Regioselective Chlorolactonization of Styrene-Type Carboxylic Esters and Amides via PhICl2-Mediated Oxidative C-O/C-Cl Bond Formations

Article abstract of DOI:10.1021/acs.joc.9b02022

A facile method employing styrene-type carboxylic esters or amides in the presence of PhICl₂ in CH₃CN was developed to achieve the synthesis of 6-endo products 3,4-dihydroisocoumarins or 3,4-dihydroisocoumarin-1-imines in good to hig

Full text of DOI:10.1021/acs.joc.9b02022

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Article
Regioselective Chlorolactonization of Styrene-type Carboxylic Esters
and Amides via PhICl2-Mediated Oxidative C-O/C-Cl Bond Formations
Linlin Xing, Yong Zhang, Yilin Zhang, Zhenkang Ai, Xuemin Li, Yunfei Du, Jun Deng, and Kang Zhao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02022 • Publication Date (Web): 16 Sep 2019
Downloaded from pubs.acs.org on September 18, 2019
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Regioselective Chlorolactonization of Styrene-type
Carboxylic Esters and Amides via PhICl2-Mediated
Oxidative C-O/C-Cl Bond Formations
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Linlin Xing,† Yong Zhang,† Yilin Zhang,‡ Zhenkang Ai,† Xuemin Li,†
Yunfei Du,†, * Jun Deng,§, * and Kang Zhao†
† Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical
Science and Technology, Tianjin University, Tianjin 300072, China
‡C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, West
Virginia 26506-6045, United States
§Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of
Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China
Tel: +86-22-27406121; +86-23-65678460; duyunfeier@tju.edu.cn; jdeng@cqu.edu.cn
O
high regioselectivities
mild conditions
simple procedure
O
Z = OMe
-20 oC to 0 oC
R1
R2
O
Cl
N
PhICl2, CH3CN
Z
R1
OMe
R2
Z = NHOMe
O
R1
-20 oC
R2
R1 = H, F, Cl, Me, CF3, NO2, styryl
R2 = aryl, alkyl
Cl
31 examples
up to 90% yield
Abstract
A facile method employing styrene-type carboxylic esters or amides in the presence of PhICl2
in CH3CN was developed to achieve the synthesis of 6-endo products 3,4-dihydroisocoumarins or
3,4-dihydroisocoumarin-1-imines in good to high yields. This metal-free regioselective
intramolecular chlorolactonization process was proposed to involve a PhICl2-mediated oxidative
C-O bond formation followed by C-Cl bond formation.
Introduction
Difunctionalization of alkenes represents one of the most important reactions in organic
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chemistry as well as an effective and straightforward strategy for the construction of
functionalized compounds.1-11 In particular, intramolecular halolactonization of alkenes, which
gives rise to a halogenated heterocyclic framework with up to two stereogenic centers and a useful
functional group, has played a vital role in organic transformations.12-18 Specifically, the
halocyclization of styrene-type carboxylic esters is a highly efficient and robust tool towards the
synthesis of the halogenated 3,4-dihydroisocoumarin derivatives. Accordingly, many synthetic
methods have been developed for the halocyclization of styrene-type carboxylic
esters/acids.12-14,19-31 However, an inherent challenge is the poor regioselectivity due to the fact
that the halocyclization can go through either the 5-exo or the 6-endo pathway.25 Furthermore, in
case of the 6-endo pathway, 3,4-dihydroisocoumarin derivatives were generated as a mixture of
both trans and cis-isomers. On the other hand, organic chemists have shown growing interests
toward the construction of chlorinated natural products, further highlighting the need of alternative
methods to introduce chlorine atom into complex molecules.32.33 Although bromolactonization of
styrene-type olefinic acids has been well established in recent years,26-30 chlorolactonization
strategy was less explored, potentially because of the lack of efficient chlorinating agent to control
the selectivity during chlorolactonization step. A few examples of chlorolactonization have been
reported so far, with 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) being the only chlorinating
reagent that is most commonly used.19-24 For instance, Wang and coworkers reported treating
styrylbenzoic acid with DCDMH in the presence of DABCO afforded chlorinated
3,4-dihydroisocourmarin product in a yield of 58%.20 Besides, the regioselectivity of the
DCDMH-mediated chlorolactonization process was believed to be highly related to the
substitution pattern on the alkene motif of the starting materials and poor regioselectivity was
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commonly seen.19,23 Zhou and coworkers found that both 6-endo/5-exo products were obtained
when carboxylic acids underwent chlorolactonization using DCDMH as a chlorine source and the
substituents on the substrate played a significant role in the process.19 Furthermore, Xia and
coauthors reported the ruthenium catalyzed, visible-light-promoted reaction of electron-enriched
styrene-type carboxylic acid with 2,6-lutidine•HCl leading to the formation of the chlorinated
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3,4-dihydroisocoumarin in high yields.34 In these regards,
chlorolactonization approach should still be desired.
a
novel regioselective
Scheme 1. ArICl2-Mediated Chlorofunctionalization Reactions of Olefinic Compounds
a) Yusubov's work
R1
Cl
I
Ph
Cl
PhICl2, I2
DCM
MeOH
PhICl2
Ph
R1
R2
Ph
MeO
R2
b) Nicolaou's work
Cl
(DHQ)2PHAL
Ar
OH
Ar
OH
p-Ph(C6H4)ICl2
Cl
+
DCM, -78 o
C
c) Sanford's work
Cl
Ph-SnBu3
Ph
Ph
R
R
PdCl2(PhCN)2
PhICl2
R
Cl
d) Our previous work
PhICl2
wet DMF, rt
OCHO
R2
R2
R1
R1
Cl
This work
e)
OMe
O
O
O
N
PhICl2, MeCN
-20 oC/-20-0 oC
Z
O
R1
or
R1
R1
R2
R2
R2
Cl
Z = OMe, NHOMe
Cl
Since first obtained in 1886, (dichloroiodo)arenes35 have found wide practical applications in
organic synthesis due to their ease of handling, nontoxicity, environmental benign properties and
easy accessibility from a convenient preparation. Now they have been widely used as surrogates
of gaseous chlorine and found broad synthetic utility in both chlorination and oxidation
processes.36-39 Specifically, several efficient strategies that employed PhICl2 to realize the
difunctionalization of alkenes with the introduction of at least one chlorine atom were
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developed.40-45 For examples, Yusubov group reported their application of PhICl2, in combination
with MeOH or I2 to achieve the chloromethoxylation, or iodochlorination of alkenes in good yields
(Scheme 1, Method a).44 Nicolaou and co-workers reported an enantioselective dichlorination of
allylic alcohols by using aryl iododichlorides as chlorine sources in the presence of (DHQ)2PHAL
(Scheme 1, Method b).42 In addition, using PhICl2 as a chlorinating reagent, Sanford and
co-workers developed a Pd-catalyzed arylchlorination strategy for diverse alkenes, resulting in
synthesis of the synthetically useful 1,2- and 1,1-arylhalogenated products in good yields and
good to excellent selectivities (Scheme 1, Method c).43 Previously, our group also found PhICl2 in
wet DMF constructed an efficient system for the regioselective chloroformyloxylation of alkenes
(Scheme 1, Method d).41 In this communication, we report the chlorolactonization of styrene-type
carboxylic esters and amides through the reaction of PhICl2 with alkene, generating
3,4-dihydroisocoumarins or 3,4-dihydroisocoumarin-1-imines in a highly regioselective manner.
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Results and discussion
Table 1. Optimization of Reaction Conditionsa
O
O
O
oxidant, solvent
temperature
OMe
Ph
Ph
Cl
2a
1a
Entry
Oxidant (1.2 equiv)
PhICl2
Solvent
Temperature (oC)
rt
Yield(%)
1
2
CH3CN
DCE
60
15
PhICl2
PhICl2
PhICl2
PhICl2
PhICl2
PhICl2
PhICl2
PhICl2
rt
rt
3
4
5
6
7
8
9
EtOAc
THF
20
18
rt
rt
CHCl3
DMF
35
ND
ND
ND
80
rt
rt
toluene
dioxane
CH3CN
rt
0
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PhICl2
PhICl2
CH3CN
CH3CN
-10-0
-20-0
86
90
6
7
aReaction conditions: 1a (0.5 mmol) and PhICl2 (0.6 mmol) in solvent (10 mL).
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We initiated our study on the model reaction of o-styrylbenzoate 1a with PhICl2 under a variety
of reaction conditions (Table 1). To our delight, when styrene 1a was treated with 1.2 equiv of
PhICl2 in acetonitrile at room temperature, the reaction regioselectively delivered the 6-endo
3,4-dihydroisocoumarin with trans isomer only as the major product and dichlorinated benzoate
ester as the minor product within 15 min (Table 1, entry 1). Next, a series of solvents were
screened in order to improve the outcome of the reaction. However, inferior results were obtained
when the reaction was performed in DCE, EtOAc, THF and CHCl3 (Table 1, entries 2-5), whereas
DMF, toluene and dioxane were proved to be entirely ineffective for this reaction (Table 1, entries
6-8). Surprisingly, by lowering the reaction temperature to 0 or -10 °C for 1 h and then keeping at
0 °C for another 3 h, the yield of the desired 6-endo product was improved to 86% (Table 1,
entries 9-10). Further decreasing the reaction temperature to -20 °C proved to be more effective as
the 6-endo product could be achieved in a 90% yield with high selectivity (Table 1, entry 11).
Thus, the most optimal reaction conditions were determined to be: 1.0 equiv of o-styrylbenzoate
1a, and 1.2 equiv of PhICl2 in CH3CN from -20 °C to 0 °C (Table 1, entry 11).
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Scheme 2. PhICl2-Mediated Chlorocyclization of Methyl o-Styrylbenzoatea
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O
O
PhICl2, CH3CN
-20 - 0 oC
O
R1
OMe
R1
O
R2
O
R2
Cl
2
1
O
O2N
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O
O
O
Cl
Cl
Cl
2b
, 65%
2c
2f
, 71%
2a
, 90%
O
O
O
F3C
O2N
Cl
O
O
O
Cl
Cl
Cl
2d
2e
, 82%
, 72%
, 68%
Ph
O
O
O
O
O
O
Cl
Cl
, 75%
Cl
2g
2h
, 75%
2i
2l
, 63%
Ph
O
O
O
O
Cl
O
O
F
Cl
Cl
, 72%
Cl
, 65%
2j
, 63%
2k
O
O
O
O
O
O
Cl
Cl
Cl
Cl
2o
Cl
, 77%
2m
, 88%
2n
, 75%
O
O
O
O
O
O
R
S
Cl
Cl
, 85%
Cl
i
2r
R = Pr, , 60%
2s
R =cyclopropyl, , 45%
2p
2q
, 42%
aReaction conditions: 1 (1.0 mmol) and PhICl2 (1.2 mmol) in CH3CN (20 mL) at -20 °C to 0 °C
for 4 h.
Having identified the optimal conditions, we next explored the scope and limitations of the
method by subjecting various o-styrylbenzoate derivatives to the chlorolactonization process, with
the results summarized in Scheme 2. Both R1 substituent on benzoate ester moiety and R2
substituent on alkene moiety were examined. As we can see, almost all the reactions gave rise to
the 6-endo trans-3,4-dihydroisocoumarins 2 selectively, regardless of the nature and position of
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the substituent. For instance, substrates bearing either electron-rich (1b) or electron-deficient R1
substituents (1c-f) consistently exhibited high efficiency towards desired products 2b–f. Sterically
hindered ortho substituents did not inhibit the reaction, and indeed 3,4-dihydroisocoumarins 2g–i
were obtained successfully and exclusively. Differing from other substrates, substrate 1g, in which
a methyl group is substituted adjacent to the styryl group, delivered 3,4-dihydroisocoumarin 2g in
cis conformation selectively. In addition, for substrates 1j and 1k bearing two substituents on the
benzoic acid moiety, the desired 6-endo products were also formed as the only products. Then a
series of substrates 1l–p with different aryl R2 substituent including p-tolyl, o/m/p-chlorophenyl
and 2-naphthyl groups were subjected to the standard conditions and the corresponding cyclization
products 2l–p were achieved in 72-88% yield. However, substrate 1q with a 2-thienyl R2
substituent gave a mixture of cis and trans products with the trans isomer as a major product.
Furthermore, the chlorolactonization approach could be further extended to the synthesis of
3-alkyl-substituded products including 3-iso-propyl 4-chloroisochroman-1-one 2r and
3-cyclopropyl 4-chloroisochroman-1-one 2s. When substrate 1s was employed, in addition to the
major product 2s, a small amount of cis product was also isolated, While for substrate 1r, the
reaction gave rise to the cis isomer. The lower yields of some substrates such as 1b compared with
1a may be attributed to the formation of some unidentified byproducts. 3,4-Dihydroisocoumarin
2e was subjected to X-ray crystal diffraction and the result demonstrated the relative configuration
of product 2 (see SI for detail).
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Scheme 3. PhICl2-Mediated Chlorocyclization of Methoxy o-Styrylbenzamidea
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OMe
N
O
PhICl2, CH3CN
O
NHOMe
R1
R2
R1
-20 oC
R2
Cl
4
3
9
OMe
OMe
O
OMe
N
N
N
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O2N
F3C
O
O
Cl
Cl
Cl
4c
, 81%
4a
, 89%
4b
, 70%
OMe
OMe
OMe
N
N
N
Cl
O
O
O
Cl
Cl
Cl
4f
4d
, 69%
4e
, 71%
, 56%
OMe
OMe
OMe
N
N
N
O
Cl
O
O
Cl
Cl
Cl
Cl
4i
Cl
4g
, 81%
4h
, 75%
, 85%
OMe
OMe
OMe
N
N
N
O
O
O
Cl
Cl
Cl
OMe
4l
, 84%
4k
, 63%
4j
, 87%
aReaction conditions: 1 (1.0 mmol) and PhICl2 (1.2 mmol) in CH3CN (20 mL) at -20 °C for 24 h.
Regarding to whether the ester moiety was indispensable for the transformation, we replaced
the ester substituent in the substrate with an N-methoxy amide group (Scheme 3). A series of
styrene-type carboxylic amides with a variety of substituent on either benzoate or alkene moieties
were prepared and subjected to the standard conditions. To our delight, these substrates all
rendered good reactivity and fulfilled regioselective synthesis of the 6-endo products. For instance,
when 2-alkenylbenzoates 3b-f, with an electron-withdrawing group of NO2, CF3 and Cl or an
electron-donating group Me or di-Me attached to the benzoate moiety, were used as the substrates,
products 4b-f were obtained with moderate to good yields (56-81%). While for substrate 3f, the
cyclization reaction led to a mixture of dihydroisocoumarinimine 4f and dihydroisoquinolinone
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4f’. In addition, substrates bearing different aryl functional groups attached to the double bond of
2-(2-alkenyl)benzoates 3 worked equally well under the optimized conditions. The substrates
bearing p-tolyl, o/m/p-chlorophenyl, p-methoxyphenyl and 2-naphthyl groups were all compatible
with the chlorolactonization process, leading to products 4g–l in 63-87% yields. Furthermore, an
X-ray analysis of 4b was performed to corroborate the stereochemistry of 4 (see SI for detail).
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Scheme 4. Explorations on Methoxy Benzoate and Non-Benzoate Substrates
OMe
OMe
CO2Me
CO2Me
PhICl2, CH3CN
rt, 30 min
eq 1
MeO
Ph
MeO
MeO
Ph
Cl
5
, 92%
1s
MeO
PhICl2, CH3CN
MeO
CO2Me
Cl
Cl
+
rt, 30 min
Ph
Ph
Ph
eq 2
eq 3
MeO2C
Cl
, 20%
MeO2C
Cl
1t
7
6a
6b
, 28%
Ph
PhICl2, CH3CN
rt, 3 h
CO2Me
CO2Me
Ph
CO2Me
Ph
+
Cl
Cl
8b
, 8%
8a
, 11%
PhICl2, CH3CN
OH
Ph
O
eq 4
-20 C, 5 h
Ph
Cl
, 55%
9
10
In order to gain further insights into the reaction mechanism, we carried out further exploration
on the substrates scope. When dimethoxybenzoate substrate 1s was used, it was selectively
chlorinated at the phenyl ring which has a high electron density due to contribution of the two
strong electron-donating methoxy groups (Scheme 4, eq 1). Substrate 1t with the MeO substituent
at para-position of the alkene moiety gave a mixture of both trans and cis-dichlorinated products
instead of the cyclized 3,4-dihydroisocoumarin (Scheme 4, eq 2). Further investigation of the
non-benzoate substrate 7 showed that monochlorination on the double bond of the linear olefin
can be observed in low yields and most of the starting material was decomposed to some
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unidentified byproducts, which emphasized the neighboring-group-participation effect exerted by
the ester or amide group in substrate 1 and 3 (Scheme 4, eq 3). Besides, styrene-type benzylic
alcohol 9 was also examined and the reaction furnished the desired chlorinated cyclization product
in a yield of 55% (Scheme 4, eq 4).
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Scheme 5. Further Investigations on Chlorination Process
O
O
O
oxidant, CH3CN
OMe
Ph
eq 1
rt to 60 C, 6 h
Ph
Cl
2a
1a
1) DCDMH
2) NCS
52%
NR
3) NCP
NR
O
PhICl2 (1.2 equiv)
MeCN (5 mL)
OEt
eq 2
eq 3
2a
Ph
-20 to 0 C, 4 h
1u
89%
O
PhICl2 (1.2 equiv)
MeCN (5 mL)
OBn
Ph
BnCl
65%
2a
+
-20 to 0 C, 4 h
83%
1v
To further understand the role of PhICl2 played in the cyclization process, other chlorinating
reagents were tested (Scheme 5, eq 1). When substrate 1a was treated with NCS or NCP in
CH3CN at rt to 60 ̊C, the reaction did not happen in both cases. When DMDCH was applied, the
reaction gave the desired 3,4-dihydroisocoumarin 2a in 52% yield and almost half of substrate 1a
was not consumed. These experimental results might indicate that these chlorinating reagents were
not “reactive” enough to promote/complete the selective chlorolactonization, while PhICl2 might
be an “appropriate” chlorinating reagent which enables the cyclization reaction to occur at low
temperature in good selectivity and high yield. With these regards, we tentatively propose that the
high efficiency of this halolactonization process might be attributed to an accumulative effect of
reaction conditions (low temperature), substrate type (benzoates) and oxidant (PhICl2).
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Besides, ethyl and benzyl ortho-alkenylbenzoates were prepared and subjected to the standard
conditions (Scheme 5, eq 2 & 3). To our delight, both of them were compatible with the method,
delivering the desired product 2a in 89% and 83% yields, respectively. It is noteworthy that for the
reaction of benzyl ortho-alkenylbenzoates, the formation of BnCl was detected by GCMS.
Scheme 6. Proposed Mechanism
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Cl
Ph
I
Ph
OMe
PhICl2
Ph
O
O
I
1a
OMe
A
Ph
Cl
Ph
I
Cl
Ph
Ph
- PhI
- MeCl
2a
reductive
elimination
O
O
Cl
O
O
C
Me
B
Based on the previous report,46 a plausible reaction pathway is proposed in Scheme 6. The
alkene C=C bond in substrate 1a first reacted with PhICl2 to give the cyclic iodonium intermediate
A. Next, upon the intermolecular nucleophilic attack of the ester group, a C-I bond was formed on
the back side of the newly formed ring to give the oxonium ion B, with the release of the chloride
anion. Subsequently, nucleophilic attack of chloride on B resulted in the removal of the methyl
group and led to the formation of intermediate C. Finally, reductive elimination of PhI from C
delivered the final product.
Scheme 7. Further Derivatization of 3,4-Dihydroisocoumarin 2a
O
O
O
K2CO3, PhSH
O
O
DBU, toluene
80 C, 75%
O
CH CN, rt, 78%
Ph
3
Ph
Ph
Cl
SPh
11a
12a
2a
It is worth noting that the obtained 3,4-dihydroisocoumarin 2a could be conveniently converted
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into phenylthiodihydroisocoumarin 11a25 and isocoumarin 12a.47 Treating 2a with PhSH and
K2CO3 in CH3CN conveniently delivered the phenylthio substituted product in 78% yield. And the
reaction of 2a with DBU was found to undergo elimination pathway, affording product 12a in a
yield of 75% (Scheme 7).
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In conclusion, a simple and regioselective strategy has been developed to perform
chlorolactonization from the more convenient styrene-type carboxylic ester in place of the
commonly used acid, eliminating the need of saponification. Using (dichloroiodo)arenes as both
oxidant and chlorinating reagent, this chlorolactonization method allows the regioselective
synthesis of 3,4-dihydroisocoumarin derivatives in a single-step C-O/C-Cl bond formation under
metal-free conditions. In addition, the methoxy amide derivatives were also compatible to this
reaction providing chlorinated 3,4-dihydroisocoumarin-1-imines in good to high yields.
Experimental Section
General Information 1H and 13C NMR spectra were recorded on a 600 or 400 MHz spectrometer
at 25 °C. Chemical shifts values are given in ppm and referred as the internal standard to TMS:
0.00 ppm. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t =
triplet, q = quartet, br = broad, m = multiplet). The coupling constants J, are reported in Hertz
(Hz). High resolution mass spectrometry (HRMS) was obtained on a Q-TOF micro spectrometer.
Melting points were determined with a Micromelting point apparatus. TLC plates were visualized
by exposure to ultraviolet light.
Reagents and solvents were purchased as reagent grade and were used without further
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purification. The starting materials 1a-v,48-50 3a-l,51 752 and PhICl2 were prepared according to
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literature methods. Flash column chromatography was performed over silica gel (200-300 m)
using a mixture of ethyl acetate (EtOAc) and petroleum ether (PE).
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General Procedure for the Halocyclization Process Using Styrene-type Carboxylic Esters as
Substrates54
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To a solution of substrate 1 (1.0 mmol) in MeCN (20 mL) was added PhICl2 (329.9 mg, 1.2
mmol) at -20 °C. Then the mixture was stirred at -20 °C for 1 h and then warmed to 0 °C slowly
and stirred for another 3 h in dark to prevent the potential side radical reaction of PhICl2 with
solvent (monitored by TLC). After the complete consumption of the substrate, the resulting
mixture was purified by flash chromatography to afford the corresponding
4-chloro-3,4-dihydroisocoumarins 2 or chlorinated product 5, 6 and 8.
General Procedure for the Halocyclization Process Using Styrene-type Carboxylic Amides as
Substrates
To a solution of substrate 3 (1.0 mmol) in MeCN (20 mL) was added PhICl2 (329.9 mg, 1.2
mmol) at -20 °C. Then the mixture was stirred at -20 °C for 24 h in dark to prevent the potential
side radical reaction of PhICl2 with solvent (monitored by TLC). After the complete consumption
of the substrate, the resulting mixture was purified by flash chromatography to afford the
corresponding 3,4-dihydroisocoumarin-1-imines 4.
(+/−)-trans-4-Chloro-3-phenylisochroman-1-one (2a).20 Following the general procedure, 2a
was purified by silica gel chromatography (5% EtOAc/PE). Yield: 232 mg, 90%, a white solid,
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mp. 98–99 C. H NMR (600 MHz, CDCl3) δ 8.18 (d, J = 7.8 Hz, 1H), 7.66 (td, J = 7.6, 1.3 Hz,
1H), 7.59 (d, J = 7.7 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.42 – 7.33 (m, 5H), 5.69 (d, J = 6.9 Hz,
1H), 5.39 (d, J = 6.9 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 163.4, 137.7, 135.8, 134.7,
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130.5, 129.8, 129.3, 128.8, 127.6, 127.0, 124.0, 84.1, 56.3.
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(+/−)-trans-4-Chloro-7-methyl-3-phenylisochroman-1-one (2b). Following the general
procedure, 2b was purified by silica gel chromatography (5% EtOAc/PE). Yield: 177 mg, 65%, a
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white solid, mp. 148–149 C. H NMR (600 MHz, CDCl3) δ 7.98 (s, 1H), 7.52 – 7.38 (m, 2H),
7.38 – 7.31 (m, 5H), 5.69 (d, J = 6.4 Hz, 1H), 5.36 (d, J = 6.4 Hz, 1H), 2.42 (s, 3H). 13C{1H}
NMR (151 MHz, CDCl3) δ 140.1, 136.0, 135.5, 134.8, 130.7, 129.2, 128.7, 127.6, 126.9, 123.8,
84.2, 56.3, 21.2. HRMS (ESI) calcd for C16H1335ClO2Na [M + Na]+ 295.0496, found 295.0493.
(+/−)-trans-4-Chloro-7-nitro-3-phenylisochroman-1-one (2c).55 Following the general
procedure, 2c was purified by silica gel chromatography (5% EtOAc/PE). Yield: 215 mg, 71%, a
white solid, mp. 176–178 oC. 1H NMR (600 MHz, CDCl3) δ 8.97 (d, J = 2.2 Hz, 1H), 8.47 (dd, J =
8.5, 2.3 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.57 – 7.32 (m, 5H), 5.72 (d, J = 7.1 Hz, 1H), 5.46 (d, J
= 7.1 Hz, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 161.3, 148.6, 143.7, 134.8, 129.7, 129.4,
129.0, 128.8, 126.9, 125.6, 125.6, 83.9, 55.2.
(+/−)-trans-4-Chloro-7-nitro-3-(p-tolyl)isochroman-1-one (2d). Following the general
procedure, 2d was purified by silica gel chromatography (5% EtOAc/PE). Yield: 228 mg, 72%, a
white solid, mp. 184–185 oC. 1H NMR (600 MHz, CDCl3) δ 8.97 (d, J = 1.7 Hz, 1H), 8.47 (dd, J =
8.5, 1.9 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.36 – 7.07 (m, 4H), 5.70 (d, J = 7.0 Hz, 1H), 5.44 (d, J
= 7.0 Hz, 1H), 2.35 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 161.5, 148.6, 143.8, 139.8, 131.9,
129.7, 129.4, 128.8, 126.8, 125.7, 125.6, 83.8, 55.2, 21.2. HRMS (ESI) calcd for
C16H1235ClNO4Na [M + Na]+ 340.0347, found 340.0350.
(+/−)-trans-4-Chloro-3-phenyl-7-(trifluoromethyl)isochroman-1-one (2e). Following the
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general procedure, 2e was purified by silica gel chromatography (5% EtOAc/PE). Yield: 267 mg,
82%, a white solid, mp. 135–136 oC. 1H NMR (600 MHz, CDCl3) δ 8.45 (s, 1H), 7.90 (dd, J = 8.1,
1.5 Hz, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.46 – 7.34 (m, 5H), 5.69 (d, J = 7.2 Hz, 1H), 5.42 (d, J =
7.2 Hz, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 162.1, 141.3, 135.2, 132.3 (q, J = 33.8 Hz),
131.1 (q, J = 3.5 Hz), 129.5, 128.9, 128.6, 127.5 (q, J = 3.8 Hz), 127.0, 124.9, 123.1 (q, J = 272.8
Hz), 84.0, 55.5. HRMS (ESI) calcd for C16H1035ClF3O2Na [M + Na]+ 349.0214, found 349.0223.
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(+/−)-trans-4,7-Dichloro-3-phenylisochroman-1-one (2f). Following the general procedure, 2f
was purified by silica gel chromatography (5% EtOAc/PE). Yield: 199 mg, 68%, a white solid,
mp. 176–177 oC. 1H NMR (600 MHz, CDCl3) δ 8.15 (d, J = 2.2 Hz, 1H), 7.61 (dd, J = 8.3, 2.2 Hz,
1H), 7.53 (d, J = 8.3 Hz, 1H), 7.41 – 7.36 (m, 3H), 7.36 – 7.33 (m, 2H), 5.70 (d, J = 6.7 Hz, 1H),
5.36 (d, J = 6.7 Hz, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 162.2, 136.1, 136.0, 135.4, 134.8,
130.3, 129.4, 129.3, 128.9, 126.9, 125.5, 84.1, 55.6. HRMS (ESI) calcd for C15H1035Cl2O2Na [M +
Na]+ 314.9950, found 314.9948.
(+/−)-cis-4-Chloro-5-methyl-3-phenylisochroman-1-one (2g). Following the general procedure,
2g was purified by silica gel chromatography (5% EtOAc/PE). Yield: 204 mg, 75%, a white solid,
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mp. 148–150 C. H NMR (600 MHz, CDCl3) δ 8.03 (d, J = 7.2 Hz, 1H), 7.43 – 7.33 (m, 2H),
7.30 – 7.22 (m, 3H), 7.16 (dd, J = 7.7, 1.3 Hz, 2H), 6.06 (s, 1H), 5.52 (d, J = 1.2 Hz, 1H), 2.39 (s,
3H). 13C{1H} NMR (151 MHz, CDCl3) δ 163.3, 136.5, 136.3, 136.2, 134.6, 129.8, 129.0, 128.7,
128.3, 125.6, 124.7, 83.5, 52.8, 17.9. HRMS (ESI) calcd for C16H1335ClO2Na [M + Na]+ 295.0496,
found 295.0489.
(+/−)-trans-4-Chloro-8-methyl-3-phenylisochroman-1-one (2h). Following the general
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procedure, 2h was purified by silica gel chromatography (5% EtOAc/PE). Yield: 204 mg, 75%, a
white solid, mp. 142–143 oC. 1H NMR (600 MHz, CDCl3) δ 7.47 (t, J = 7.7 Hz, 1H), 7.38 (d, J =
7.6 Hz, 1H), 7.37 – 7.29 (m, 6H), 5.65 (d, J = 6.2 Hz, 1H), 5.34 (d, J = 6.2 Hz, 1H), 2.74 (s, 3H).
13C{1H} NMR (151 MHz, CDCl3) δ 162.5, 143.4, 138.5, 136.0, 133.5, 133.2, 129.0, 128.7, 126.8,
125.5, 122.5, 83.3, 57.3, 22.3. HRMS (ESI) calcd for C16H1335ClO2Na [M + Na]+ 295.0496, found
295.0499.
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(+/−)-trans-4-Chloro-3-phenyl-8-((E)-styryl)isochroman-1-one (2i). Following the general
procedure, 2i was purified by silica gel chromatography (5% EtOAc/PE). Yield: 227 mg, 63%, a
white solid, mp. 148–150 oC. 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 16.2 Hz, 1H), 7.78 (d, J =
7.9 Hz, 1H), 7.57 (dd, J = 14.1, 7.4 Hz, 3H), 7.44 (d, J = 7.6 Hz, 1H), 7.34 (m, 8H), 7.07 (d, J =
16.2 Hz, 1H), 5.68 (d, J = 6.2 Hz, 1H), 5.35 (d, J = 6.2 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3)
δ 162.4, 141.8, 138.6, 137.1, 135.8, 133.7, 133.1, 129.1, 128.78, 128.76, 128.5, 128.3, 127.2,
126.9, 126.8, 126.6, 121.2, 83.3, 57.2. HRMS (ESI) calcd for C23H1735ClO2Na [M + Na]+
383.0809, found 383.0810.
(+/−)-trans-4-Chloro-6,8-dimethyl-3-phenylisochroman-1-one (2j). Following the general
procedure, 2j was purified by silica gel chromatography (5% EtOAc/PE). Yield: 180 mg, 63%, a
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white solid, mp. 130–132 C. H NMR (600 MHz, CDCl3) δ 7.42 – 7.27 (m, 5H), 7.17 (s, 1H),
7.12 (s, 1H), 5.64 (d, J = 5.9 Hz, 1H), 5.30 (d, J = 5.9 Hz, 1H), 2.69 (s, 3H), 2.35 (s, 3H). 13C{1H}
NMR (151 MHz, CDCl3) δ 162.7, 144.6, 143.4, 138.4, 136.1, 134.1, 129.0, 128.7, 126.8, 126.2,
119.8, 83.2, 57.4, 22.3, 21.6. HRMS (ESI) calcd for C17H1535ClO2Na [M + Na]+ 309.0653, found
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(+/−)-trans-4-Chloro-6-fluoro-3-phenyl-8-((E)-styryl)isochroman-1-one (2k). Following the
general procedure, 2k was purified by silica gel chromatography (5% EtOAc/PE). Yield: 246 mg,
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65%, a white solid, mp. 176–178 C. H NMR (600 MHz, CDCl3) δ 8.20 (d, J = 16.2 Hz, 1H),
7.59 (d, J = 7.6 Hz, 2H), 7.47 (d, J = 8.3 Hz, 1H), 7.38 (dd, J = 9.3, 6.4 Hz, 7H), 7.32 (t, J = 7.2
Hz, 1H), 7.21 (d, J = 6.8 Hz, 1H), 7.08 (d, J = 16.2 Hz, 1H), 5.60 (m, 1H), 5.30 (d, J = 7.0 Hz,
1H). 13C{1H} NMR (151 MHz, CDCl3) δ 165.1 (d, J = 256.5 Hz), 161.7, 145.4 (d, J = 10.1 Hz),
142.1 (d, J = 9.4 Hz), 136.5, 135.4, 134.2, 129.3, 128.8, 128.7, 127.4, 127.0, 126.0, 117.5 (d, J =
2.3 Hz), 115.0 (d, J = 22.6 Hz), 113.9 (d, J = 23.9 Hz), 83.0, 56.8. HRMS (ESI) calcd for
C23H1635ClFO2Na [M + Na]+ 401.0715, found 401.0716.
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(+/−)-trans-4-Chloro-3-(2-chlorophenyl)isochroman-1-one (2l).23 Following the general
procedure, 2l was purified by silica gel chromatography (5% EtOAc/PE). Yield: 210 mg, 72%, a
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white solid, mp. 96–98 C. H NMR (600 MHz, CDCl3) δ 8.21 (d, J = 7.8 Hz, 1H), 7.65 (td, J =
7.6, 1.3 Hz, 1H), 7.55 (td, J = 7.7, 0.8 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.43 (d, J = 7.9 Hz, 1H),
7.32 – 7.27 (m, 1H), 7.25 – 7.22 (m, 2H), 6.21 (d, J = 5.6 Hz, 1H), 5.49 (d, J = 5.6 Hz, 1H).
13C{1H} NMR (151 MHz, CDCl3) δ 163.2, 137.2, 134.7, 133.4, 133.1, 130.4, 130.3, 130.2, 129.9,
127.9, 127.8, 127.3, 124.0, 81.0, 54.8. HRMS (ESI) calcd for C15H1035Cl2O2Na [M + Na]+
314.9950, found 314.9955.
(+/−)-trans-4-chloro-3-(3-chlorophenyl)isochroman-1-one (2m). Following the general
procedure, 2m was purified by silica gel chromatography (5% EtOAc/PE). Yield: 257 mg, 88%, a
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white solid, mp. 126–128 C. H NMR (600 MHz, CDCl3) δ 8.17 (dd, J = 7.8, 1.1 Hz, 1H), 7.69
(td, J = 7.6, 1.3 Hz, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.56 – 7.52 (m, 1H), 7.41 (t, J = 1.7 Hz, 1H),
7.37 – 7.34 (m, 1H), 7.32 (t, J = 7.7 Hz, 1H), 7.27 (d, J = 7.5 Hz, 1H), 5.61 (d, J = 7.6 Hz, 1H),
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5.34 (d, J = 7.6 Hz, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 162.9, 137.8, 137.6, 134.80, 134.76,
130.6, 130.0, 129.8, 129.5, 127.5, 127.3, 125.4, 123.8, 83.3, 56.2. HRMS (ESI) calcd for
C15H1035Cl2O2Na [M + Na]+ 314.9950, found 314.9958.
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(+/−)-trans-4-Chloro-3-(4-chlorophenyl)isochroman-1-one (2n). Following the general
procedure, 2n was purified by silica gel chromatography (5% EtOAc/PE). Yield: 219 mg, 75%, a
white solid, mp. 147–148 oC. 1H NMR (600 MHz, CDCl3) δ 8.17 (d, J = 7.7 Hz, 1H), 7.68 (td, J =
7.6, 1.1 Hz, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.38 – 7.31 (m, 4H), 5.62 (d, J
= 7.5 Hz, 1H), 5.33 (d, J = 7.5 Hz, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 163.0, 137.7, 135.3,
134.8, 134.3, 130.6, 129.8, 129.0, 128.5, 127.5, 123.9, 83.4, 56.3. HRMS (ESI) calcd for
C15H1035Cl2O2Na [M + Na]+ 314.9950, found 314.9945.
(+/−)-trans-4-Chloro-3-(4-methylphenyl)isochroman-1-one (2o).34 Following the general
procedure, 2o was purified by silica gel chromatography (5% EtOAc/PE). Yield: 209 mg, 77%, a
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white solid, mp. 134–135 C. H NMR (600 MHz, CDCl3) δ 8.16 (dd, J = 7.8, 0.9 Hz, 1H), 7.65
(td, J = 7.6, 1.3 Hz, 1H), 7.57 (d, J = 7.7 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.23 (d, J = 8.1 Hz,
2H), 7.16 (d, J = 8.0 Hz, 2H), 5.66 (d, J = 6.7 Hz, 1H), 5.37 (d, J = 6.7 Hz, 1H), 2.33 (s, 3H).
13C{1H} NMR (151 MHz, CDCl3) δ 163.4, 139.2, 137.8, 134.6, 132.9, 130.4, 129.7, 129.5, 129.4,
127.6, 126.9, 124.1, 84.0, 56.4, 21.2. HRMS (ESI) calcd for C16H1335ClO2Na [M + Na]+ 295.0496,
found 295.0495.
(+/−)-trans-4-Chloro-3-(naphthalen-2-yl)isochroman-1-one (2p). Following the general
procedure, 2p was purified by silica gel chromatography (5% EtOAc/PE). Yield: 262 mg, 85%, a
white solid, mp. 150–152 oC. 1H NMR (600 MHz, CDCl3) δ 8.20 (d, J = 7.8 Hz, 1H), 7.86 (d, J =
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8.6 Hz, 1H), 7.82 (t, J = 7.6 Hz, 3H), 7.65 (td, J = 7.6, 1.1 Hz, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.54
– 7.49 (m, 3H), 7.47 (dd, J = 8.5, 1.7 Hz, 1H), 5.86 (d, J = 6.8 Hz, 1H), 5.50 (d, J = 6.8 Hz, 1H).
13C{1H} NMR (151 MHz, CDCl3) δ 163.3, 137.8, 134.7, 133.5, 133.1, 132.9, 130.5, 129.8, 128.8,
128.3, 127.7, 127.6, 126.87, 126.86, 126.7, 124.1, 123.7, 84.2, 56.3. HRMS (ESI) calcd for
C19H1335ClO2Na [M + Na]+ 331.0496, found 331.0489.
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(+/−)-trans-4-Chloro-3-(thiophen-2-yl)isochroman-1-one
(2q)
and
(+/−)-cis-4-Chloro-3-(thiophen-2-yl)isochroman-1-one (2q’). Following the general procedure,
2q was purified by silica gel chromatography (5% EtOAc/PE). Major isomer (2q): Yield: 111.1
mg, 42%, colorless oil.1H NMR (600 MHz, CDCl3) δ 8.18 – 8.14 (m, 1H), 7.68 (td, J = 7.6, 1.3 Hz,
1H), 7.60 – 7.51 (m, 2H), 7.27 (dd, J = 5.1, 1.2 Hz, 1H), 7.05 (d, J = 3.5 Hz, 1H), 6.94 (dd, J = 5.1, 3.6
Hz, 1H), 5.99 (d, J = 4.6 Hz, 1H), 5.38 (d, J = 4.7 Hz, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 162.5,
138.4, 137.4, 134.7, 130.7, 130.1, 128.0, 127.9, 126.9, 124.2, 80.2, 55.7. HRMS (ESI) calcd for
C13H935ClO2SNa [M + Na]+ 286.9904, found 286.9902. Minor isomer (2q’): Yield: 37 mg, 14%,
1
colorless oil. H NMR (600 MHz, CDCl3) δ 8.23 – 8.14 (m, 1H), 7.69 (td, J = 7.6, 1.3 Hz, 1H), 7.58
(td, J = 7.7, 1.1 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.40 (dd, J = 5.1, 1.2 Hz, 1H), 7.33 – 7.20 (m, 1H),
7.07 (dd, J = 5.0, 3.6 Hz, 1H), 6.05 (dd, J = 2.0, 0.5 Hz, 1H), 5.25 (d, J = 2.0 Hz, 1H). 13C NMR (151
MHz, CDCl3) δ 163.3, 139.0, 137.2, 134.6, 131.0, 130.4, 127.3, 126.9, 126.6, 126.6, 123.8, 77.7, 57.0.
HRMS (ESI) calcd for C13H935ClO2SNa [M + Na]+ 286.9904, found 286.9903.
(+/−)-cis-4-Chloro-3-isopropylisochroman-1-one (2r). Following the general procedure, 2r was
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purified by silica gel chromatography (5% EtOAc/PE). Yield: 134 mg, 60%, colorless oil. H
NMR (600 MHz, CDCl3) δ 7.91 (d, J = 7.7 Hz, 1H), 7.77 – 7.65 (m, 1H), 7.57 (t, J = 7.5 Hz, 1H),
7.50 (dd, J = 7.7, 0.5 Hz, 1H), 5.78 (d, J = 2.2 Hz, 1H), 4.10 (dd, J = 7.2, 2.3 Hz, 1H), 2.34 (dd, J
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= 13.6, 6.8 Hz, 1H), 1.20 (d, J = 6.8 Hz, 3H), 1.15 (d, J = 6.7 Hz, 3H). 13C{1H} NMR (151 MHz,
CDCl3) δ 170.1, 147.6, 134.3, 129.7, 126.7, 125.7, 121.8, 80.3, 68.6, 33.2, 20.5, 20.0. HRMS (ESI)
calcd for C12H1335ClO2Na [M + Na]+ 247.0496, found 247.0497.
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(+/−)-trans-4-Chloro-3-cyclopropylisochroman-1-one
(2s)
and
(+/−)-cis-4-Chloro-3-cyclopropylisochroman-1-one (2s’). Following the general procedure, 2s
and 2s’ was purified by silica gel chromatography (5% EtOAc/PE). Major isomer (2s): Yield: 134
mg, 45%, colorless oil. 1H NMR (600 MHz, CDCl3) δ 8.16 (d, J = 7.7 Hz, 1H), 7.68 (td, J = 7.6,
1.1 Hz, 1H), 7.55 (dd, J = 16.0, 7.9 Hz, 2H), 5.22 (d, J = 3.8 Hz, 1H), 4.01 (dd, J = 9.4, 3.8 Hz,
1H), 1.08 – 0.87 (m, 1H), 0.84 – 0.57 (m, 3H), 0.57 – 0.40 (m, 1H). 13C{1H} NMR (151 MHz,
CDCl3) δ 163.0, 137.8, 134.5, 130.5, 129.9, 128.0, 124.2, 87.4, 55.3, 13.8, 3.9, 3.7. HRMS (ESI)
calcd for C12H1135ClO2Na [M + Na]+ 245.0340, found 245.0336. Minor isomer (2s’): Yield: 44
o
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mg, 20%, white solid, mp. 110-114 C. H NMR (600 MHz, CDCl3) δ 8.06 (d, J = 7.7 Hz, 1H),
7.57 (t, J = 7.2 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.37 (d, J = 7.5 Hz, 1H), 5.06 (s, 1H), 3.73 (d, J
= 9.0 Hz, 1H), 1.70 – 1.44 (m, 1H), 0.87 – 0.73 (m, 1H), 0.72 – 0.61 (m, 1H), 0.56 (dd, J = 9.7,
5.2 Hz, 1H), 0.30 (dd, J = 9.6, 5.1 Hz, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 164.1, 139.4,
134.4, 130.8, 130.2, 127.3, 124.0, 84.6, 56.1, 12.7, 4.3, 2.1. HRMS (ESI) calcd for
C12H1135ClO2Na [M + Na]+ 245.0340, found 245.0339.
(+/−)-trans-(Z)-4-Chloro-3-phenylisochroman-1-one O-methyl oxime (4a). Following the
general procedure, 4a was purified by silica gel chromatography (5% EtOAc/PE). Yield: 255 mg,
89%, a white solid, mp. 104–105 oC. 1H NMR (600 MHz, CDCl3) δ 7.96 (d, J = 7.8 Hz, 1H), 7.44
(d, J = 7.6 Hz, 1H), 7.39 (t, J = 7.4 Hz, 1H), 7.37 – 7.26 (m, 6H), 5.52 (d, J = 5.5 Hz, 1H), 5.31 (d,
J = 5.5 Hz, 1H), 3.98 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 148.4, 136.6, 132.8, 130.7,
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129.2, 128.9, 128.7, 127.9, 126.7, 125.1, 124.6, 82.3, 63.0, 57.1. HRMS (ESI) calcd for
C16H1435ClNO2Na [M + Na]+ 310.0605, found 310.0613.
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(+/−)-trans-(Z)-4-Chloro-7-nitro-3-phenylisochroman-1-one O-methyl oxime (4b). Following
the general procedure, 4b was purified by silica gel chromatography (5% EtOAc/PE). Yield: 232
mg, 70%, a white solid, mp. 136–138 oC. 1H NMR (600 MHz, CDCl3) δ 8.81 (d, J = 2.1 Hz, 1H),
8.22 (dd, J = 8.5, 2.1 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.54 – 7.29 (m, 5H), 5.49 (d, J = 6.2 Hz,
1H), 5.35 (d, J = 6.2 Hz, 1H), 4.03 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 148.2, 146.8,
138.7, 135.6, 129.5, 129.4, 129.0, 126.7, 126.4, 124.7, 120.5, 81.8, 63.4, 55.8. HRMS (ESI) calcd
for C16H1335ClN2O4Na [M + Na]+ 355.0456, found 355.0449.
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(+/−)-trans-(Z)-4-Chloro-7-trimethylsilyl-3-phenylisochroman-1-one O-methyl oxime (4c).
Following the general procedure, 4c was purified by silica gel chromatography (5% EtOAc/PE).
Yield: 288 mg, 81%, a white solid, mp. 122–123 oC. 1H NMR (600 MHz, CDCl3) δ 8.25 (s, 1H),
7.74 – 7.56 (m, 2H), 7.34 (ddd, J = 7.1, 4.8, 2.4 Hz, 5H), 5.48 (d, J = 6.1 Hz, 1H), 5.32 (d, J = 6.1
Hz, 1H), 4.00 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 147.4, 136.3, 136.0, 131.5 (q, J = 33.0
Hz), 129.2, 128.9, 128.7, 126.9 (q, J = 3.5 Hz), 126.8, 125.5, 123.5 (q, J = 272.7 Hz), 122.3 (q, J =
3.9 Hz), 82.0, 63.2, 56.2. HRMS (ESI) calcd for C17H1335ClF3NO2Na [M + Na]+ 378.0479, found
378.0487.
(+/−)-trans-(Z)-4,7-Dichloro-3-phenylisochroman-1-one O-methyl oxime (4d). Following the
general procedure, 4d was purified by silica gel chromatography (5% EtOAc/PE). Yield: 221 mg,
69%, a white solid, mp. 135–136 oC. 1H NMR (600 MHz, CDCl3) δ 7.96 (d, J = 2.1 Hz, 1H), 7.45
– 7.29 (m, 7H), 5.52 (d, J = 5.6 Hz, 1H), 5.28 (d, J = 5.6 Hz, 1H), 4.00 (s, 3H).13C{1H} NMR (151
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MHz, CDCl3) δ 147.4, 136.2, 135.3, 131.1, 130. 8 , 129.5, 129.1, 128.8, 126.6, 126.1, 124.9, 82.2,
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63.2, 56.3. HRMS (ESI) calcd for C16H1335Cl2NO2Na [M + Na]+ 344.0216, found 344.0219.
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(+/−)-trans-(Z)-4-Chloro-8-methyl-3-phenylisochroman-1-one
O-methyl
oxime
(4e).
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Following the general procedure, 4e was purified by silica gel chromatography (5% EtOAc/PE).
Yield: 214 mg, 71%, a white solid, mp. 83–85 oC. 1H NMR (600 MHz, CDCl3) δ 7.34 – 7.15 (m,
8H), 5.58 (d, J = 4.6 Hz, 1H), 5.28 (d, J = 4.6 Hz, 1H), 4.00 (s, 3H), 2.64 (s, 3H). 13C{1H} NMR
(151 MHz, CDCl3) δ 148.4, 138.2, 136.8, 133.7, 133.0, 129.6, 128.7, 126.4, 125.8, 123.4, 81.5,
63.0, 58.3, 23.9. HRMS (ESI) calcd for C17H1635ClNO2Na [M + Na]+ 324.0762, found 324.0769.
(+/−)-trans-(Z)-4-Chloro-6,8-dimethyl-3-phenylisochroman-1-one O-methyl oxime (4f) and
(+/−)-cis-4-Chloro-2-methoxy-6,8-dimethyl-3-phenyl-3,4-dihydroisoquinolin-1(2H)-one (4f’).
Following the general procedure, 4f and 4f’ was purified by silica gel chromatography (5%
EtOAc/PE). Major isomer (4f): Yield: 176 mg, 56%, a white solid, mp. 114-116 oC. 1H NMR (600
MHz, CDCl3) δ 7.31 – 7.24 (m, 3H), 7.21 (d, J = 7.0 Hz, 2H), 7.03 (d, J = 16.2 Hz, 2H), 5.59 (d, J
= 4.4 Hz, 1H), 5.25 (d, J = 4.4 Hz, 1H), 4.00 (s, 3H), 2.60 (s, 3H), 2.27 (s, 3H). 13C{1H} NMR
(151 MHz, CDCl3) δ 148.6, 139.8, 138.1, 136.9, 133.9, 133.5, 128.7, 128.6, 126.40, 126.35,
120.6, 81.5, 63.0, 58.4, 23.9, 21.2. HRMS (ESI) calcd for C18H1835ClNO2Na [M + Na]+ 338.0918,
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found 338.0923. Minor isomer (4f’): Yield: 69 mg, 22%, white solid, mp. 166-168 C.1H NMR
(600 MHz, CDCl3) δ 7.30 – 7.22 (m, 1H), 7.12 (d, J = 6.9 Hz, 1H), 7.06 (s, 1H), 6.81 (s, 1H), 5.31
(d, J = 1.7 Hz, 1H), 5.19 (d, J = 2.0 Hz, 1H), 3.96 (s, 3H), 2.78 (s, 3H), 2.25 (s, 3H). 13C{1H}
NMR (151 MHz, CDCl3) δ 161.3, 142.5, 142.2, 136.0, 135.1, 134.7, 129.0, 128.5, 127.2, 126.4,
123.2, 69.1, 61.7, 60.1, 22.4, 21.2. HRMS (ESI) calcd for C18H1835ClNO2Na [M + Na]+ 338.0918,
found 338.0915.
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(+/−)-trans-(Z)-4-Chloro-3-(2-chlorophenyl)isochroman-1-one
O-methyl
oxime
(4g).
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Following the general procedure, 4g was purified by silica gel chromatography (5% EtOAc/PE).
Yield: 261 mg, 81%, a white solid, mp. 112-114 oC. 1H NMR (600 MHz, CDCl3) δ 8.00 (dd, J =
6.4, 2.7 Hz, 1H), 7.40 – 7.32 (m, 4H), 7.23 – 7.18 (m, 2H), 7.18 – 7.13 (m, 1H), 6.04 (d, J = 4.5
Hz, 1H), 5.39 (d, J = 4.6 Hz, 1H), 3.99 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 148.3, 134.5,
132.7, 132.1, 130.8, 130.0, 129.9, 129.5, 128.1, 127.5, 127.3, 125.2, 124.5, 79.4, 63.0, 55.7
HRMS (ESI) calcd for C16H1335Cl2NO2Na [M + Na]+ 344.0216, found 344.0219.
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(+/−)-trans-(Z)-4-Chloro-3-(3-chlorophenyl)isochroman-1-one
O-methyl
oxime
(4h).
Following the general procedure, 4h was purified by silica gel chromatography (5% EtOAc/PE).
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Yield: 242 mg, 75%, a white solid, mp. 108–109 C. H NMR (600 MHz, CDCl3) δ 7.97 (d, J =
7.5 Hz, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.43 (td, J = 7.6, 1.2 Hz, 1H), 7.36 (dd, J = 11.8, 3.4 Hz,
2H), 7.33 – 7.26 (m, 2H), 7.23 (d, J = 7.3 Hz, 1H), 5.42 (d, J = 6.3 Hz, 1H), 5.26 (d, J = 6.3 Hz,
1H), 3.98 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 148.1, 138.5, 134.7, 132.7, 130.7, 130.0,
129.3, 129.2, 127.8, 127.1, 125.2, 125.1, 124.4, 81.6, 63.0, 56.8. HRMS (ESI) calcd for
C16H1335Cl2NO2Na [M + Na]+ 344.0216, found 344.0210.
(+/−)-trans-(Z)-4-Chloro-3-(4-chlorophenyl)isochroman-1-one
O-methyl
oxime
(4i).
Following the general procedure, 4i was purified by silica gel chromatography (5% EtOAc/PE).
Yield: 273 mg, 85%, a white solid, mp. 120–121 oC. 1H NMR (600 MHz, CDCl3) δ 7.96 (dd, J =
7.9, 0.6 Hz, 1H), 7.46 (d, J = 7.7 Hz, 1H), 7.41 (td, J = 7.6, 1.2 Hz, 1H), 7.35 (td, J = 7.8, 1.1 Hz,
1H), 7.33 – 7.29 (m, 2H), 7.29 – 7.26 (m, 2H), 5.44 (d, J = 6.1 Hz, 1H), 5.24 (d, J = 6.1 Hz, 1H),
3.97 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 148.2, 135.1, 134.9, 132.7, 130.7, 129.3, 129.0,
128.2, 127.8, 125.1, 124.5, 81.6, 63.0, 56.9. HRMS (ESI) calcd for C16H1335Cl2NO2Na [M + Na]+
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344.0216, found 344.0217.
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O-methyl
oxime
(4j).
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Following the general procedure, 4j was purified by silica gel chromatography (5% EtOAc/PE).
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Yield: 262 mg, 87%, a white solid, mp. 112–114 C. H NMR (600 MHz, CDCl3) δ 7.96 (d, J =
7.8 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.39 (td, J = 7.6, 1.1 Hz, 1H), 7.36 – 7.31 (m, 1H), 7.19 (d,
J = 8.1 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 5.50 (d, J = 5.5 Hz, 1H), 5.30 (d, J = 5.5 Hz, 1H), 3.97
(s, 3H), 2.29 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 148.5, 138.7, 133.7, 132.9, 130.6, 129.4,
129.2, 128.0, 126.6, 125.1, 124.7, 82.2, 62.9, 57.1, 21.2. HRMS (ESI) calcd for C17H1635ClNO2Na
[M + Na]+ 324.0762, found 324.0769.
(+/−)-trans-(Z)-4-Chloro-3-(4-methoxyphenyl)isochroman-1-one O-methyl oxime (4k).
Following the general procedure, 4k was purified by silica gel chromatography (5% EtOAc/PE).
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Yield: 200 mg, 63%, a white solid, mp. 142–144 C. H NMR (600 MHz, CDCl3) δ 7.96 (d, J =
7.8 Hz, 1H), 7.47 (d, J = 7.7 Hz, 1H), 7.44 – 7.39 (m, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.23 (d, J =
8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 5.45 (d, J = 5.8 Hz, 1H), 5.28 (d, J = 5.8 Hz, 1H), 3.97 (s,
3H), 3.77 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 156.0, 148.6, 133.1, 130.6, 129.1, 128.7,
128.2, 127.9, 125.1, 124.7, 114.1, 82.1, 62.9, 57.1, 55.3. HRMS (ESI) calcd for C17H1635ClNO3Na
[M + Na]+ 340.0711, found 340.0712.
(+/−)-trans-(Z)-4-Chloro-3-(naphthalen-2-yl)isochroman-1-one
O-methyl
oxime
(4l).
Following the general procedure, 4l was purified by silica gel chromatography (5% EtOAc/PE).
Yield: 283 mg, 84%, a white solid, mp. 134–136 oC. 1H NMR (600 MHz, CDCl3) δ 7.98 (dd, J =
7.9, 0.9 Hz, 1H), 7.84 – 7.75 (m, 4H), 7.49 – 7.44 (m, 3H), 7.43 (dd, J = 8.5, 1.7 Hz, 1H), 7.38 (td,
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J = 7.6, 1.3 Hz, 1H), 7.33 (td, J = 7.7, 1.2 Hz, 1H), 5.68 (d, J = 5.7 Hz, 1H), 5.43 (d, J = 5.7 Hz,
1H), 4.00 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 148.5, 133.9, 133.4, 133.0, 132.9, 130.7,
129.2, 128.7, 128.3, 127.9, 127.7, 126.7, 126.6, 126.5, 125.1, 124.7, 123.8, 82.5, 63.0, 57.0.
HRMS (ESI) calcd for C20H1635ClNO2Na [M + Na]+ 360.0762, found 360.0766.
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(E)-Methyl 3-chloro-4,6-dimethoxy-2-styrylbenzoate (5). Following the general procedure, 5
1
was purified by silica gel chromatography (10% EtOAc/PE). Yield: 306 mg, 92%, yellow oil. H
NMR (600 MHz, CDCl3) δ 7.39 (d, J = 7.6 Hz, 2H), 7.26 (t, J = 7.6 Hz, 2H), 7.19 (t, J = 7.3 Hz,
1H), 7.13 (d, J = 16.5 Hz, 1H), 6.71 (d, J = 16.5 Hz, 1H), 6.39 (s, 1H), 3.84 (s, 3H), 3.77 (s, 3H),
3.69 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 167.8, 156.6, 156.1, 136.8, 136.2, 134.9, 128.7,
128.3, 126.8, 124.2, 116.5, 114.1, 95.5, 56.5, 56.4, 52.5. HRMS (ESI) calcd for C18H1735ClO4Na
[M + Na]+ 355.0708, found 355.0704.
(+/−)-erythro-Methyl 2-(1, 2-dichloro-2-phenylethyl)-5-methoxybenzoate (6a). Following the
general procedure, 6a was purified by silica gel chromatography (2% EtOAc/PE). Yield: 68 mg,
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20%, colorless oil. H NMR (600 MHz, CDCl3) δ 7.53 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 2.8 Hz,
1H), 7.40 (dd, J = 7.6, 1.9 Hz, 2H), 7.38 – 7.33 (m, 3H), 7.07 (dd, J = 8.8, 2.8 Hz, 1H), 6.71 (d, J
= 8.5 Hz, 1H), 5.26 (d, J = 8.5 Hz, 1H), 3.93 (s, 3H), 3.86 (s, 3H). 13C{1H} NMR (151 MHz,
CDCl3) δ 167.1, 159.2, 138.1, 131.9, 130.5, 128.8, 128.4, 128.3, 118.6, 114.9, 66.0, 60.4, 55.5,
52.5. HRMS (ESI) calcd for C17H1635Cl2O3Na [M + Na]+ 361.0368, found 361.0367.
(+/−)-threo-Methyl 2-(1, 2-dichloro-2-phenylethyl)-5-methoxybenzoate (6b). Following the
general procedure, 6b was purified by silica gel chromatography (2% EtOAc/PE). Yield: 95 mg,
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28%, colorless oil. H NMR (600 MHz, CDCl3) δ 7.76 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 7.1 Hz,
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2H), 7.32 (d, J = 2.7 Hz, 1H), 7.31 – 7.19 (m, 3H), 7.07 (dd, J = 8.8, 2.7 Hz, 1H), 6.47 (d, J = 5.4
Hz, 1H), 5.43 (d, J = 5.4 Hz, 1H), 3.89 (s, 3H), 3.81 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ
167.0, 159.0, 138.3, 132.0, 131.8, 129.4, 128.4, 128.1, 128.0, 118.2, 114.9, 67.8, 63.2, 55.5, 52.5.
HRMS (ESI) calcd for C17H1635Cl2O3Na [M + Na]+ 361.0368, found 361.0365.
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(Z)-Methyl 4-chloro-5-phenylpent-4-enoate (8a). Following the general procedure, 8a was
purified by silica gel chromatography (2% EtOAc/PE). Yield: 25 mg, 11%, colorless oil. 1H NMR
(600 MHz, CDCl3) δ 7.57 (d, J = 7.3 Hz, 2H), 7.34 (t, J = 7.6 Hz, 2H), 7.27 (t, J = 7.4 Hz, 1H),
6.55 (s, 1H), 3.70 (s, 3H), 2.83 (t, J = 7.5 Hz, 2H), 2.69 (t, J = 7.5 Hz, 2H). 13C{1H} NMR (151
MHz, CDCl3) δ 172.7, 134.8, 132.6, 129.0, 128.2, 127.7, 125.6, 51.7, 36.5, 32.5. HRMS (ESI)
calcd for C12H1335ClO2Na [M + Na]+ 247.0496, found 247.0494.
(E)-Methyl 4-chloro-5-phenylpent-4-enoate (8b). Following the general procedure, 8b was
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purified by silica gel chromatography (2% EtOAc/PE). Yield: 18 mg, 8%, colorless oil. H NMR
(600 MHz, CDCl3) δ 7.35 (t, J = 7.6 Hz, 2H), 7.30 – 7.25 (m, 1H), 7.21 (d, J = 7.6 Hz, 2H), 6.77
(s, 1H), 3.66 (s, 3H), 3.18 – 2.81 (m, 2H), 2.81 – 2.42 (m, 2H).13C{1H} NMR (151 MHz, CDCl3)
δ 172.6, 135.6, 135.4, 129.4, 128.6, 128.3, 127.5, 51.7, 32.2, 29.9. HRMS (ESI) calcd for
C12H1335ClO2Na [M + Na]+ 247.0496, found 247.0494.
(+/−)-trans-4-Chloro-3-phenylisochroman (10). Following the general procedure, 10 was
purified by silica gel chromatography (5% EtOAc/PE). Yield: 134.6 mg, 55%, colorless oil.1H
NMR (400 MHz, CDCl3) δ 7.66 (d, J = 7.4 Hz, 1H), 7.53 – 7.46 (m, 2H), 7.45 – 7.35 (m, 3H), 7.35 –
7.26 (m, 2H), 7.17 – 6.95 (m, 1H), 5.24 (d, J = 9.1 Hz, 1H), 5.06 (d, J = 15.2 Hz, 1H), 4.93 (d, J = 15.2
Hz, 1H), 4.72 (d, J = 9.1 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 138.6, 135.1, 134.1, 129.2,
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128.7, 128.5, 127.9, 127.5, 127.3, 123.8, 83.0, 68.7, 58.7. HRMS (ESI) calcd for C15H1335ClONa [M
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+ Na]+ 267.0547, found 267.0544. The configuration of 10 was determined through elimination of
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the chlorine atom by heating compound 10 in DMSO at 180
compound which was identified as 3-phenyl-1H-isochromene.56
̊C for 15 min to give a known
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(+/−)-cis-3-Phenyl-4-(phenylthio)isochroman-1-one (11a).25 To a stirred solution of 2a (100 mg,
0.39 mmol) in dry CH3CN (2 mL) was added thiophenol (107 mg, 0.98 mmol) and K2CO3 (346
mg, 2.34 mmol) in one portion, and then reaction was stirred at rt overnight. After the reaction
was completed, the reaction mixture was concentrated in vacuo. The residue was purified by flash
column chromatography (5% EtOAc/PE) on silica gel to afford 11a (100 mg, 78%) as a white
solid, mp. 154–155 oC. 1H NMR (600 MHz, CDCl3) δ 8.00 (dd, J = 7.5, 1.4 Hz, 1H), 7.49 (d, J =
7.6 Hz, 2H), 7.40 – 7.26 (m, 5H), 7.11 (t, J = 7.4 Hz, 1H), 7.00 (dd, J = 10.7, 4.7 Hz, 2H), 6.90
(dd, J = 8.1, 1.0 Hz, 2H), 6.86 – 6.83 (m, 1H), 5.83 (d, J = 2.5 Hz, 1H), 4.42 (d, J = 2.6 Hz, 1H).
13C{1H} NMR (151 MHz, CDCl3) δ 164.5, 140.9, 136.3, 135.5, 133.5, 131.8, 130.6, 128.8, 128.7,
128.6, 128.5, 128.5, 127.4, 126.3, 124.2, 80.7, 52.8.
3-Phenyl-1H-isochromen-1-one (12a).57 A solution of 2a (100 mg, 0.39 mmol) in dry toluene (5
mL) was treated with DBU (582 µL, 3.9 mmol) and then the reaction mixture was heated in an oil
bath at 80 °C overnight. After the completion of the starting material, the reaction mixture was
cooled down and diluted with EtOAc (20 mL) and washed with H2O (20 mL). Then the aqueous
layer was extracted with EtOAc (20 mL x 2), and the combined organic extract was successively
washed with 5% HCl and sat. NaHCO3 and brine (10 mL), dried over Na2SO4 and concentrated in
vacuo. The residue was purified by flash column chromatography (2% EtOAc/PE) on silica gel to
afford 12a (65 mg, 75%) as a white solid, mp. 87–88 oC. 1H NMR (600 MHz, CDCl3) δ 8.29 (d, J
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= 8.0 Hz, 1H), 7.87 (d, J = 7.7 Hz, 2H), 7.70 (t, J = 7.5 Hz, 1H), 7.50 – 7.40 (m, 5H), 6.94 (s, 1H).
13C{1H} NMR (151 MHz, CDCl3) δ 162.4, 153.6, 137.5, 134.9, 132.0, 130.0, 129.7, 128.9, 128.2,
126.0, 125.3, 120.6, 101.9.
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Supporting Information Available: The kinetic plots for the reaction of substrate 1a and 3a.
NMR spectra for all compounds. X-ray crystallographic data analysis for 2e and 4b. The material
is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We acknowledge the National Natural Science Foundation of China
(#21472136) for financial support.
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