Palladium-catalyzed intermolecular tandem cyclization reaction: a highly regioselective synthesis of functionalized 3H-spiro[isobenzofuran-1,3′-isochroman] scaffolds

Article abstract of DOI:10.1039/c6ob02802k

A highly regioselective synthesis of functionalized 3H-spiro[isobenzofuran-1,3′-isochroman] scaffolds using a novel palladium-catalyzed tandem cyclization reaction is explored. During the reaction process, C-O, C-C and C-O bonds are sequentially formed in one pot via decarboxylative allenylpalladium formation, nucleophilic attack, arylpalladium addition and intramolecular nucleophilic attack.

Full text of DOI:10.1039/c6ob02802k

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Biomolecular Chemistry
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Palladium-catalyzed intermolecular tandem
cyclization reaction: a highly regioselective
synthesis of functionalized 3H-spiro
Cite this: DOI: 10.1039/c6ob02802k
[isobenzofuran-1,3’-isochroman] scaffolds†
Liang Wang,a,b Xuehu Li,a Hua Tao,c Xiang Zhou,a Xihong Lu,a Wenyue Du,a
Tingting Jiang,a,b Zhijun Xin*a and Jianping Liang*a
Received 26th December 2016,
Accepted 24th February 2017
A highly regioselective synthesis of functionalized 3H-spiro[isobenzofuran-1,3’-isochroman] scaffolds
using a novel palladium-catalyzed tandem cyclization reaction is explored. During the reaction process,
C–O, C–C and C–O bonds are sequentially formed in one pot via decarboxylative allenylpalladium for-
mation, nucleophilic attack, arylpalladium addition and intramolecular nucleophilic attack.
DOI: 10.1039/c6ob02802k
rsc.li/obc
tandem cyclization,3 and double Friedel–Crafts cyclization.4 In
addition, the reported methods have certain limitations: (1)
Introduction
Eleganketal A 1, isolated from the fungus Spicaria elegans the starting materials are restricted by complex multi-step
KLA03, is the first naturally occurring aromatic polyketide with syntheses; (2) the starting materials are limited to alkynediols
a rare 3H-spiro[isobenzofuran-1,3′-isochroman] ring system or equivalents; (3) strong acidic/basic conditions do not toler-
(Fig. 1).1 Its permethylated analogue 1a demonstrates good ate sensitive functionality. As a consequence, the development
bioactivity against the influenza A H1N1 virus. However, only a of novel and efficient strategies for the synthesis of 3H-spiro
few synthetic methods for the construction of this [6-5-6-6] [isobenzofuran-1,3′-isochroman] scaffolds from the readily
tetracyclic skeleton have been reported, including strong acid/ accessible starting materials is of great significance.
base induced spiroketalization,2 transition-metal catalyzed
The palladium-catalyzed tandem cyclization of propargylic
carbonates has emerged as an extremely efficient and powerful
approach for the construction of various polycyclic
frameworks.5–12 Nevertheless, limited number of studies on
the synthesis of spiro ring systems have been presented.11,12
Remarkably, Liang et al. disclosed an efficient method for the
synthesis of aromatic 5,5-spirocycles from propargylic com-
pounds with 2-iodophenols; however, the reaction did not
proceed at all if 2-iodobenzyl alcohol was used.12 Inspired by
these findings, we envisioned that the intermolecular tandem
cyclization between propargylic carbonates and 2-halobenzyl
alcohols could provide straightforward access to 3H-spiro[iso-
benzofuran-1,3′-isochroman] scaffolds. To our knowledge, no
prior report has addressed this type of strategy for creating aro-
matic 5,6-spiroketal skeletons. The vital challenges have to be
considered in this strategy: (1) control the velocity of decarb-
oxylation of propargylic carbonates prior to oxidative addition
of 2-iodobenzyl alcohols with the palladium catalyst;13 (2)
sequential formation of C–O, C–C and C–O bonds with high
regioselectivity. Herein, we describe the development of a
novel palladium-catalyzed intermolecular tandem cyclization
that provides an ideal and concise approach for creating func-
tionalized 3H-spiro[isobenzofuran-1,3′-isochroman] scaffolds
(Scheme 1).
Fig. 1 A natural product and an analog containing 3H-spiro[isobenzo-
furan-1,3’-isochroman] scaffolds.
aInstitute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Rd,
Lanzhou, Gansu 730000, P. R. China. E-mail: xinzhj@impcas.ac.cn,
liangjp100@impcas.ac.cn
bUniversity of Chinese Academy of Sciences, Beijing 100049, P. R. China
cNorthwest Institute of Eco-Environment and Resources, Chinese Academy of
Sciences, 320 Western Dong gang Rd, Lanzhou, Gansu 730000, P. R. China
†Electronic supplementary information (ESI) available. CCDC 1518214 (4c). For
ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c6ob02802k
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was conducted at 120 °C under Ar for 2 h, using DMF as the
solvent and 3 equiv. of K2CO3 as the base. The results demon-
strated that Pd(OAc)2/P(2-Tol)3 was the most effective catalyst
in this protocol, affording the desired and exclusive product in
60% yield (entries 1–3). No reaction occurred in the absence of
a Pd catalyst (entry 4). Subsequently, we investigated solvent
effects and found that polar aprotic solvents were much better
than other solvents for the examined transformation. DMF
was proven to be the most suitable of the tested solvents for
this cyclization reaction; other aprotic solvents, such as DMSO,
CH3CN and NMP, produced less satisfactory results (entries
5–7). Furthermore, among the bases that we evaluated, organic
bases were inferior to inorganic bases, and Na2CO3 was the
Scheme 1 Several strategies for the synthesis of 3H-spiro[isobenzo- most effective base, producing a yield of 65% (entries 8–11).
furan-1,3’-isochroman] scaffolds.
To further improve the yield of the reaction, a series of
ligands, such as PPh3, BINAP and DPPF, were examined;
P(2-Tol)3 was superior to any of the other tested ligands (entries
12–14). Finally, the effects of TBAC and TBAB on the reaction
Results and discussion
were investigated (entries 15 and 16). Unfortunately, both of
these chemicals reduced the yield of the desired product.
Based on the aforementioned results, the optimal conditions
At the beginning of this study, the profile of a model reaction
between propargylic carbonate 2a and 2-iodobenzyl alcohol 3a
were found to be Pd(OAc)2/P(2-Tol)3, 3 equiv. Na2CO3 and DMF
was optimized to improve the yield of this palladium-catalyzed
at 120 °C under Ar for 2 h.
process. Diverse reaction conditions were examined that
involved different catalysts, solvents, bases, and ligands, as
We then investigated the scope and generality of this
tandem reaction with various substituted propargylic sub-
well as certain ionic liquids. The outcomes of this investi-
strates and 2-iodobenzyl alcohols under the optimal con-
gation are presented in Table 1.
ditions (Table 1, entry 7). As illustrated in Table 2, different
In initial experiments, various Pd catalysts (10% mol) were
screened for promoting the reaction of 2a and 3a; the reaction
types of 2-iodobenzyl alcohols were examined first. When
6-methyl-2-iodobenzyl alcohol was utilized, the desired
product was isolated in 57% yield, which was less than the
corresponding yield obtained when using 2-iodobenzyl alcohol
Table 1 Optimization of the palladium-catalyzed tandem cyclization
reaction of propargylic carbonate 2a with 3a a
(products 4a, 4b). 2-Iodobenzyl alcohols with a halo-substi-
tution at the ortho or para position of the hydroxyl could react
well and generate the corresponding products in moderate
yields (products 4c–4f). Notably, the examined transformation
was tolerant to the substitution of the strong electron-with-
drawing p-trifluoromethyl group (product 4g), whereas no
desired product was observed when an m-acetoxy group was
Entry
Catalyst
Base
Solvent
Yieldb (%)
substituted into the substrate (product 4h). Various tandem
reactions were then attempted with a monooxygen substituent
at either the para or meta position; the corresponding spiroke-
tal skeletons were afforded in moderate yields, without signifi-
cant differences in yield (products 4i–4k). Even though steri-
cally encumbered 3,4,5-trimethoxy-2-iodobenzyl alcohol was
also investigated and furnished the corresponding spiroketal
in 55% yield (product 4l). An acceptable result was obtained
when 1-(2-iodophenyl) ethanol was utilized for the reaction
(product 4m). A substrate bearing a naphthalene ring or
6-iodo-1,3-benzodioxole-5-methanol was tolerant and reacted
well to afford the desired cyclization product (products 4n,
4o). However, when the substrate was 2-iodophenol, signifi-
cantly poorer reaction performance was observed which might
be caused by a weaker nucleophilic attack of phenol (product
4p). In contrast, 3-(hydroxymethyl)-4-iodophenol and 2-iodo-
benzoic acid were a complete failure in the tandem cyclization
(product 4q and 4r). The structure of the newly synthesized
1
2
3
4
5
6
7
8
Pd(PPh3)4
Pd(dba)2
Pd(OAc)2/P(2-Tol)3
None
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
DMAP
DABCO
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
DMF
DMF
DMF
DMF
DMSO
NMP
CH3CN
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF/TBAC
DMF/TBAB
54
48
58
N.Rc
53
Pd(OAc)2/P(2-Tol)3
Pd(OAc)2/P(2-Tol)3
Pd(OAc)2/P(2-Tol)3
Pd(OAc)2/P(2-Tol)3
Pd(OAc)2/P(2-Tol)3
Pd(OAc)2/P(2-Tol)3
Pd(OAc)2/P(2-Tol)3
Pd(OAc)2/PPh3
Pd(OAc)2/BINAP
Pd(OAc)2/DPPF
Pd(OAc)2/P(2-Tol)3
Pd(OAc)2/P(2-Tol)3
45
20
65
33
29
Trace
46
50
55
9
10
11
12
13
14
15
16
52
39
a Reaction conditions: 2a (2.5 equiv.), 3a (1 equiv.), base (3.0 equiv.),
[Pd] (10 mol%), ligand (20 mol%), DMF (5 mL), 120 °C and under Ar
for 2 h. b Isolated yield. c N.R = No reaction. BINAP = 2,2′-bis(diphenyl-
phosphino)-1,1′-binaphthyl, DPPF
ferrocene.
=
1,1′-bis(diphenylphosphino)
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Table 2 Palladium-catalyzed tandem cyclization reaction between
propargylic carbonate 2a and various 2-iodobenzyl alcohols 3a,b
Table 3 Scope of various propargylic carbonates 2 for the palladium-
catalyzed tandem cyclization reactiona
Entry
1
Substrate 2
Substrate 3
Product 4
Yieldb (%)
52
3a
4s
2
3
4
5
6
3a
3a
3a
3a
3a
4t
54
4u
4a
4a
4a
N.D.
63
64
52
a All reactions were carried out under the optimal conditions reported
in the text. b Isolated yield N.D = no detected.
a All reactions were carried out under the optimal conditions reported
in the text. b Isolated yield N.D = no detected.
compound 4c was unambiguously confirmed by single crystal
X-ray diffraction analysis (Fig. 2).
Following the above experiments, we devoted our attention
to diverse substituents or leaving groups on various pro-
pargylic carbonates (Table 3). Lower yields were observed for
reactions involving an oxygen substituent or naphthalene on
the propargylic carbonates (entries 1 and 2); even worse, the
reaction did not proceed successfully when the carbonate had
a meta-acetoxyl group (entry 3). Reactions involving propargyl
acetate 2e and propargyl carboxybenzyl 2f were found to be
well compatible with the tested conditions and afforded
moderate yields (entries 4 and 5). Meanwhile, the reaction with
propargyl phosphate 2g was effective, with 52% yield (entry 6).
To explore the potential and robustness of this protocol, a
facile route to the synthesis of 1a was then conducted (for
details, see the ESI†). As summarized in Scheme 2, the investi-
Scheme 2 A facile route to the synthesis of 1a.
gations show that 1a could be acquired smoothly within 7 syn-
thetic steps.
Based on earlier reports12 and our own experimental obser-
vations, a plausible mechanism for the formation of function-
alized 3H-spiro[isobenzofuran-1,3′-isochroman] scaffolds is
depicted in Scheme 3. We envisioned that an SN2′ reaction
of palladium(0), which attacks the propargylic carbonate 2a,
will occur to afford an allenylpalladium intermediate 12.
Subsequently, regioselective intramolecular nucleophilic attack
of the hydroxyl might lead to intermediate 13, which could be
captured by the arylpalladium compound and transformed
into the π-allylpalladium compound 14. Finally, the hydroxyl
will regioselectively attack the more hindered site to generate
the spirocyclic compound 4a and regenerate the palladium(0)
Fig. 2 X-ray crystal structure of 4c.
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Daltonics APEX II 47e mass spectrometer. Column chromato-
graphy was generally performed on silica gel (200–300 mesh)
and TLC inspections were performed on silica gel GF254
plates. Substrates 3a, 3f and 3o were purchased from commer-
cial suppliers and used without further treatment.
General procedure for the preparation of 3H-spiro
[isobenzofuran-1,3′-isochroman] compounds 4
To a solution of propargylic compound 2 (1.5 mmol) in DMF
(5.0 mL) was added Na2CO3 (188 mg, 3 mmol). The mixture was
stirred for 5 min and Pd(OAc)2/P(2-Tol)3 (13.4 mg, 0.06 mmol,
10 mol%), and aryl halides 3 (0.60 mmol) were added. The
resulting mixture was then heated under an argon atmosphere
at 120 °C. When the reaction was considered complete as deter-
mined by TLC analysis, the reaction mixture was allowed to cool
to room temperature and quenched with a saturated aqueous
solution of ammonium chloride, and the mixture was extracted
with EtOAc. The combined organic extracts were washed with
water and saturated brine. The organic layers were dried over
Na2SO4 and filtered. The solvents were evaporated under
reduced pressure. The residue was purified by chromatography
on silica gel to afford spriocyclic compound 4.
Scheme 3 The proposed mechanism.
catalyst. Additionally, electronic effects might be the key con-
trolling factor that produces regioselectivity.
Conclusions
4′-Methylene-3H-spiro[isobenzofuran-1,3′-isochroman] (4a)
In summary, we have described a palladium-catalyzed highly
regioselective intermolecular tandem cyclization of propargylic
compounds with 2-iodobenzyl alcohols. This tandem cycliza-
tion protocol furnishes functionalized 3H-spiro[isobenzofuran-
1,3′-isochroman] scaffolds with
a broad substrate scope.
Notably, the reaction proceeds efficiently, with sequential C–O,
C–C and C–O bond formation in a one-pot procedure.
Currently, further investigations involving the mechanism of
this reaction and their applications in other organic reactions
are ongoing in our laboratory.
Pale yellow oil; (65%); 1H NMR (400 MHz, CDCl3) δ 7.76–7.74 (m,
1H), 7.44–7.27 (m, 6H), 7.14–7.12 (m, 1H), 5.83 (s, 1H), 5.32–5.29
(d, J = 12.8 Hz, 1H), 5.28–5.24 (d, J = 15.0 Hz, 1H), 5.20–5.17
(d, J = 12.8 Hz, 1H), 5.08 (s, 1H), 4.83–4.80 (d, J = 15 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 140.4, 140.3, 139.8, 134.1, 130.8,
129.2, 127.9, 127.6, 127.2, 124.3, 124.0, 123.7, 121.1, 111.3, 109.6,
71.7, 63.7; FT-IR (KBr, cm−1) 3365, 3069, 3035, 2945, 2860, 1655,
1597, 1578, 1461, 1371, 1230, 1074, 1053, 1006, 959, 760; HRMS
(ESI): m/z calcd for C17H15O2 [M + H]+ 251.1067, found 251.1068.
Experimental
General information
Unless stated otherwise, all reactions were carried out in
flame-dried glassware under a dry argon atmosphere. All sol-
vents were purified and dried according to standard methods
prior to use. For product purification by flash column chrom-
atography, silica gel (200–300 mesh) and light petroleum ether
(bp. 60–90 °C) are used. The 1H and 13C NMR data were
recorded on a Bruker-400 MHz spectrometer at room tempera-
ture in CDCl3 or DMSO-d6 or CD3COCD3 solvent. Chemical
shifts for protons are reported using residual CHCl3 or DMSO
or CD3COCD3 as an internal reference (δ = 7.27, 2.50,
8′-Methyl-4′-methylene-3H-spiro[isobenzofuran-
1,3′-isochroman] (4b)
2.05 ppm). Carbon spectra were referenced to the shift of the Pale yellow solid; (57%); 1H NMR (400 MHz, d6-DMSO)
13C signal of CDCl3 (δ = 77.00, 39.52 ppm, 29.84 and δ 7.38–7.33 (m, 2H), 7.28–7.19 (m, 3H), 7.12–7.10 (d, J = 7.2 Hz,
206.26 ppm). The data for 1H NMR are recorded as follows: 1H), 6.76–6.74 (d, J = 7.6 Hz, 1H), 5.63 (s, 1H), 5.51 (s, 1H),
chemical shift (δ, ppm), multiplicity (s = singlet, d = doublet, 5.19–5.12 (d, J = 13.1 Hz, J = 15.2 Hz, 2H), 4.74–4.71 (d, J = 13.5
t = triplet, m = multiplet or unresolved, br = broad singlet, coup- Hz, 1H), 4.60–4.57(d, J = 13.5 Hz, 1H), 2.40 (s, 3H); 13C NMR
ling constant (s) in Hz, integration). The data for 13C NMR is (100 MHz, d6-DMSO) δ 141.3, 141.2, 138.8, 137.9, 134.7, 132.4,
reported in terms of chemical shift (δ, ppm). High-resolution 130.2, 128.6, 127.5, 126.9, 122.1, 121.8, 121.4, 117.0, 110.1, 70.9,
mass spectra (HRMS) data were obtained on
a
Bruker 64.2, 20.3; FT-IR (KBr, cm−1) 3365, 3071, 3033, 2965, 2860, 1633,
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1603, 1460, 1382, 1223, 1058, 1007, 971, 760; HRMS (ESI): m/z (m, 2H), 5.98 (s, 1H), 5.16–5.13 (d, J = 13.0 Hz, 1H), 5.10–5.07 (d,
calcd for C18H17O2 [M + H]+ 265.1223, found 265.1222.
J = 13.0 Hz, 1H), 5.01–4.98 (d, J = 15.3 Hz, 1H), 4.94 (s, 1H),
4.78–4.74 (d, J = 15.3 Hz, 1H); 13C NMR (100 MHz, d6-DMSO)
δ 140.3, 139.1, 138.9, 132.8, 132.5, 131.9, 129.2, 127.7, 127.4,
126.5, 123.7, 123.3, 121.3, 112.8, 108.5, 71.1, 62.2; FT-IR (KBr,
cm−1) 3433, 3080, 3047, 2927, 2850, 1641, 1593, 1461, 1363,
1225, 1047, 1000, 946, 764; HRMS (ESI): m/z calcd for
C17H14ClO2 [M + H]+ 285.0677, found 285.0676.
8′-Fluoro-4′-methylene-3H-spiro[isobenzofuran-
1,3′-isochroman] (4c)
6′-Bromo-5′-methylene-3H-spiro[isobenzofuran-
1,3′-isochroman] (4f)
1
White solid; (63%); H NMR (400 MHz, d6-DMSO) δ 7.67–7.65
(d, J = 7.8 Hz, 1H), 7.48–7.42 (m, 2H), 7.39–7.34 (m, 2H),
7.27–7.25 (d, J = 7.5 Hz, 1H), 7.20–7.15 (t, J = 8.8 Hz, 1H),
5.94 (s, 1H), 5.18–5.15 (d, J = 13.1 Hz, 1H), 5.11–5.07 (d, J = 13.1
Hz, 1H), 5.01–4.97 (d, J = 15.4 Hz, 2H), 4.92–4.88 (d, J = 15.4 Hz,
1H); 13C NMR (100 MHz, d6-DMSO) δ 157.7 (d, J = 240 Hz),
140.4, 138.6, 138.6, 132.9 (d, J = 5 Hz), 129.2, 128.4 (d, J = 8 Hz),
127.4, 123.5, 121.4, 121.0 (d, J = 17 Hz), 120.1 (d, J = 3 Hz), 114.0
(d, J = 20 Hz), 112.1, 108.3, 71.2, 57.6 (d, J = 5 Hz); FT-IR (KBr,
cm−1) 3434, 3106, 3044, 2950, 2864, 1639, 1612, 1575, 1462,
1374, 1239, 1078, 1048, 994, 956, 757; HRMS (ESI): m/z calcd for
C17H14FO2 [M + H]+ 269.0972, found 269.0971.
1
White solid; (53%); H NMR (400 MHz, d6-CDCl3) δ 7.59–7.56
(d, J = 8.48 Hz, 1H), 7.42–7.39 (m, 2H), 7.36–7.25 (m, 4H),
5.79 (s, 1H), 5.28–5.25 (d, J = 12.7 Hz, 1H), 5.20–5.13 (m, 2H),
5.07 (s, 1H), 4.75–4.71 (d, J = 15.1 Hz, 1H); 13C NMR (100 MHz,
d6-CDCl3) δ 140.3, 139.4, 139.3, 136.0, 130.3, 129.7, 129.3, 127.7,
127.2, 125.8, 123.6, 121.9, 121.1, 111.8, 109.3, 71.8, 63.0; FT-IR
(KBr, cm−1) 3394, 3098, 3076, 2892, 2856, 1635, 1590, 1483,
1466, 1406, 1369, 1229, 1047, 994, 954, 759; HRMS (ESI): m/z
calcd for C17H14BrO2 [M + H]+ 329.0177, found 329.0178.
6′-Fluoro-4′-methylene-3H-spiro[isobenzofuran-
1,3′-isochroman] (4d)
4′-Methylene-6′-(trifluoromethyl)-3H-spiro[isobenzofuran-
1,3′-isochroman] (4g)
1
White solid; (68%); H NMR (400 MHz, d6-DMSO) δ 7.67–7.64
(dd, J = 10.6 Hz, J = 2.5 Hz, 1H), 7.45–7.42 (m, 2H), 7.38–
7.34 (m, 1H), 7.27–7.21 (m, 2H), 7.19–7.14 (m, 1H), 5.97 (s, 1H),
5.17–5.13 (d, J = 13.1 Hz, 1H), 5.11–5.08 (d, J = 13.1 Hz, 1H),
5.02–4.98 (d, J = 14.9 Hz, 1H), 4.95 (s, 1H), 4.77–4.73 (d, J =
14.9 Hz, 1H); 13C NMR (100 MHz, d6-DMSO) δ 161.5 (d, J =
240 Hz), 140.3, 139.3, 139.2, 132.6 (d, J = 8 Hz), 130.1 (d, J =
2 Hz), 129.2, 127.5, 126.7 (d, J = 8 Hz), 123.3, 121.4, 115.1 (d, J =
22 Hz), 112.8, 110.3 (d, J = 22 Hz), 108.4, 71.0, 62.1; FT-IR
(KBr, cm−1) 3436, 3102, 2921, 2867, 1613, 1585, 1490, 1460,
1365, 1229, 1048, 1001, 959, 768; HRMS (ESI): m/z calcd for
C17H14FO2 [M + H]+ 269.0972, found 269.0972.
Pale yellow solid; (57%); 1H NMR (400 MHz, d6-DMSO)
δ 8.03–8.01 (d, J = 8.2 Hz, 1H), 7.65–7.62 (m, 2H), 7.47–7.42 (m,
2H), 7.38–73.4 (td, J = 7.6 Hz, J = 1.8 Hz, 1H), 7.24–7.22 (d, J = 7.6
Hz, 1H), 6.05 (s, 1H), 5.18–5.15 (d, J = 13.2 Hz, 1H), 5.12–5.05
(m, 3 H), 4.90–4.82 (d, J = 15.6 Hz, 1H); 13C NMR (100 MHz,
d6-DMSO) δ 140.3, 139.0, 138.9, 135.0, 134.4, 129.2, 128.0 (d, J =
32 Hz), 127.5, 125.1, 124.1 (d, J = 270 Hz), 123.7 (d, J = 4 Hz),
123.3, 121.7 (d, J = 4 Hz), 121.4, 114.0, 108.6, 71.1, 62.3; FT-IR
(KBr, cm−1) 3433, 3086, 3051, 2957, 2879, 1639, 1616, 1579, 1504,
1465, 1363, 1338, 1164, 1116, 1047, 997, 958, 759; HRMS (ESI):
m/z calcd for C18H14F3O2 [M + H]+ 319.0640, found 319.0939.
6′-Chloro-4′-methylene-3H-spiro[isobenzofuran-
1,3′-isochroman] (4e)
6′-Methoxy-4′-methylene-3H-spiro[isobenzofuran-
1,3′-isochroman] (4i)
White solid; (62%); 1H NMR (400 MHz, d6-DMSO) δ 7.87–7.87 (d,
J = 2 Hz, 1H), 7.46–7.41 (m, 2H), 7.38–7.33 (m, 2H), 7.24–7.21
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1
White solid; (65%); H NMR (400 MHz, CDCl3) δ 744–7.40 (m, 5′,6′,7′-Trimethoxy-4′-methylene-3H-spiro[isobenzofuran-
1H), 7.37–7.32 (m, 3H), 7.25–7.24 (d, J = 2.9 Hz, 1H), 7.06–7.04 1,3′-isochroman] (4l)
(d, J = 8.4 Hz, 1H), 6.91–6.89 (d, J = 8.4 Hz, J = 2.5 Hz, 1H), 5.80
(s, 1H), 5.31–5.28 (d, J = 12.7 Hz, 1H), 5.22–5.16 (m, 2H), 5.10
(s, 1H), 4.79–4.75 (d, J = 14.4 Hz, 1H), 3.86 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 158.7, 140.5, 140.3, 139.8, 131.8, 129.0,
127.5, 126.6, 125.4, 123.5, 121.0, 114.7, 111.4, 109.3, 108.4,
71.6, 63.3, 55.3; FT-IR (KBr, cm−1) 3433, 3055, 3024, 2909,
2868, 1636, 1605, 1579, 1497, 1462, 1384, 1338, 1233, 1050,
1004, 962, 770; HRMS (ESI): m/z calcd for C18H17O3 [M + H]+
281.1172, found 281.1174.
Colorless oil; (55%); 1H NMR (400 MHz, CD3COCD3) δ 7.40–7.38
(m, 2H), 7.33–7.30 (m, 2H), 7.20–7.18 (d, J = 7.6 Hz, 1H), 6.67 (s,
7′-Mthoxy-4′-methylene-3H-spiro[isobenzofuran-
1,3′-isochroman] (4j)
1H), 6.21–6.21 (d, J = 1.5 Hz, 1H), 5.18–5.18 (d, J = 1.5 Hz, 1H),
5.17–5.08 (dd, J = 12.8 Hz, J = 21.5 Hz, 2H), 4.97–4.93 (d, J = 14.4
Hz, 1H), 4.62–4.58 (d, J = 14.4 Hz, 1H), 3.87 (s, 2H), 3.82 (s, 2H),
3.80 (s, 2H); 13C NMR (100 MHz, CD3COCD3) δ 154.1, 153.6,
142.9, 142.1, 141.3, 139.0, 133.0, 129.6, 128.1, 124.2, 121.9,
118.8, 115.7, 111.1, 104.6, 71.9, 64.3, 60.9, 60.2, 56.3. FT-IR (KBr,
cm−1) 3455, 2935, 2861, 1655, 1596, 1488, 1461, 1413, 1358,
1337, 1278, 1242, 1118, 1098, 1048, 1013, 958, 764; HRMS (ESI):
m/z calcd for C24H21O3 [M + H]+ 341.1485, found 341.1484.
White solid; (63%); 1H NMR (400 MHz, CDCl3) δ 7.68–7.66
(d, J = 8.7 Hz, 1H), 7.43–7.39 (m, 1H), 7.35–7.32 (m, 3H),
6.89–6.86 (dd, J = 8.7 Hz, J = 2.6 Hz, 1H), 6.64–6.63 (d, J =
2.6 Hz, 1H), 5.69 (s, 1H), 5.30–5.27 (d, J = 12.6 Hz, 1H),
5.25–5.21 (d, J = 14.7 Hz, 1H), 5.19–5.16 (d, J = 12.6 Hz, 1H),
4.94 (s, 1H), 4.79–4.75 (d, J = 14.7 Hz, 1H), 3.83 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 159.3, 140.4, 139.8, 139.7, 135.4,
129.1, 127.5, 125.6, 123.6, 123.5, 121.0, 113.9, 109.6, 109.0,
108.3, 71.6, 63.7, 55.2; FT-IR (KBr, cm−1) 3428, 3055, 3012, 2925,
2868, 1632, 1609, 1579, 1498, 1462, 1365, 1249, 1075, 1006, 961,
766; HRMS (ESI): m/z calcd for C18H17O3 [M + H]+ 281.1172,
found 281.1174.
1′-Methyl-4′-methylene-3H-spiro[isobenzofuran-
1,3′-isochroman] (4m)
Pale yellow solid; (64%); 1H NMR (400 MHz, d6-DMSO)
δ 7.76–7.72 (m, 1H), 7.43–7.21 (m, 6H), 6.90–6.88 (d, J = 7.6 Hz,
1H), 5.81–5.75 (s, 1H), 5.20–4.85 (m, 4H), 1.53–1.52 (d, J = 6.6 Hz,
3H); 13C NMR (100 MHz, d6-DMSO) δ 141.0, 140.9, 140.3, 139.8,
139.7, 139.6, 138.6, 138.3, 130.6, 130.4, 128.9, 128.8, 128.2, 128.0,
127.3, 127.2, 127.1, 127.0, 124.8, 124.3, 124.0, 123.9, 123.5, 122.3,
121.6, 121.2, 110.9, 110.0, 109.0, 107.9, 70.8, 70.2, 67.3, 23.1,
20.4; FT-IR (KBr, cm−1) 3367, 3067, 3032, 2979, 2931, 2864, 1632,
1610, 1576, 1460, 1372, 1234, 1106, 1007, 962, 752; HRMS (ESI):
m/z calcd for C18H17O2 [M + H]+ 265.1223, found 265.1224.
7′-(Benzyloxy)-4′-methylene-3H-spiro[isobenzofuran-
1,3′-isochroman] (4k)
8-Methylene-5,8-dihydro-3′H-spiro[[1,3]dioxolo[4,5-g]
isochromene-7,1′-isobenzofuran] (4n)
1
White solid; (60%); H NMR (400 MHz, CDCl3) δ 7.69–7.67 (d,
J = 8.7 Hz, 1H), 7.47–7.40 (m, 5H), 7.38–7.33 (m, 4H), 6.97–6.94
(dd, J = 8.7 Hz, J = 2.4 Hz, 1H), 6.72–6.72 (d, J = 2.1 Hz, 1H),
5.70 (s, 1H), 5.31–5.28 (d, J = 12.7 Hz, 1H), 5.25–5.21 (d, J =
14.9 Hz, 1H), 5.19–5.16 (d, J = 12.7 Hz, 1H), 5.11 (s, 2H), 4.95
(s, 1H), 4.78–4.74 (d, J = 14.9 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 158.6, 140.4, 139.8, 139.7, 136.7, 135.4, 129.1, 128.5,
1
127.9, 127.5, 127.3, 125.6, 123.8, 123.6, 121.0, 114.7, 109.6, Pale red oil; (56%); H NMR (400 MHz, CDCl3) δ 7.43–7.39 (m,
109.5, 109.2, 71.6, 70.0, 63.7; FT-IR (KBr, cm−1) 3402, 3062, 1H), 7.37–7.31 (m, 3H), 7.17 (s, 1H), 6.56 (s, 1H), 5.98–5.96
3033, 2921, 2861, 1607, 1574, 1498, 1382, 1359, 1277, 1244, (dd, J = 6.8 Hz, J = 1.2 Hz, 2H), 5.61 (s, 1H), 5.29–5.26 (d, J =
1074, 1049, 1005, 958, 758; HRMS (ESI): m/z calcd for 12.7 Hz, 1H), 5.18–5.13 (m, 2H), 4.95 (s, 1H), 4.71–4.67 (d, J =
C24H21O3 [M + H]+ 357.1485, found 357.1484.
14.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 147.7, 147.2, 140.3,
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140.1, 139.7, 129.1, 128.4, 127.5, 124.6, 123.6, 121.0, 109.7, 6.03–5.98 (dd, J = 16.6 Hz, J = 1.2 Hz, 2H), 5.81 (s, 1H),
109.3, 104.1, 103.9, 101.0, 71.6, 63.7; FT-IR (KBr, cm−1) 3372, 5.25–5.17 (m, 2H), 5.11 (s, 1H), 5.08–5.04 (d, J = 12.2 Hz, 1H),
3037, 2905, 2862, 1625, 1610, 1561, 1501, 1482, 1377, 1355, 4.81–4.77 (d, J = 14.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
1274, 1243, 1089, 1038, 957, 937, 756; HRMS (ESI): m/z calcd δ 149.2, 147.8, 140.4, 134.1, 133.8, 132.9, 130.7, 127.9, 127.1,
for C18H15O4 [M + H]+ 295.0965, found 295.0966.
124.3, 124.0 1112, 109.6, 104.0, 101.6, 101.2, 71.6, 63.7; FT-IR
(KBr, cm−1) 3395, 3066, 3021, 2951, 2899, 2860, 1617, 1600,
1577, 1501, 1478, 1387, 1368, 1278, 1263, 1061, 1032, 1011,
962, 938, 773, 733; HRMS (ESI): m/z calcd for C18H15O4
[M + H]+ 295.0965, found 295.0963.
4-Methylene-1,4-dihydro-3′H-spiro [benzo[g]isochromene-3,1′-iso-
benzofuran] (4o).
4-Methylene-3′H-spiro[isochroman-3,1′-naphtho[2,3-c]furan] (4t)
1
Pale yellow solid; (55%); H NMR (400 MHz, CDCl3) δ 8.21 (s,
1H), 7.90–7.87 (m, 1H), 7.82–7.80 (m, 1H), 7.61 (s, 1H), 7.51–7.46
(m, 2H), 7.44–7.40 (m, 1H), 7.35–7.27 (m, 3H), 6.02 (s, 1H),
5.40–5.33 (m, 2H), 5.24–5.21 (d, J = 13.6 Hz, 2H), 4.97–4.94 (d,
J = 14.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 141.5, 140.5, 140.0,
132.8, 132.8, 132.6, 130.2, 129.0, 128.1, 127.6, 127.3, 126.4,
125.8, 123.3, 123.1, 122.5, 121.0, 113.2, 109.9, 71.7, 64.0; FT-IR
(KBr, cm−1) 3432, 3047, 2919, 2854, 1638, 1597, 1499, 1460,
1370, 1316, 1229, 1188, 1094, 1048, 1002, 957, 855, 758; HRMS
(ESI): m/z calcd for C21H17O2 [M + H]+ 301.1223, found 301.1225.
1
White solid; (54%); H NMR (400 MHz, d6-DMSO) δ 7.98–7.95
(m, 2H), 7.91 (s, 1H), 7.85–7.82 (m, 1H), 7.79 (s, 1H), 7.56–7.47
(m, 2H), 7.35–7.33 (m, 2H), 7.22–7.20 (m, 1H), 5.94 (s, 1H),
5.30–5.26 (d, J = 13.6 Hz, 1H), 5.25–5.21 (d, J = 13.6 Hz, 1H),
5.09–5.05 (d, J = 15.1 Hz, 1H), 5.02 (s, 1H), 4.80–4.76 (d, J =
15.1 Hz, 1H); 13C NMR (100 MHz, d6-DMSO) δ 139.9, 138.7,
138.4, 133.9, 133.5, 132.5, 130.4, 128.5, 127.9, 127.7, 127.2,
126.5, 125.8, 124.4, 123.9, 122.3, 119.5, 111.6, 108.2, 70.2, 62.6;
FT-IR (KBr, cm−1) 3431, 3057, 2919, 2865, 1629, 1608, 1503,
1486, 1461, 1442, 1370, 1312, 1232, 1209, 1105, 1065, 1050,
1009, 958, 900, 878, 777; HRMS (ESI): m/z calcd for C21H17O2
[M + H]+ 301.1223, found 301.1224.
3-Methylene-3H,3′H-spiro[benzofuran-2,1′-isobenzofuran] (4p)
Acknowledgements
We gratefully acknowledge the financial support by the
1
Pale yellow oil; (20%); H NMR (400 MHz, CDCl3) δ 7.52–7.50
International
S&T Cooperation
Program
of
China
(dd, J = 7.5 Hz, J = 0.72 Hz, 1H), 7.47–7.43 (m, 1H), 7.38–7.34
(m, 2H), 7.31–7.27 (m, 1H), 7.25–7.23 (m, 1H), 7.02–6.98 (td,
J = 7.5 Hz, J = 0.72 Hz, 1H), 6.88–6.86 (d, J = 8.0 Hz, 1H), 5.80
(s, 1H), 5.44–5.40 (d, J = 12.8 Hz, 1H), 5.27–5.24 (d, J = 12.8 Hz,
1H), 5.09 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 159.1, 146.0,
139.9, 138.5, 130.9, 129.6, 128.2, 124.1, 123.1, 121.1, 121.0,
120.8, 118.9, 110.4, 108.6, 72.6; FT-IR (KBr, cm−1) 3394, 3051,
3034, 2924, 2870, 1645, 1608, 1594, 1463, 1357, 1280, 1267,
1242, 1057, 990, 912, 750; HRMS (ESI): m/z calcd for C16H13O2
[M + H]+ 237.0910, found 237.0908.
(1504WKCA098) and Gansu Province Special Funds for Gansu
Medicine Industry Development (Y361010SJ0).
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Pale red oil; (52%); H NMR (400 MHz, CDCl3) δ 7.73–7.71 (m,
1H), 7.32–7.27 (m, 2H), 7.14–7.10 (m, 1H), 6.73 (s, 2H),
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