Direct Arylation of Benzyl Ethers with Organozinc Reagents

Article abstract of DOI:10.1021/acs.joc.8b00776

A novel C(sp³)-H bond arylation of benzyl ethers with Knochel-type arylzinc reagents has been developed. This transition-metal-catalyst-free reaction proceeds well under mild conditions in a simple and effective manner and enables the synthesis of a wide range of potentially biologically active benzyl ethers by using highly functionalized organozinc reagents as a carbon nucleophile.

Full text of DOI:10.1021/acs.joc.8b00776

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Article
Direct Arylation of Benzyl Ethers with Organozinc Reagents
Zhihua Peng, Yilei Wang, Zhi Yu, Dezhi Zhao, Linhua Song, and Cuiyu Jiang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00776 • Publication Date (Web): 12 Jun 2018
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Direct Arylation of Benzyl Ethers with Organozinc Reagents
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Zhihua Peng*, Yilei Wang, Zhi Yu, Dezhi Zhao, Linhua Song, and Cuiyu Jiang
Department of Chemistry, College of Science, China University of Petroleum (East China),
Qingdao, Shandong, 266580, P. R. China
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ABSTRACT: A novel C(sp3)−H bond arylation of benzyl ethers with Knochelꢀtype
arylzinc reagents has been developed. This transitionꢀmetalꢀcatalyst free reaction
proceeds well under mild conditions in a simple and effective manner, and enables the
synthesis of a wide range of potentially biologically active benzyl ethers by using
highly functionalized organozinc reagents as a carbon nucleophile.
INTRODUCTION
Functionalized benzyl ethers such as isochroman are common structural motifs in
biologically active natural compounds and pharmaceuticals.1 In particular, 1ꢀarylated
benzyl ethers not only possess significant antioxidants, antiviral, and anticancer
activities,2 but also have been found widespread applications as an important building
block in the synthesis of drug molecules.3 Considering the importance and widespread
applications of 1ꢀarylated benzyl ethers, the synthesis of these compounds therefore
has been an ongoing challenge, and is a promising area of research. In the past few
decades, the selective functionalization of reactive C(sp3)−H bonds at the C1 position
of benzyl ethers has become the most attractive methodology for the synthesis of
1ꢀfunctionalized benzyl ethers as it may represent a stepꢀ and atomꢀeconomic
strategy.4 In this context, crossꢀdehydrogenative coupling (CDC) reactions5 have been
developed as an effective method for the construction of αꢀsubstituted benzyl ethers.
Although a few oxidation systems and CDCs between benzyl ethers and a series of
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carbon nucleophiles have been studied,6 much fewer methods for the synthesis of
1ꢀarylated benzyl ethers were reported7 because performing a CDC reaction between
benzyl ethers and aromatic rings acting as nucleophiles is still a challenge.
Alternatively, the reaction of organometallic reagents with preꢀoxidized benzyl ethers
offered an effective approach for the synthesis of 1ꢀarylated benzyl ethers. The
advantages of this kind of C(sp3)ꢀH bond functionalization of benzyl ethers with
organomentallic reagents includes transitionꢀmetalꢀfree, mild reaction conditions, and
high regioselectivity. Muramatsu reported several oxidation systems to achieve a
oneꢀpot oxidative coupling of isochroman with Grignard reagents, affording diverse
αꢀsubstituted derivatives in high efficiency.8 In addition, Liu group has disclosed a
trityl ionꢀmediated practical C−H functionalization of benzopyrans with a wide range
of nucleophiles (organoboranes and C−H molecules) at ambient temperature.9 Despite
the great innovation has been achieved, some disadvantages such as unfavorable
regioselectivity and poor functional group tolerance might be brought by the used
organometallic reagents, which may limit the broad application of this protocol in
organic synthesis. To overcome the limitation, the employment of highly
functionalized organometallic reagents with better selectivity and reactivity is crucial
in this transformation. Among various organometallics, organozinc reagents exhibit
better compatibility with sensitive functional groups, and they are one of the most
versatile organometallic reagents for the synthesis of complex compounds.10 To date,
most of the C(sp3)ꢀH bond functionalizations with organozinc reagents mainly involve
oxidative couplings next to nitrogen atoms. The group of Menche revealed
CuCl2ꢀcatalyzed alkylation and benzylation of THIQ derivatives with organozinc
reagents.11 In 2017, our group has demonstrated a novel transitionꢀmetalꢀcatalyst free
C(sp3)–H bond arylation of tetrahydroisoquinoline (THIQ) derivatives with
Knochelꢀtype arylzinc reagents.12 However, the reports on the reaction of the
corresponding less reactive C(sp3)–H bonds next to an oxygen atom with less reactive
organozinc reagents are scarce. One case was reported by Muramatsu in which Ph2Zn
was used in the catalytic C(sp3)ꢀH bond arylation of isochroman during the
optimization process. In view of the synthetic utility and certain limitations of existing
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methods in particular regarding substrate scope, herein, we describe a convenient,
transitionꢀmetalꢀcatalyst free, and broadly applicable oxidative crossꢀcoupling
reaction of benzyl ethers with arylzinc reagents to access diverse 1ꢀarylated benzyl
ether derivatives in an effective manner.
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RESULTS AND DISCUSSION
According to the analogous study in our group, phenylzinc reagent coordinated
with MgCl2 and LiCl (PhZnBr·MgCl2·LiCl)13 shows increasing reactivity to the
iminium cation formed by a nucleophilic substitution of tetrahydroisoquinoline
(THIQ) to [bis(trifluoroacetoxy)iodo]benzene (PIFA) and deprotonation of the
generated ammonium cation with the trifluoroacetate ion because of the presence of
MgCl2 and LiCl.12 We assumed that this kind of organozinc reagents might also
display better reactivity to the oxonium cation generated by the oxidation of benzyl
ethers with organic oxidants. Therefore, we selected the coupling of isochroman with
PhZnBr·MgCl2·LiCl as a starting point for our initial study. The oxidation of
isochroman to
an
oxonium ion
could
be
achieved
by
using
o
2,3ꢀdicyanoꢀ5,6ꢀdichlorobenzoquinone (DDQ) as an organic oxidant in PhCl at 80 C
within 2 h.8a The treatment of this intermediate ion with PhZnBr·MgCl2·LiCl,
prepared by the insertion of magnesium turnings into phenyl bromide in the presence
of ZnCl2 and LiCl, afforded the desired product 3a in the yield of 77% (Table 1, entry
1). The use of PhZnI·MgCl2·LiCl, prepared by the insertion of magnesium turnings
into phenyl iodide in the presence of ZnCl2 and LiCl, slightly decreased the yield to
70% (Table 1, entry 2). Unsurprisingly, the oxidation of isochroman (1a) in the
presence of DDQ in PhCl and subsequent reaction with PhZnI·LiCl14 (2 equiv)
provided the corresponding product 3a in the isolated yield of 16% (Table 1, entry 3).
In 1,2ꢀdichloroethane (DCE), the reaction proceeded well to afford 3a in a 79% yield
(Table 1, entry 4). However, the usage of THF as a solvent did not give a satisfactory
result (Table 1, entry 5). Oxidant screening was also carried out. When oxidants such
as 3,3',5,5'ꢀtetraꢀtertꢀbutyldiphenoquinone, diethyl azodicarboxylate (DEAD) or their
mixtures with PIFA were used instead of DDQ, only trace of coupling products 3a
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were obtained or no desired product was observed (Table 1, entries 6ꢀ9).
Table 1. Optimization of Reaction Conditionsa
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entry
oxidant
DDQc
DDQc
DDQc
DDQc
DDQc
solvent
PhCl
PhCl
PhCl
DCE
THF
PhZnX
yeld of 3ab
77%
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7
PhZnBr·MgCl2·LiCl
PhZnI·MgCl2·LiCl
PhZnI·LiCl
70%
16%
PhZnBr·MgCl2·LiCl
PhZnBr·MgCl2·LiCl
PhZnBr·MgCl2·LiCl
PhZnBr·MgCl2·LiCl
79%
trace
3,3',5,5'ꢀtetraꢀtertꢀbutyldiphenoquinonec DCE
3,3',5,5'ꢀtetraꢀtertꢀbutyldiphenoquinone, DCE
PIFAd
trace
trace
8
9
DEADe
THF
PhZnBr·MgCl2·LiCl
PhZnBr·MgCl2·LiCl
0
0
DEAD, PIFAf
THF
aGeneral conditions: after the mixture of 1a (0.5 mmol) and oxidant (0.2 to 1.1 equiv) was stirred
o
for 2 h in solvent (2.5 mL) at room temperature to 80 C, organozinc reagent (1.5 mmol) was
added, and the reaction mixture was stirred for 12 h at room temperature.
bIsolated yield.
c1.1 equivalents of oxidant were used.
d PIFA (1.1 equiv) and 3,3',5,5'ꢀtetraꢀtertꢀbutyldiphenoquinone (20 mol%) were used.
eThe oxidation of 1a (0.5 mmol) with DEAD (1.1 equiv) was conducted at room temperature
within 5 h.
fThe oxidation of 1a (0.5 mmol) with DEAD (20 mol%) and PIFA (1.1 equiv) was conducted at
room temperature within 5 h.
Having established the optimized reaction conditions, we tested the substituent
effect of arylzinc reagents on this transformation (Scheme 1). The reaction of arylzinc
reagents bearing electronꢀdonating groups with isochroman proceeded well, providing
the desired products in good to excellent yields. The oxidation of isochroman (0.5
o
mmol) with DDQ (1.1 equiv) in DCE (2.5 mL) at 80 C within 2 h, and subsequent
treatment with 2ꢀmethylphenylzinc reagent prepared by the insertion of magnesium
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into 1ꢀbromoꢀ2ꢀmethylbenzene in the presence of ZnCl2 and LiCl afforded the
coupling product 3b in the yield of 81%. Under similar conditions, the oxidative
crossꢀcoupling of arylzinc reagents bearing a methoxy group with isochroman gave
the corresponding products 3c-d in 64ꢀ66% yields. In addition, compound 3e
containing a trifluoromethoxy group was produced in the yield of 78% in a similar
manner. Arylzinc reagents containing electronꢀwithdrawing groups could also react
with isochroman, producing the desired products 3f-i in good yields. Notably, the
oxidative arylation reaction of isochroman with arylzinc reagents could tolerate an
ester group. The reaction of isochroman with (4ꢀ(ethoxycarbonyl)phenyl)zinc reagent
under similar conditions delivered the coupling product 3j in 33% yield. Interestingly,
arylzinc reagent containing a cyano group reacted well with isochroman, affording the
expected product 3k in 36% yield. Additionally, the heterocyclic compound 3l could
also be obtained in the yield of 83%. It is worth mentioning that a variety of
functional groups such as OMe (3c, 3d, 3f), OCF3 (3e), F (3f, 3g), CF3 (3h), Cl (3i),
CO2Et (3j), and CN (3k) were tolerated well under the reaction conditions. However,
the reaction of arylzinc reagents containing azide, amide, pyridinyl or carbonyl groups
under the optimum conditions didn’t provide the desired products.
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Scheme 1. Coupling of Isochroman with Various Arylzinc Reagents.a, b
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aThe reaction was performed by the oxidation of 1a (0.5 mmol) and DDQ (1.1 equiv) in DCE (2.5
o
mL) at 80 C for 2 h and subsequent treatment with organozinc reagent (1.5 mmol) at room
temperature for 12 h.
bIsolated yield.
We next studied the generality of benzyl ethers (Scheme 2). In a similar manner,
isochroman bearing Meꢀgroup at the C7 position reacted successfully with
2ꢀMeC6H4ZnBr·MgCl2·LiCl, affording the corresponding coupled product 3m in the
yield of 62%. Gratifyingly, the treatment of 2ꢀmethylphenyl zinc reagent with
7ꢀmethoxyisochroman or 6,7ꢀdimethoxyisochroman, which are the less reactive
coupling partners due to the presence of MeOꢀgroup at the C6 or C7 position of
isochroman, furnished the desired coupling products 3n-o in 37ꢀ41% yields. In
addition, 4ꢀmethylisochroman coupled smoothly with 2ꢀMeC6H4ZnBr·MgCl2·LiCl,
leading to the arylated product 3p in 64% yield with good selectivity (trans/cis ≥ 7:1).
The C(sp3)–H bond arylation of benzyl ethers with arylzinc reagents displays a good
compatibility with a halideꢀsubstituent. The reaction went smoothly when a
bromoꢀsubstituent was placed at C7 or C5 position, and the coupled products 3q-r
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were produced in 61ꢀ72% yields. Under identical conditions, the reaction of
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isochroman bearing
2ꢀMeC6H4ZnBr·MgCl2·LiCl provided the corresponding coupled product 3s in the
yield of 65%. In addition, isothiochroman reacted well with
a
chlorine group at the C7 position with
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2ꢀMeC6H4ZnBr·MgCl2·LiCl under the standard conditions, giving the isothiochroman
derivative 3t in the yield of 55%. Xanthene also reacted smoothly with
2ꢀmethylphenyl zinc reagent under the standard conditions, and afforded the desired
product
3u
in
26%
yield.
Acyclic
benzyl
ethers
such
as
1ꢀmethoxyꢀ4ꢀ(methoxymethyl)benzene, 1ꢀbromoꢀ4ꢀ(methoxymethyl)benzene, and
benzyl methyl sulfide were also compatible with this coupling system, though the
expected products 3v-x were obtained only in moderate yields.
6ꢀBromoꢀ2Hꢀchromene also proved to be a competent substrate. The reaction of
6ꢀbromoꢀ2Hꢀchromene with 2ꢀMeC6H4ZnBr·MgCl2·LiCl led to the expected product
3y in 68% yield.
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Scheme 2. Scope of Benzyl Ethers in The C-H Bond Arylation.a,b
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aThe reaction was performed by the oxidation of 1 (1 mmol) and DDQ (1.1 equiv) in DCE (5 mL)
at 80 oC for 2 h and subsequent treatment with organozinc reagent (3 mmol) at room temperature
for 12 h.
bIsolated yield.
A plausible reaction mechanism for the C(sp3)ꢀH arylation of benzyl ethers with
arylzinc reagents is shown in Scheme 3. A radical cation generated by a single
electron transfer from benzyl ethers to DDQ is accessed through Hꢀatom abstraction
to form an oxonium cation.15 The subsequent addition of reactive arylzinc reagents to
oxonium cation affords the desired coupling products.
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Scheme 3. Proposed Mechanism for The C-H Bond Arylation of Benzyl Ethers with Arylzinc
Reagents.
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CONCLUSION
In summary, we have developed a novel C(sp3)–H bond arylation of benzyl ethers
derivatives with Knochelꢀtype arylzinc reagents. The reactions could be readily
performed under mild conditions without the use of a heavy metal catalyst, affording
a wide range of potentially biologically active compounds. In addition, this
transformation exhibits excellent compatibility with various sensitive functional
groups such as an ester group. Further studies on the scope, and applications of this
reaction are now under investigation.
EXPERIMENTAL SECTION
General Information. All reactions were carried out under nitrogen atmosphere in
flameꢀdried glassware. Syringes which were used to transfer anhydrous solvents or
reagents were purged with nitrogen prior to use. THF was continuously refluxed and
freshly distilled from sodium benzophenone ketyl under nitrogen. Yields refer to
1
isolated yields of compounds estimated to be > 95% pure as determined by H NMR
(25 °C) and capillaryꢀGC. NMR spectra were recorded on solutions in deuterated
chloroform (CDCl3) with residual chloroform (δ7.25 ppm for 1H NMR and δ77.0 ppm
for 13C NMR). Abbreviations for signal coupling are as follows: s, singlet; d, doublet;
t, triplet; q, quartet; m, multiplet, br., broad. ESIꢀQTOFꢀMS measurements were
performed in the positive ion mode (m/z 50−2000 range). Column chromatographical
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purifications were performed using SiO2 (200 – 300 mesh ASTM) from Branch of
Qingdao Haiyang Chemical Co., Ltd if not indicated otherwise. Magnesium turning,
zinc chloride anhydrous (98%) and lithium chloride (AR) were purchased from
Sinopharm Chemical Reagent Co., Ltd.
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Typical procedure for the preparation of aryl zinc reagents:
A dry and nigrogenꢀflushed Schlenkꢀflask, equipped with a magnetic stirrer and a
septum, was charged with LiCl (191 mg, 4.5 mmol) and was heated under vacuum
until dry. ZnCl2 (450 mg, 3.3 mmol) was added and also heated under vacuum until
dry. Magnesium powder (180 mg, 7.5 mmol) was added and heated under vacuum
until dry. Dry THF (6 mL) was added, and the mixture was stirred for 30 min at room
o
temperature. Then, aryl halide (3.0 mmol) was added in one portion at 0ꢀ25 C. The
reaction mixture was stirred for 2ꢀ12 h, affording the corresponding arylzinc reagents.
Typical procedure (TP1) for the reaction of benzyl ethers with aryl zinc reagents.
A clean Schlenk tube was dried for 5 min at 380 ºC (heat gun) under high vacuum (1
mbar). After cooled to room temperature, the tube was evacuated and backfilled with
nitrogen three times. To the mixture of DDQ (1.1 equiv) and 1,2ꢀdichloroethane (0.2
M) was added benzyl ethers (1 equiv). The reaction mixture was stirred for 2 h at 80
oC. The mixture was allowed to cool to room temperature, and the corresponding
aromatic zinc reagent (3 equiv) was added dropwise at room temperature. After
stirring for 12ꢀ16 h, water (20 mL) were then added to the reaction mixture. The
aqueous layer was extracted with ethyl acetate (3 × 20 mL). The combined organic
phases were washed with brine and dried over magnesium sulfate. The solvent was
removed by rotary evaporation and purification by flash column chromatography on
silica gel using petroleum ether/ethyl acetate as an eluent gave the expected products.
1-Phenylisochroman (3a). According to TP1, the reaction of isochroman (67 mg, 0.5
mmol) with phenylzinc reagent (4.5 mL, 0.33 M) afforded the desired product 3a
which was isolated by flash chromatography (eluent: ethyl acetate : petroleum ether =
o
1
1:50) as a white solid (83 mg, 79%). mp: 85ꢀ87 C (ethyl ether/petroleum ether); H
NMR (400 MHz, CDCl3) δ (ppm) 7.24ꢀ7.14 (m, 5 H), 7.06ꢀ6.99 (m, 2 H), 6.96ꢀ6.89
(m, 1 H), 6.63(d, J = 7.8 Hz, 1 H), 5.60 (s, 1 H), 4.06 (ddd, J = 11.3, 5.6, 3.9 Hz, 1 H),
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3.79 (ddd, J = 11.3, 9.5, 3.9 Hz, 1 H), 3.00 (ddd, J = 16.3, 9.5, 5.6 Hz, 1 H), 2.66 (dt,
13
J = 16.3, 3.9 Hz, 1 H); C NMR (100 MHz, CDCl3) δ (ppm) 142.1, 137.2, 133.7,
128.8, 128.6, 128.3, 127.9, 126.8, 126.5, 125.8, 79.5, 63.7, 28.7; IR (KBr) 3151, 2964,
2873, 1599, 1489, 1452, 1281, 1100, 904 cmꢀ1; HRMS (ESI) Calcd. for C15H14NaO
[M + Na]+ 233.0942, found 233.0936; Rf 0.50 (petroleum ether/EtOAc, 20/1).
1-(o-Tolyl)isochroman (3b). According to TP1, the reaction of isochroman (67 mg,
0.5 mmol) with 2ꢀmethylphenylzinc reagent (3.3 mL, 0.46 M) afforded the desired
product 3b which was isolated by flash chromatography (eluent: ethyl acetate :
petroleum ether = 1:50) as a pale yellow oil (92 mg, 81%). 1H NMR (400 MHz,
CDCl3) δ (ppm) 7.15ꢀ6.92 (m, 7 H), 6.60 (d, J = 7.6 Hz, 1 H), 5.83 (s, 1 H), 4.11 (ddd,
J = 11.3, 5.5, 3.7 Hz, 1 H), 3.84 (ddd, J = 11.3, 9.7, 3.9 Hz, 1 H), 3.05 (ddd, J = 15.9,
9.7, 5.6 Hz, 1 H), 2.66 (dt, J = 16.3, 3.7 Hz, 1 H), 2.26 (s, 3 H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 139.9, 137.5, 137.2, 133.9, 130.9, 129.9, 128.6, 128.0, 126.5, 126.3,
125.9, 125.7, 77.7, 64.0, 28.8, 19.3; IR (KBr) 3064, 3021, 2927, 1489, 1257, 1088
cmꢀ1; HRMS (ESI) Calcd. for C16H16NaO [M + Na]+ 247.1099, found 247.1090; Rf
0.54 (petroleum ether/EtOAc, 20/1).
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1-(3-Methoxyphenyl)isochroman (3c). According to TP1, the reaction of isochroman
(67 mg, 0.5 mmol) with 3ꢀmethoxyphenylzinc reagent (3.8 mL, 0.40 M) afforded the
desired product 3c which was isolated by flash chromatography (eluent: ethyl acetate :
petroleum ether = 1:30) as a colorless oil (79 mg, 66%). 1H NMR (400 MHz, CDCl3)
δ (ppm) 7.20ꢀ6.95 (m, 4 H), 6.81 (d, J = 7.6 Hz, 1 H), 6.79ꢀ6.73 (m, 2 H), 6.69 (d, J =
7.6 Hz, 1 H), 5.61 (s, 1 H), 4.10 (ddd, J = 11.3, 5.4, 4.2 Hz, 1 H), 3.83 (ddd, J = 11.3,
9.5, 3.9 Hz, 1 H), 3.67 (s, 3 H), 3.03 (ddd, J = 15.8, 9.6, 5.6 Hz, 1 H), 2.70 (dt, J =
16.3, 3.7 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ (ppm) 159.6, 143.6, 137.1, 133.7,
129.3, 128.6, 126.8, 126.6, 125.8, 121.2, 114.2, 113.6, 79.5, 63.8, 55.1, 28.7; IR (KBr)
3151, 2929, 2851, 1665, 1578, 1124 cmꢀ1; HRMS (ESI) Calcd. for C16H16NaO2 [M +
Na]+ 263.1048, found 263.1038; Rf 0.48 (petroleum ether/EtOAc, 10/1).
1-(4-Methoxyphenyl)isochroman (3d). According to TP1, the reaction of isochroman
(67 mg, 0.5 mmol) with 4ꢀmethoxyphenylzinc reagent (3.7 mL, 0.41 M) afforded the
desired product 3d which was isolated by flash chromatography (eluent: ethyl acetate :
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petroleum ether = 1:30) as a white solid (77 mg, 64%). mp: 72ꢀ74 C (ethyl
ether/petroleum ether); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.13 (d, J = 8.6 Hz, 2 H),
7.08ꢀ7.04 (m, 2 H), 7.01ꢀ6.95 (m, 1 H), 6.78 (d, J = 8.6 Hz, 2 H), 6.66 (d, J = 7.6 Hz,
1 H), 5.60 (s, 1 H), 4.08 (ddd, J = 11.3, 5.4, 3.9 Hz, 1 H), 3.82 (ddd, J = 11.3, 9.4, 3.9
Hz, 1 H), 3.69 (s, 3 H), 3.03 (ddd, J = 16.3, 9.4, 5.4 Hz, 1 H), 2.70 (dt, J = 16.3, 3.9
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Hz, 1 H); C NMR (100 MHz, CDCl3) δ (ppm) 159.3, 137.6, 134.4, 133.8, 130.0,
128.6, 126.9, 126.5, 125.8, 113.7, 79.0, 63.7, 55.2, 28.8; IR (KBr) 3001, 2949, 2831,
1615, 1517, 1250, 1176 cmꢀ1; HRMS (ESI) Calcd. for C16H16NaO2 [M + Na]+
263.1048, found 263.1045; Rf 0.47 (petroleum ether/EtOAc, 10/1).
1-(4-(Trifluoromethoxy)phenyl)isochroman (3e). According to TP1, the reaction of
isochroman (67 mg, 0.5 mmol) with 4ꢀ(trifluoromethoxy)phenylzinc reagent (3.2 mL,
0.47 M) afforded the desired product 3e which was isolated by flash chromatography
(eluent: ethyl acetate : petroleum ether = 1:30) as a pale yellow oil (115 mg, 78%). 1H
NMR (400 MHz, CDCl3) δ (ppm) 7.27 (d, J = 8.6 Hz, 2 H), 7.18ꢀ7.07 (m, 4 H),
7.05ꢀ6.98 (m, 1 H), 6.65 (d, J = 7.8 Hz, 1 H), 5.67 (s, 1 H), 4.11 (ddd, J = 11.4, 5.5,
3.7 Hz, 1 H), 3.85 (ddd, J = 11.4, 9.6, 3.7 Hz, 1 H), 3.07 (ddd, J = 16.5, 9.6, 5.5 Hz, 1
H), 2.74 (dt, J = 16.5, 3.6 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ (ppm) 148.9 (q, J
= 2.2 Hz), 140.9, 136.7, 133.8, 130.3, 128.9, 126.8, 126.7, 126.0, 120.9, 120.4 (q, J =
257.8 Hz), 78.8, 63.9, 28.7; IR (KBr) 3068, 2931, 2858, 1600, 1508, 1261, 1166,
1092 cmꢀ1; HRMS (ESI) Calcd. for C16H13F3NaO2 [M + Na]+ 317.0765, found
317.0753; Rf 0.45 (petroleum ether/EtOAc, 10/1).
1-(5-Fluoro-2-methoxyphenyl)isochroman (3f). According to TP1, the reaction of
isochroman (67 mg, 0.5 mmol) with 5ꢀfluoroꢀ2ꢀmethoxyphenylzinc reagent (3.3 mL,
0.46 M) afforded the desired product 3f which was isolated by flash chromatography
(eluent: ethyl acetate : petroleum ether = 1:30) as a colorless oil (110 mg, 85%). 1H
NMR (400 MHz, CDCl3) δ (ppm) 7.19ꢀ7.13 (m, 2 H), 7.09ꢀ7.04 (m, 1 H), 6.95 (ddd, J
= 9.1, 7.6, 3.2 Hz, 1 H), 6.88 (dd, J = 9.1, 4.4 Hz, 1 H), 6.82 (dd, J = 9.1, 3.2 Hz, 1 H),
6.75 (d, J = 7.6 Hz, 1 H), 6.22 (s, 1 H), 4.19 (ddd, J = 11.4, 5.4, 3.9 Hz, 1 H), 3.94
(ddd, J = 11.4, 9.4, 3.9 Hz, 1 H), 3.87 (s, 3 H), 3.18ꢀ3.08 (m, 1 H), 2.80 (dt, J = 16.2,
3.9 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ (ppm) 157.0 (d, J = 239.1 Hz), 153.5 (d,
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J = 2.2 Hz), 137.1, 133.9, 132.6 (d, J = 6.6 Hz), 128.7, 126.5, 126.4, 126.0, 116.5 (d, J
= 23.5 Hz), 115.1 (d, J = 23.4 Hz), 111.9 (d, J = 8.1 Hz), 72.2 (d, J = 1.5 Hz), 63.9,
56.3, 28.8; IR (KBr) 2962, 2925, 2854, 1776, 1591, 1558, 1361, 1187, 1028 cmꢀ1;
HRMS (ESI) Calcd. for C16H16FO2 [M + H]+ 259.1134, found 259.1124; Rf 0.44
(petroleum ether/EtOAc, 10/1).
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1-(2,4-Difluorophenyl)isochroman (3g). According to TP1, the reaction of
isochroman (67 mg, 0.5 mmol) with (2,4ꢀdifluorophenyl)zinc reagent (3.2 mL, 0.47
M) afforded the desired product 3g which was isolated by flash chromatography
(eluent: ethyl acetate : petroleum ether = 1:30) as a colorless oil (95 mg, 77%). 1H
NMR (400 MHz, CDCl3) δ (ppm) 7.13ꢀ6.95 (m, 4 H), 6.80ꢀ6.68 (m, 2 H), 6.64 (d, J =
7.6 Hz, 1 H), 5.97 (s, 1 H), 4.09 (ddd, J = 11.4, 5.6, 3.6 Hz, 1 H), 3.84 (ddd, J = 11.4,
9.8, 3.9 Hz, 1 H), 3.10ꢀ3.00 (m, 1 H), 2.70 (dt, J = 16.4, 3.6 Hz, 1 H); 13C NMR (100
MHz, CDCl3) δ (ppm) 162.6 (dd, J = 249.4, 11.7 Hz), 161.1 (dd, J = 250.9, 11.7 Hz),
136.4, 134.0, 131.4 (dd, J = 9.9, 5.5 Hz), 128.8, 126.8, 126.2, 126.1, 125.6 (dd, J =
13.2, 3.7 Hz), 111.3 (dd, J = 21.3, 3.7 Hz), 103.8 (t, J = 24.9 Hz), 72.2 (d, J = 2.9 Hz),
64.1, 28.7; IR (KBr) 3078, 2928, 2856, 1664, 1609, 1502, 1425, 1271, 1141 cmꢀ1;
HRMS (ESI) Calcd. for C15H12F2NaO [M + Na]+ 269.0754, found 269.0747; Rf 0.23
(petroleum ether/EtOAc, 20/1).
1-(2-(Trifluoromethyl)phenyl)isochroman (3h). According to TP1, the reaction of
isochroman (67 mg, 0.5 mmol) with (2ꢀ(trifluoromethyl)phenyl)zinc reagent (3.3 mL,
0.46 M) afforded the desired product 3h which was isolated by flash chromatography
(eluent: ethyl acetate : petroleum ether = 1:50) as a pale yellow oil (103 mg, 74%). 1H
NMR (400 MHz, CDCl3) δ (ppm) 7.71 (d, J = 7.8 Hz, 1 H), 7.44 (ddd, J = 29.2, 7.3,
7.2 Hz, 2 H), 7.31 (d, J = 7.8 Hz, 1 H), 7.17 (d, J = 3.9 Hz, 2 H), 7.05 (ddd, J = 8.0,
4.3, 4.1 Hz, 1 H), 6.60 (d, J = 7.8 Hz, 1 H), 6.14 (s, 1 H), 4.29 (ddd, J = 11.5, 5.9, 2.5
Hz, 1 H), 3.99 (ddd, J = 11.2, 11.2, 3.6 Hz, 1 H), 3.26 (ddd, J = 16.6, 10.7, 5.9 Hz, 1
13
H), 2.84ꢀ2.73 (m, 1 H); C NMR (100 MHz, CDCl3) δ (ppm) 141.2 (q, J = 1.5 Hz),
137.6, 133.9, 132.1 (q, J = 2.2 Hz), 131.4, 129.1 (q, J = 30.1 Hz), 128.7, 127.9, 126.9,
126.8, 126.2, 125.2 (q, J = 5.9 Hz), 124.4 (q, J = 273.6 Hz), 74.9 (q, J = 2.2 Hz), 64.9,
28.8; IR (KBr) 3068, 2952, 2858, 1606, 1261, 1171, 1085 cmꢀ1; HRMS (ESI) Calcd.
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for C16H13F3NaO [M + Na]+ 301.0816, found 301.0813; Rf 0.54 (petroleum
ether/EtOAc, 20/1).
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1-(3-Chlorophenyl)isochroman (3i). According to TP1, the reaction of isochroman
(134 mg, 1 mmol) with (3ꢀchlorophenyl)zinc reagent (8.3 mL, 0.36 M) afforded the
desired product 3j which was isolated by flash chromatography (eluent: ethyl acetate :
petroleum ether = 1:50) as a colorless oil (144 mg, 59%). 1H NMR (400 MHz, CDCl3)
δ (ppm) 7.31ꢀ7.26 (m, 3 H), 7.23ꢀ7.14 (m, 3 H), 7.12ꢀ7.07 (m, 1 H), 6.74 (d, J = 7.8
Hz, 1 H), 5.69 (s, 1 H), 4.17 (ddd, J = 11.4, 5.6, 3.8 Hz, 1 H), 3.92 (ddd, J = 11.4, 9.5,
4.0 Hz, 1 H), 3.19ꢀ3.09 (m, 1 H), 2.81 (dt, J = 16.4, 3.8 Hz, 1 H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 144.2, 136.5, 134.4, 133.8, 129.6, 128.9, 128.8, 128.3, 127.0, 126.8,
126.7, 126.1, 78.9, 63.9, 28.7; IR (KBr) 3003, 2944, 2293, 1444, 1376, 1196, 1133,
cmꢀ1; HRMS (ESI) Calcd. for C15H13ClNaO [M + Na]+ 267.0553, found 267.0542; Rf
0.51 (petroleum ether/EtOAc, 20/1).
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Ethyl 4-(isochroman-1-yl)benzoate (3j). According to TP1, the reaction of
isochroman (67 mg, 0.5 mmol) with (4ꢀ(ethoxycarbonyl)phenyl)zinc reagent (6.5 mL,
0.23 M) afforded the desired product 3j which was isolated by flash chromatography
(eluent: ethyl acetate : petroleum ether = 1:20) as a colorless oil (47 mg, 33%). 1H
NMR (400 MHz, CDCl3) δ (ppm) 8.02 (d, J = 8.6 Hz, 2 H), 7.38 (d, J = 8.6 Hz, 2 H),
7.20ꢀ7.15 (m, 2 H), 7.09ꢀ7.03 (m, 1 H), 6.69 (d, J = 7.8 Hz, 1 H), 5.76 (s, 1 H), 4.37
(q, J = 7.1 Hz, 2 H), 4.19 (ddd, J = 11.4, 5.5, 3.9 Hz, 1 H), 3.93 (ddd, J = 11.4, 9.5,
4.0 Hz, 1 H), 3.19ꢀ3.10 (m, 1 H), 2.81 (dt, J = 16.4, 3.9 Hz, 1 H), 1.38 (t, J = 7.1 Hz, 3
13
H); C NMR (100 MHz, CDCl3) δ (ppm) 166.4, 147.0, 136.7, 133.7, 130.3, 129.7,
128.9, 128.7, 126.9, 126.7, 126.0, 79.1, 64.0, 60.9, 28.7, 14.3; IR (KBr) 3067, 2929,
2853, 1716, 1453, 1407, 1276, 1105 cmꢀ1; HRMS (ESI) Calcd. for C18H19O3 [M + H]+
283.1334, found 283.1328; Rf 0.38 (petroleum ether/EtOAc, 10/1).
4-(Isochroman-1-yl)benzonitrile (3k). According to TP1, the reaction of isochroman
(67 mg, 0.5 mmol) with (4ꢀcyanophenyl)zinc reagent (7.1 mL, 0.21 M) afforded the
desired product 3k which was isolated by flash chromatography (eluent: ethyl acetate :
1
petroleum ether = 1:10) as a colorless oil (43 mg, 36%). H NMR (400 MHz, CDCl3)
δ (ppm) 7.64 (d, J = 8.3 Hz, 2 H), 7.43 (d, J = 8.3 Hz, 2 H), 7.23ꢀ7.15 (m, 2 H),
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7.12ꢀ7.05 (m, 1 H), 6.67 (d, J = 7.6 Hz, 1 H), 5.76 (s, 1 H), 4.17 (ddd, J = 11.2, 5.3,
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3.8 Hz, 1 H), 3.97ꢀ3.88 (m, 1 H), 3.19ꢀ3.08 (m, 1 H), 2.86ꢀ2.77 (m, 1 H); C NMR
(100 MHz, CDCl3) δ (ppm) 147.4, 135.9, 133.7, 132.3, 129.5, 129.1, 127.1, 126.5,
126.2, 118.7, 111.9, 78.8, 64.1, 28.6; IR (KBr) 3064, 2924, 2853, 2228, 1492, 1276,
1096 cmꢀ1; HRMS (ESI) Calcd. for C16H14NO [M + H]+ 236.1075, found 236.1064;
Rf 0.33 (petroleum ether/EtOAc, 10/1).
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1-(Thiophen-2-yl)isochroman (3l). According to TP1, the reaction of isochroman (67
mg, 0.5 mmol) with thiophenꢀ2ꢀylzinc reagent (6.0 mL, 0.25 M) afforded the desired
product 3l which was isolated by flash chromatography (eluent: ethyl acetate :
o
petroleum ether = 1:50) as a pale yellow solid (90 mg, 83%). mp: 51ꢀ53 C (ethyl
1
ether/petroleum ether); H NMR (400 MHz, CDCl3) δ (ppm) 7.22ꢀ7.19 (m, 1 H),
7.15ꢀ7.02 (m, 3 H), 6.92ꢀ6.85 (m, 3 H), 5.96 (s, 1 H), 4.04 (ddd, J = 11.4, 6.3, 5.0 Hz,
1 H), 3.84 (ddd, J = 11.4, 6.6, 4.9 Hz, 1 H), 2.92ꢀ2.77 (m, 2 H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 145.9, 136.3, 133.5, 128.8, 127.2, 126.9, 126.8, 126.2, 126.1, 125.8,
73.8, 62.3, 28.4; IR (KBr) 3138, 2961, 2873, 1603, 1491, 1401, 1284, 1108 cmꢀ1;
HRMS (ESI) Calcd. for C13H12NaOS [M + Na]+ 239.0507, found 239.0500; Rf 0.46
(petroleum ether/EtOAc, 20/1).
7-Methyl-1-(o-tolyl)isochroman (3m). According to TP1, the reaction of
7ꢀmethylisochroman (148 mg, 1 mmol) with 2ꢀmethylphenylzinc reagent (6.5 mL,
0.46 M) afforded the desired product 3m which was isolated by flash chromatography
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(eluent: ethyl acetate : petroleum ether = 1:50) as a colorless oil (148 mg, 62%). H
NMR (400 MHz, CDCl3) δ (ppm) 7.24ꢀ7.03 (m, 5 H), 6.99 (d, J = 7.8 Hz, 1 H), 6.51
(s, 1 H), 5.90 (s, 1 H), 4.18 (ddd, J = 11.4, 5.5, 3.9 Hz, 1 H), 3.90 (ddd, J = 11.4, 9.5,
3.9 Hz, 1 H), 3.15ꢀ3.05 (m, 1 H), 2.78 (dt, J = 16.2, 3.8 Hz, 1 H), 2.37 (s, 3 H), 2.19 (s,
3 H); 13C NMR (100 MHz, CDCl3) δ (ppm) 139.9, 137.3, 137.2, 135.5, 130.9, 130.8,
129.9, 128.5, 127.9, 127.4, 126.7, 125.7, 77.6, 64.1, 28.5, 21.1, 19.4; IR (KBr) 3018,
2958, 2854, 1503, 1461, 1272, 1195, 1091 cmꢀ1; HRMS (ESI) Calcd. for C17H19O [M
+ H]+ 239.1436, found 239.1430; Rf 0.56 (petroleum ether/EtOAc, 20/1).
7-Methoxy-1-(o-tolyl)isochroman (3n). According to TP1, the reaction of
7ꢀmethoxyisochroman (164 mg, 1 mmol) with 2ꢀmethylphenylzinc reagent (6.5 mL,
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0.46 M) afforded the desired product 3n which was isolated by flash chromatography
(eluent: ethyl acetate : petroleum ether = 1:20) as a colorless viscous oil (94 mg, 37%).
1H NMR (400 MHz, CDCl3) δ (ppm) 7.23ꢀ7.05 (m, 5 H), 6.75 (dd, J = 8.3, 2.2 Hz, 1
H), 6.23 (d, J = 2.5 Hz, 1 H), 5.88 (s, 1 H), 4.17 (ddd, J = 11.3, 5.4, 3.9 Hz, 1 H), 3.89
(ddd, J = 11.3, 9.5, 3.9 Hz, 1 H), 3.64 (s, 3 H), 3.11ꢀ3.01 (m, 1 H), 2.75 (dt, J = 15.9,
3.9 Hz, 1 H), 2.35 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ (ppm) 157.8, 139.7, 138.5,
137.3, 130.9, 129.9, 129.5, 128.0, 126.2, 125.7, 112.6, 111.4, 77.8, 64.2, 55.2, 27.9,
19.4; IR (KBr) 3003, 2943, 2293, 1503, 1444, 1376, 1196, 1133, 1077 cmꢀ1; HRMS
(ESI) Calcd. for C17H18NaO2 [M + Na]+ 277.1204, found 277.1197; Rf 0.37
(petroleum ether/EtOAc, 10/1).
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6,7-Dimethoxy-1-(o-tolyl)isochroman (3o). According to TP1, the reaction of
6,7ꢀdimethoxyisochroman (194 mg, 1 mmol) with 2ꢀmethylphenylzinc reagent (6.5
mL, 0.46 M) afforded the desired product 3o which was isolated by flash
chromatography (eluent: ethyl acetate : petroleum ether = 1:10) as a white solid (117
mg, 41%). mp: 71ꢀ73 oC (ethyl ether/petroleum ether); 1H NMR (400 MHz, CDCl3) δ
(ppm) 7.24ꢀ7.17 (m, 2 H), 7.15ꢀ7.09 (m, 1 H), 7.05 (d, J = 7.6 Hz, 1 H), 6.65 (s, 1 H),
6.19 (s, 1 H), 5.87 (s, 1 H), 4.12 (ddd, J = 11.3, 4.9, 4.8 Hz, 1 H), 3.88 (s, 3 H),
3.92ꢀ3.84 (m, 1 H), 3.64 (s, 3 H), 3.06ꢀ2.96 (m, 1 H), 2.75 (dt, J = 16.1, 4.3 Hz, 1 H),
2.38 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ (ppm) 147.8, 147.4, 139.7, 137.5, 130.9,
129.8, 129.1, 128.0, 126.2, 125.6, 111.3, 109.4, 77.2, 63.5, 55.9, 55.8, 28.3, 19.3; IR
(KBr) 2957, 2929, 2861, 1609, 1518, 1463, 1375, 1245, 1126, 1078 cmꢀ1; HRMS (ESI)
Calcd. for C18H21O3 [M + H]+ 285.1491, found 285.1482; Rf 0.39 (petroleum
ether/EtOAc, 5/1).
4-Methyl-1-(o-tolyl)isochroman (3p). According to TP1, the reaction of
4ꢀmethylisochroman (148 mg, 1 mmol) with 2ꢀmethylphenylzinc reagent (6.5 mL,
0.46 M) afforded the desired product 3p which was isolated by flash chromatography
(eluent: ethyl acetate : petroleum ether = 1:50) as a colorless oil (153 mg, 64%). 1H
NMR (400 MHz, CDCl3) δ (ppm) 7.31 (d, J = 7.8 Hz, 1 H), 7.24ꢀ7.16 (m, 3 H),
7.14ꢀ7.01 (m, 3 H), 6.69 (d, J = 7.8 Hz, 1 H), 5.96 (s, 1 H), 4.12 (dd, J = 11.3, 5.1 Hz,
1 H), 3.56 (dd, J = 11.3, 8.2 Hz, 1 H), 3.17 (ddd, J = 19.8, 7.1, 6.9 Hz, 1 H), 2.36 (s, 3
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H), 1.32 (d, J = 6.9 Hz, 3 H); C NMR (100 MHz, CDCl3) δ (ppm) 139.9, 139.3,
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137.3, 136.8, 130.9, 129.9, 128.0, 126.8, 126.7, 126.2, 125.8, 125.6, 77.9, 69.9, 31.8,
19.4, 17.7; IR (KBr) 3022, 2959, 2868, 1489, 1462, 1381, 1133, 1086 cmꢀ1; HRMS
(ESI) Calcd. for C17H19O [M + H]+ 239.1436, found 239.1430; Rf 0.60 (petroleum
ether/EtOAc, 20/1).
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7-Bromo-1-(o-tolyl)isochroman (3q). According to TP1, the reaction of
7ꢀbromoisochroman (213 mg, 1 mmol) with 2ꢀmethylphenylzinc reagent (6.5 mL,
0.46 M) afforded the desired product 3q which was isolated by flash chromatography
(eluent: ethyl acetate : petroleum ether = 1:50) as a colorless oil (220 mg, 72%). 1H
NMR (400 MHz, CDCl3) δ (ppm) 7.30 (dd, J = 8.3, 1.5 Hz, 1 H), 7.24ꢀ7.11 (m, 3 H),
7.09ꢀ7.01 (m, 2 H), 6.83 (d, J = 1.5 Hz, 1 H), 5.85 (s, 1 H), 4.18 (ddd, J = 11.4, 5.6,
3.7 Hz, 1 H), 3.89 (ddd, J = 11.4, 9.5, 4.0 Hz, 1 H), 3.12ꢀ3.01 (m, 1 H), 2.77 (ddd, J =
13
16.5, 3.8, 3.7 Hz, 1 H), 2.33 (s, 3 H); C NMR (100 MHz, CDCl3) δ (ppm) 139.7,
138.9, 137.2, 132.9, 131.1, 130.3, 129.9, 129.7, 129.1, 128.4, 125.9, 119.7, 77.4, 63.8,
28.3, 19.4; IR (KBr) 3019, 2925, 2853, 1593, 1482, 1266, 1175, 1090 cmꢀ1; HRMS
(ESI) Calcd. for C16H15BrNaO [M + Na]+ 325.0204, found 325.0194; Rf 0.43
(petroleum ether/EtOAc, 20/1).
5-Bromo-1-(o-tolyl)isochroman (3r). According to TP1, the reaction of
5ꢀbromoisochroman (213 mg, 1 mmol) with 2ꢀmethylphenylzinc reagent (6.5 mL,
0.46 M) afforded the desired product 3r which was isolated by flash chromatography
(eluent: ethyl acetate : petroleum ether = 1:50) as a white solid (187 mg, 62%). mp:
98ꢀ100 oC (ethyl ether/petroleum ether); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.44 (d,
J = 7.8 Hz, 1 H), 7.24ꢀ7.10 (m, 3 H), 7.05 (d, J = 7.3 Hz, 1 H), 6.94 (t, J = 7.8 Hz, 1
H), 6.66 (d, J = 7.8 Hz, 1 H), 5.87 (s, 1 H), 4.22 (ddd, J = 11.6, 5.8, 3.9 Hz, 1 H), 3.92
(ddd, J = 11.6, 9.2, 4.5 Hz, 1 H), 3.07ꢀ2.96 (m, 1 H), 2.88 (dt, J = 17.1, 4.0 Hz, 1 H),
2.33 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ (ppm) 140.2, 139.3, 137.3, 133.8, 131.0,
130.5, 129.9, 128.3, 127.2, 125.8, 125.5, 125.1, 77.6, 63.8, 29.6, 19.4; IR (KBr) 3068,
2984, 2921, 1559, 1490, 1443, 1380, 1315, 1256, 1172, 1095, 1053 cmꢀ1; HRMS (ESI)
Calcd. for C16H15BrNaO [M + Na]+ 325.0204, found 325.0196; Rf 0.54 (petroleum
ether/EtOAc, 20/1).
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7-Chloro-1-(o-tolyl)isochroman (3s). According to TP1, the reaction of
7ꢀchloroisochroman (169 mg, 1 mmol) with 2ꢀmethylphenylzinc reagent (6.5 mL,
0.46 M) afforded the desired product 3s which was isolated by flash chromatography
(eluent: ethyl acetate : petroleum ether = 1:50) as a colorless oil (168 mg, 65%). 1H
NMR (400 MHz, CDCl3) δ (ppm) 7.24ꢀ7.04 (m, 6 H), 6.68 (d, J = 1.7 Hz, 1 H), 5.85
(s, 1 H), 4.19 (ddd, J = 11.4, 5.6, 3.7 Hz, 1 H), 3.89 (ddd, J = 11.4, 9.6, 3.9 Hz, 1 H),
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3.14ꢀ3.04 (m, 1 H), 2.78 (dt, J = 16.5, 3.8, 1 H), 2.33 (s, 3 H); C NMR (100 MHz,
CDCl3) δ (ppm) 139.4, 139.0, 137.2, 132.4, 131.7, 131.1, 130.0, 129.8, 128.3, 126.8,
126.2, 125.9, 77.5, 63.9, 28.2, 19.4; IR (KBr) 3021, 2962, 2853, 1599, 1484, 1267,
1177, 1091 cmꢀ1; HRMS (ESI) Calcd. for C16H15ClNaO [M + Na]+ 281.0709, found
281.0701; Rf 0.41 (petroleum ether/EtOAc, 20/1).
1-(o-Tolyl)isothiochroman (3t). According to TP1, the reaction of isothiochroman
(150 mg, 1 mmol) with 2ꢀmethylphenylzinc reagent (6.5 mL, 0.46 M) afforded the
desired product 3t which was isolated by flash chromatography (eluent: ethyl acetate :
petroleum ether = 1:50) as a pale yellow oil (132 mg, 55%). 1H NMR (400 MHz,
CDCl3) δ (ppm) 7.23ꢀ7.11 (m, 4 H), 7.10ꢀ7.04 (m, 2 H), 6.84 (dd, J = 11.9, 7.7 Hz, 2
H), 5.33 (s, 1 H), 3.24 (ddd, J = 16.3, 5.1, 5.0 Hz, 1 H), 3.19ꢀ3.10 (m, 1 H), 2.93ꢀ2.83
13
(m, 2 H), 2.45 (s, 3 H); C NMR (100 MHz, CDCl3) δ (ppm) 140.8, 136.9, 136.8,
136.2, 130.7, 129.8, 129.2, 128.9, 126.9, 126.8, 126.1, 125.7, 42.4, 31.1, 24.3, 19.7;
IR (KBr) 2963, 2920, 2360, 1645, 1486, 1261, 1196, 1132 cmꢀ1; HRMS (ESI) Calcd.
for C16H17S [M + H]+ 241.1051, found 241.1046; Rf 0.62 (petroleum ether/EtOAc,
20/1).
9-(o-Tolyl)-9H-xanthene (3u). According to TP1, the reaction of 9Hꢀxanthene (182
mg, 1 mmol) with 2ꢀmethylphenylzinc reagent (6.5 mL, 0.46 M) afforded the desired
product 3u which was isolated by flash chromatography (eluent: ethyl acetate :
o
petroleum ether = 1:100) as a white solid (72 mg, 26%). mp: 129ꢀ131 C (ethyl
ether/petroleum ether); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.23ꢀ7.15 (m, 6 H), 7.10
(dd, J = 8.1, 1.2 Hz, 2 H), 6.93 (td, J = 7.4, 1.4 Hz, 2 H), 6.87 (d, J = 7.6 Hz, 2 H),
5.56 (s, 1 H), 2.22 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ (ppm) 150.9, 143.5, 135.9,
131.2, 131.1, 129.2, 127.8, 126.9, 126.4, 124.1, 123.1, 116.3, 41.3, 20.0; IR (KBr)
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3015, 2925, 1599, 1571, 1461, 1449, 1321, 1254, 1120, 1034 cmꢀ1; HRMS (ESI)
Calcd. for C20H16NaO [M + Na]+ 295.1099, found 295.1092; Rf 0.60 (petroleum
ether/EtOAc, 50/1).
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1-(Methoxy(4-methoxyphenyl)methyl)-2-methylbenzene (3v). According to TP1, the
reaction of 1ꢀmethoxyꢀ4ꢀ(methoxymethyl)benzene (76 mg, 0.5 mmol) with
2ꢀmethylphenylzinc reagent (3.3 mL, 0.46 M) afforded the desired product 3v which
was isolated by flash chromatography (eluent: ethyl acetate : petroleum ether = 1:20)
as a colorless oil (56 mg, 45%). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.44 (d, J = 7.3
Hz, 1 H), 7.24ꢀ7.10 (m, 5 H), 6.84 (d, J = 8.8 Hz, 2 H), 5.35 (s, 1 H), 3.78 (s, 3 H),
3.36 (s, 3 H), 2.23 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ (ppm) 158.9, 139.8, 135.8,
133.1, 130.5, 128.9, 127.3, 126.5, 125.9, 113.7, 82.2, 56.9, 55.2, 19.3; IR (KBr) 2931,
2835, 1610, 1510, 1461, 1303, 1247, 1172, 1096 cmꢀ1; HRMS (ESI) Calcd. for
C16H18NaO2 [M + Na]+ 265.1204, found 265.1196; Rf 0.65 (petroleum ether/EtOAc,
10/1).
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1-((4-Bromophenyl)(methoxy)methyl)-2-methylbenzene (3w). According to TP1, the
reaction of 1ꢀbromoꢀ4ꢀ(methoxymethyl)benzene (201 mg, 1 mmol) with
2ꢀmethylphenylzinc reagent (6.5 mL, 0.46 M) afforded the desired product 3w which
was isolated by flash chromatography (eluent: ethyl acetate : petroleum ether = 1:80)
1
as a colorless oil (149 mg, 51%). H NMR (400 MHz, CDCl3) δ (ppm) 7.35 (d, J =
8.6 Hz, 2 H), 7.31ꢀ7.26 (m, 1 H), 7.16ꢀ7.03 (m, 5 H), 5.27 (s, 1 H), 3.28 (s, 3 H), 2.16
(s, 3 H); 13C NMR (100 MHz, CDCl3) δ (ppm) 140.1, 138.9, 135.9, 131.4, 130.7,
129.1, 127.7, 126.9, 126.1, 121.3, 82.0, 57.0, 19.4; IR (KBr) 2935, 2822, 1660, 1588,
1484, 1396, 1281, 1092 cmꢀ1; HRMS (ESI) Calcd. for C15H15BrNaO [M + Na]+
313.0204, found 313.0193; Rf 0.38 (petroleum ether/EtOAc, 50/1).
Methyl(phenyl(o-tolyl)methyl)sulfane (3x). According to TP1, the reaction of benzyl
methyl sulfide (138 mg, 1 mmol) with 2ꢀmethylphenylzinc reagent (6.5 mL, 0.46 M)
afforded the desired product 3x which was isolated by flash chromatography (eluent:
1
ethyl acetate : petroleum ether = 1:100) as a colorless oil (96 mg, 42%). H NMR
(400 MHz, CDCl3) δ (ppm) 7.58 (d, J = 7.6 Hz, 1 H), 7.39ꢀ7.26 (m, 4 H), 7.24ꢀ7.11
13
(m, 4 H), 5.24 (s, 1 H), 2.33 (s, 3 H), 2.00 (s, 3 H); C NMR (100 MHz, CDCl3) δ
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(ppm) 140.6, 138.9, 136.1, 130.5, 128.6, 128.4, 128.1, 127.0, 126.9, 126.2, 52.4, 19.6,
16.1; IR (KBr) 2953, 2852, 1491, 1451, 1261, 1133, 1076 cmꢀ1; HRMS (ESI) Calcd.
for C15H16NaS [M + Na]+ 251.0870, found 251.0864; Rf 0.55 (petroleum ether/EtOAc,
50/1).
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6-Bromo-2-(o-tolyl)-2H-chromene (3y). According to TP1, the reaction of
6ꢀbromoꢀ2Hꢀchromene (105 mg, 0.5 mmol) with 2ꢀmethylphenylzinc reagent (3.3 mL,
0.46 M) afforded the desired product 3y which was isolated by flash chromatography
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(eluent: ethyl acetate : petroleum ether = 1:100) as a colorless oil (102 mg, 68%). H
NMR (400 MHz, CDCl3) δ (ppm) 7.41 (d, J = 7.3 Hz, 1 H), 7.24ꢀ7.10 (m, 5 H), 6.62
(d, J = 8.6 Hz, 1 H), 6.49 (dd, J = 9.8, 1.9 Hz, 1 H), 6.16ꢀ6.12 (m, 1 H), 5.79 (dd, J =
13
9.8, 3.3 Hz, 1 H), 2.45 (s, 3 H); C NMR (100 MHz, CDCl3) δ (ppm) 152.4, 137.7,
136.0, 131.9, 130.9, 129.0, 128.5, 127.7, 126.2, 125.6, 123.5, 123.2, 117.7, 113.0,
74.8, 19.2; IR (KBr) 3018, 2927, 2861, 1494, 1452, 1403, 1059 cmꢀ1; HRMS (ESI)
Calcd. for C16H13BrNaO [M + Na]+ 323.0047, found 323.0036; Rf 0.58 (petroleum
ether/EtOAc, 50/1).
ASSOCIATED CONTENT
Supporting Information
1H NMR and 13C NMR spectra of compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: zpech@upc.edu.cn.
ORCID
0000ꢀ0001ꢀ6971ꢀ4456
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank the Shandong Provincial Natural Science Foundation (ZR2012BQ006), and
the National Natural Science Foundation of China (21202205) the Fundamental
Research Funds for the Central Universities (17CX02069) for financial support.
REFERENCES
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