-3-yl)propanal (3n). White solid (24 mg,
1
58%); mp 71−72 °C; H NMR (400 MHz, CDCl3) δ 9.86 (s, 1H),
8.24 (d, J = 7.6 Hz, 1H), 7.71−7.66 (m, 1H), 7.49−7.45 (m, 1H), 7.37
(d, J = 8.0 Hz, 1H), 6.34 (s, 1H), 2.95−2.85 (m, 4H); 13C NMR (100
MHz, CDCl3) δ 199.9, 162.6, 155.6, 137.1, 134.8, 129.4, 127.9, 125.2,
120.1, 103.8, 40.6, 25.9; IR (KBr) ν 3073, 2918, 2856, 2765, 1716,
1656, 1480, 1429, 1289, 1159, 1044, 1025, 964, 814, 761, 689 cm−1;
MS (m/z, ESI) 203 [M + H]+; HRMS (ESI) calcd for C12H11O3 [M +
H]+ 203.0703, found 203.0703.
Diethyl 1-(4-Chlorophenyl)-1-hydroxy-6-oxo-1,2,4,6-tetrahydro-
3H-benzo[c]chromene-3,3-dicarboxylate (2i). White solid (71 mg,
1
79%); mp 174−175 °C; H NMR (400 MHz, CDCl3) δ 8.24 (d, J =
7.2 Hz, 1H), 7.43−7.25 (m, 7H), 5.31 (s, 1H), 4.35−4.10 (m, 4H),
3.38 (d, J = 18.0 Hz, 1H), 3.28 (dd, J = 18.0, 2.4 Hz, 1H), 2.93 (dd, J =
14.8, 2.4 Hz, 1H), 2.20 (d, J = 15.2 Hz, 1H), 1.29−1.23 (m, 6H); 13C
NMR (100 MHz, CDCl3) δ 172.5, 169.2, 161.6, 150.3, 145.7, 134.9,
134.0, 132.9, 129.5, 128.7, 127.6, 126.8, 126.6, 121.5, 113.9, 72.9, 62.9,
62.4, 52.9, 47.4, 33.5, 13.8, 13.7; IR (KBr) ν 3487, 3445, 2981, 2918,
1728, 1700, 1646, 1488, 1448, 1379, 1264, 1245, 1207, 1184, 1088,
1065, 1048, 996, 866, 825, 804, 771, 706 cm−1; MS (m/z, ESI) 471 [M
+ H]+; HRMS (ESI) calcd for C25H24ClO7 [M + H]+ 471.1205, found
471.1213.
Diethyl 2-((1-Oxo-1H-isochromen-3-yl)methyl)-2-(3-oxo-3-
1
phenylpropyl)malonate (3o). Colorless oil (75 mg, 84%); H NMR
(400 MHz, CDCl3) δ 8.21 (d, J = 8.0 Hz, 1H), 7.97−7.95 (m, 2H),
7.67 (td, J = 7.6, 1.1 Hz, 1H), 7.55 (t, J = 7.4 Hz, 1H), 7.48−7.43 (m,
3H), 7.35 (d, J = 8.0 Hz, 1H), 6.38 (s, 1H), 4.33−4.19 (m, 4H), 3.25
(s, 2H), 3.11 (t, J = 7.6 Hz, 2H), 2.40 (t, J = 7.8 Hz, 2H), 1.26 (t, J =
7.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 198.5, 170.2, 161.7,
152.7, 136.7, 136.4, 134.7, 133.1, 129.4, 128.5, 128.1, 128.0, 125.3,
120.3, 106.4, 61.8, 56.3, 37.7, 33.8, 27.2, 13.9; IR (KBr) ν 2981, 1724,
1684, 1656, 1600, 1484, 1448, 1368, 1181, 1091, 1043, 1020, 856, 736,
689 cm−1; MS (m/z, ESI) 468 [M + NH4]+; HRMS (ESI) calcd for
C26H30NO7 [M + NH4]+ 468.2017, found 468.2026.
11-Hydroxyindeno[1,2-c]isochromen-5(11H)-one (2p). White
solid (36 mg, 72%); mp 173−174 °C; 1H NMR (400 MHz,
CDCl3) δ 8.17−8.14 (m, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.77−7.72 (m,
1H), 7.65 (dd, J = 4.6, 3.4 Hz, 1H), 7.46−7.37 (m, 4H), 5.60 (s, 1H),
2.32 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 162.6, 154.2, 144.9,
135.3, 135.0, 134.2, 130.9, 129.2, 128.9, 127.6, 124.4, 122.9, 119.6,
119.2, 117.5, 72.3; IR (KBr) ν 3274, 1748, 1628, 1606, 1486, 1302,
1000, 758 cm−1; MS (EI, 70 eV) m/z (%) 250 [M]+, 249, 248, 220,
204, 176, 163, 137, 124, 110, 96, 89, 82, 62, 50; HRMS (ESI) calcd for
C16H11O3 [M + H]+ 251.0703, found 251.0705.
Diethyl 1-Hydroxy-1-(4-nitrophenyl)-6-oxo-1,2,4,6-tetrahydro-
3H-benzo[c]chromene-3,3-dicarboxylate (2j). White solid (81 mg,
84%); mp 177−178 °C; 1H NMR (400 MHz, CDCl3) δ 8.25 (dd, J =
7.6, 1.2 Hz, 1H), 8.15 (d, J = 8.0 Hz, 2H), 7.66 (br s, 2H), 7.42−7.36
(m, 2H), 7.31−7.29 (m, 1H), 5.58 (s, 1H), 4.38−4.13 (m, 4H), 3.43
(d, J = 18.0 Hz, 1H), 3.33 (dd, J = 18.0, 1.6 Hz, 1H), 2.97 (dd, J =
15.2, 2.0 Hz, 1H), 2.18 (d, J = 15.2 Hz, 1H), 1.31−1.25 (m, 6H); 13C
NMR (100 MHz, CDCl3) δ 172.5, 169.0, 161.4, 154.5, 150.7, 147.0,
134.6, 134.2, 129.7, 127.8, 126.3, 126.2, 123.9, 121.5, 113.4, 73.1, 63.1,
62.5, 53.0, 46.9, 33.6, 13.8, 13.7; IR (KBr) ν 3482, 3438, 2986, 1728,
1647, 1601, 1520, 1479, 1450, 1349, 1312, 1266, 1246, 1209, 1184,
1084, 1013, 997, 858, 703 cm−1; MS (70 eV, EI) m/z (%) 481 [M]+,
463, 432, 390, 362, 344, 318, 287, 272, 257, 243, 215, 202, 189, 178,
165, 150, 105, 92, 77; HRMS (EI) calcd for C25H23NO9 [M]+
481.1373, found 481.1369.
Diethyl 1-Hydroxy-1-(naphthalen-2-yl)-6-oxo-1,2,4,6-tetrahydro-
3H-benzo[c]chromene-3,3-dicarboxylate (2k). Yellow solid (78 mg,
ASSOCIATED CONTENT
■
1
81%); mp 145−146 °C; H NMR (400 MHz, CDCl3) δ 8.25−8.23
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b00128.
(m, 1H), 8.10 (br s, 1H), 7.82−7.72 (m, 3H), 7.51−7.25 (m, 6H),
5.38 (s, 1H), 4.36−4.05 (m, 4H), 3.45 (d, J = 18.0 Hz, 1H), 3.34 (dd, J
= 18.0, 2.0 Hz, 1H), 3.00 (dd, J = 15.2, 2.0 Hz, 1H), 2.33 (d, J = 15.2
Hz, 1H), 1.28 (t, J = 7.2 Hz, 3H), 1.20 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 172.6, 169.4, 161.9, 150.3, 144.4, 135.2, 134.0,
133.2, 132.4, 129.4, 128.5, 127.5, 127.4, 126.8, 126.2, 126.0, 124.0,
Copies of 1H and 13C NMR spectral data for all
compounds (PDF)
F
DOI: 10.1021/acs.joc.6b00128
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
AUTHOR INFORMATION
Corresponding Authors
*E-mail: xlhan@mail.sioc.ac.cn.
*E-mail: xylu@mail.sioc.ac.cn.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Basic Research Program of China
(2011CB808706), National Natural Science Foundation of
China (21232006, 21272249), and Chinese Academy of
Sciences for financial support.
REFERENCES
■
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DOI: 10.1021/acs.joc.6b00128
J. Org. Chem. XXXX, XXX, XXX−XXX