Synthesis of isocoumarins via silver(I)-mediated annulation of enol esters

Article abstract of DOI:10.1021/acs.joc.5b02602

Silver-mediated annulation of 2-iodo enol esters leading to 4- and 3,4-substituted isocoumarins was accomplished selectively at room temperature. Coupling of 2-iodo benzoic acids with enolates that were produced in situ from the simple esters was also performed to produce isocoumarins under analogous reaction conditions. Owing to the mildness of the current protocol, 4-acyl 3-substituted isocoumarins were efficiently produced without any deacylation.

Full text of DOI:10.1021/acs.joc.5b02602

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Article
Synthesis of Isocoumarins via Silver(I)-mediated Annulation of Enol-esters
Niranjan Panda, Priyadarshani Mishra, and Irshad Mattan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02602 • Publication Date (Web): 08 Jan 2016
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Synthesis of Isocoumarins via Silver(I)ꢀmediated Annulation of
Enolꢀesters
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Niranjan Panda,* Priyadarshani Mishra† and Irshad Mattan†
Department of Chemistry, National Institute of Technology Rourkela, Rourkelaꢀ769008,
Odisha, India
Email: npanda@nitrkl.ac.in
TOC Graphic
O
R1 = H
R2 = H
O
O
O
I
R2
O
I
R2
COR1
COR1
O
R
O
COR1
[Ag] / base
rt
[Ag] / base
O
+
R
O
O
HO
R2 = CH3, Ph
R
R2 = CH3, Ph
OH
R2
R
COR1
I
R
Abstract
Silverꢀmediated annulation of 2ꢀiodo enol esters leading to 4ꢀ and 3, 4ꢀsubstituted
isocoumarins was accomplished selectively at room temperature. Coupling of 2ꢀiodo benzoic
acids with enolates that were produced inꢀsitu from the simple esters was also performed to
produce isocoumarins under analogous reaction conditions. Owing to the mildness of the
current protocol, 4ꢀacyl 3ꢀsubstituted isocoumarins were efficiently produced without any
deacylation.
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Introduction
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Isocoumarin, a privileged molecular skeleton, is present in numerous natural as well as
synthetic products that exhibit wide range of pharmacological properties including antifungal,
antitumor, antiallergic, antimicrobial, antiꢀinflammatory, antidiabetic, phytotoxic, anticancer
and inhibitory activities.1ꢀ3 Isocoumarins are also endowed as a pivotal intermediate in the
synthesis of several other compounds such as isoquinolines, isochromenes, and
isocarbostyrils.4 These physiochemical features have spurred considerable interest in
developing new methods with enhanced scope, generality, and cost effectiveness for their
synthesis. Of the reported methods, the transition metal (TM) mediated Sonogashira type
coupling of terminal alkynes with halo carboxylic acids or their equivalents followed by 6-
endo-dig cyclization has been strenuously developed and recognized as an attractive strategy
to construct the isocoumarin ring.5 Besides, some other methods that involve the oxidative
annulation of the carboxylic acid with alkynes through CꢀH activation reaction using Ruꢀ,
Rhꢀ, Irꢀcomplexes have been reported.6 Though these methods are of high synthetic value,
multistep access to generate the starting material, stoichiometric use of toxic and expensive
TM catalyst and high temperature above 100 °C often limit their application. Moreover, some
of these reactions have reduced substrate scope and also result in a number of undesired side
products (e.g. phthalides).7 Consequently, Cuꢀcatalyzed crossꢀcoupling of 2ꢀhalobenzoic
acids or their derivatives with 1,3ꢀdicarbonyl compounds have thus appeared as a potential
alternate strategy to achieve isocoumarins.8 For instance, Fan and his coꢀworkers prepared 3ꢀ
and 3,4ꢀsubstituted isocoumarins through a CuIꢀcatalyzed tandem reaction of 2ꢀ
bromobenzoates with acyclic 1,3ꢀdiones followed by annulation.9a Xi et al. also adopted a
similar annulation strategy for the synthesis of 3ꢀsubstituted coumarins.9b Indeed, these
reactions proceed with the initial Cuꢀcatalyzed Cꢀarylation of 1,3ꢀdiketone (Hurtley reaction)
followed by annulation reaction. Evidently, deacylation occurs through a four membered ring
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with CꢀC and CꢀO bond cleavage to give the 3ꢀsubstituted isocoumarins. Yao and coꢀworkers
also reported a Cuꢀcatalyzed tandem C−C/C−O coupling reaction of 2ꢀiodoꢀNꢀphenylꢀ
benzamides with 1,3ꢀdiketones to produce 3ꢀsubstituted isocoumarins.9c Notably, Shen et al.
reported a proficient ligand assisted Cuꢀcatalyzed protocol for the synthesis of 3ꢀsubstituted
isocoumarins from the intramolecular CꢀC coupling and rearrangement of 1ꢀ(2ꢀhalophenyl)ꢀ
1,3ꢀdiones.9d
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Despite these formidable advances, limited investigations have been aimed
particularly at the synthesis of 4ꢀsubstituted isocoumarins although they possess significant
antiangiogenic, antitumor and antibiotic activities against plant cells, bacteria and plant
pathogenic fungi.10 Notably, Vilsmeier reaction of homophthalic acid followed by hydrolysis
has been mostly employed to access 4ꢀsubstituted isocoumarins11 though few 4ꢀakyl/arylꢀ
substituted isocoumarins have been prepared in the presence of Pdꢀcatalyst.12 Nevertheless,
restricted substrate scope, inconvenient reaction procedures, and multistep syntheses of the
reagents often precluded their widespread use. A general catalytic method to various 4ꢀ
substituted isocoumarins is therefore demanding and would also serve to provide an excellent
opportunity to accelerate biological and biosynthetic studies of these valuable compounds.13
Furthermore, Agꢀcatalyzed coupling reactions are relatively less literature precedented though
stoichiometric amounts of Ag(I) salts are uniquely used as coꢀoxidant for Pd, Au, Cu, Rh, Ru
and Pt catalyzed reactions.14 In continuation of our effort towards the synthesis of newer
heterocycles,15 we here report a novel Agꢀmediated efficient method for the selective
synthesis of 4ꢀ substituted isocoumarins from readily accessible enol esters under mild
reaction conditions even at room temperature. This method is also useful to enable 3,4ꢀ
disubstituted isocoumarins in good yield. Furthermore, the first example of a silverꢀmediated
reaction of the oꢀhalo benzoic acid and enol ester leading to isocoumarins through the Cꢀ
arylation of enolates followed by annulation is also presented.
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Results and Discussion
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In contrast to the previous methods for the preparation of 3ꢀsubstituted coumarins
(Scheme 1),5,16 we speculated that suitably functionalized enol esters would undergo
transition metalꢀcatalyzed intramolecular cyclization to produce 4ꢀsubstituted isocoumarins
selectively. Consequently, a number of enol esters were prepared by the reaction of esters of
propiolic acid with oꢀhalo benzoic acids following the similar procedure reported earlier.16 To
study the annulation reaction 2ꢀ(ethoxycarbonyl)vinyl 2ꢀiodobenzoate (1a) was chosen as a
model substrate. Recently, we observed that treatment of 1a with CuI in the presence of base
(e.g. K3PO4), produces substituted αꢀnaphthol16 and no trace of isocoumarin was observed.
Replacement of CuI by Pd(OAc)2 (5 mol%) was also found to be unsuccessful.
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O
O
O
[Pd] or [Cu]
base
OH
OH
O
R
+
I
R
R
base
ref. 5
OH
O
O
O
COR'
O
O
R'
conditions
CuI
K3PO4
DMSO
I
COR'
present work
COR'
ref. 16
Scheme 1. Synthetic strategy for the 4ꢀsubstituted isocoumarin
However, the addition of Ag2CO3 (1 equiv.) as coꢀoxidant, fascinatingly desired 4ꢀsubstituted
isocoumarin 2a was produced (15% yield) along with the decomposition of the remaining
starting material. Inspired by this result, we believed that silver salts might be exclusively
responsible for the annulation reaction.17 Thus, we turned our attention towards the use of
silver salt as the only catalyst for the above transformation though no report on such type of
silverꢀmediated Cꢀarylation is yet the precedent. Optimization study was performed by
varying the catalyst, solvent, base, etc. to develop a suitable condition for the annulation
reaction (Table 1). Among the screened solvents (e.g. THF, toluene, DMF, DCE, CH3CN,
1,4ꢀdioxane, etc.), CH3CN was served as the most efficient solvent to produce the highest
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yield of 2a. AgOAc (1 equiv.) showed to be the best catalyst to enable the highest yield of 2a
(95%) when compared with other catalysts such as Ag2O, Ag2CO3 and AgNO3 during the
catalyst screening. Ag2O was also results in 79% of isocoumarin at room temperature.
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Table 1. Optimization of reaction conditions a
O
O
O
O
O
OEt
Catalyst
Solvent, base
Additive, rt, 12h
I
COOEt
1a
2a
Entry Catalyst (mol%)
Solvent
Base
Additive
Yield (%)
1
2
3
4
5
6
7
8
9
CuI
toluene
toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
K3PO4
K2CO3
K3PO4
NaOAc
DMAP
DMAP
DMAP
Py
016
0
Pd(OAc)2 (5 )
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Ag2CO3 (100)
Ag2O (100)
AgOAc (100)
AgOAc (100)
Ph3P
0
0
Ag2CO3
15
38
79
56
34
15
18
95
66
80
38
42
78
Et3N
10 AgOAc (100)
11 AgOAc (100)
12 AgOAc (100)
13 AgOAc (50)
14 AgOAc (70)
15 AgOAc (100)
16 AgOAc (100)
17 AgOAc (100)
K2CO3
NaOAc
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMF
DCE
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18 AgOAc (100)
19 AgOAc (100)
20 AgOAc (100)
21 Ag2O (30)
22 Ag2CO3 (30)
23 Ag2O (30)
24 AgOAc (30)
25 AgOAc (100)
26
1,4ꢀdioxane DMAP
26
33
NR
76
toluene
H2O
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
CH3CN
CH3CN
CH3CN
CH3CN
EtOH
K2S2O8
NaBO3.4H2O 0
10
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oxone
0
K2S2O8
45
7
CH3CN
CH3CN
<10
15
27 AgOAc (100)
a Reaction Conditions: enolꢀester 1a (50 mg, 0.14 mmol), catalyst, base (1.2 equiv.), additive
(1 equiv) solvent (2 mL), rt, 12h
To reduce the catalyst consumption, several oxidants were used to perform the reaction.
Notably, when 1.1 equiv. of K2S2O8 was used along with 0.3 equiv. of Ag2O and base (1
equiv.), 76% of 2a was isolated. However, AgOAc (0.3 equiv) in the presence of 1 equiv. of
K2S2O8 was observed to be less efficient (entry 24). Next, we investigated the effect of
different bases in CH3CN the presence of AgOAc. To our delight, 4ꢀdimethylaminopyridine
(DMAP) was observed to be most effective to catalyze the reaction whereas other bases such
as pyridine, Et3N, K2CO3, and NaOAc were substantially less useful. Significantly, in the
absence of the base, only small amount of product (15%) was produced with the recovery of
remaining enol ester. When the reaction was performed in the absence of Agꢀcatalyst,
decomposition of starting material occurs, and 10% of the product 2a was isolated.
Furthermore, we observed that the reaction does not require any dedicated inert atmosphere
and more importantly it completes at room temperature in the presence of atmospheric air
over a period of 12h. Notably, under the optimum reaction conditions (1 equiv. AgOAc, 1.2
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equiv. DMAP in acetonitrile at rt) 1a did not undergo 5ꢀexoꢀdig cyclization and 5ꢀmembered
5
6
phthalide was not formed.
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Next, we extended the utility of the protocol for the annulation of various enol esters under
the optimized reaction conditions. As shown in Scheme 2, enol esters, prepared from several
propiolates were underwent intramolecular cyclization by offering 4ꢀsubstituted coumarins in
moderate to good yields.
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O
R2
O
O
O
R1
O
AgOAc (1 equiv)
R2
COR1
I
DMAP (1.2 equiv)
CH3CN, rt, 12h
R
R
1aꢀq
2aꢀq
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
n
O
O
O
O
Ph
2a; n = 1, 95%
2b; n = 2, 65%
2c; n = 3, 76%
2d; n = 4, 74%
2e; n = 7, 80%
O
2i; 70%
2g; 53%
2h; 60%
2f; 66%
O
O
Me
O
O
O
O
O
O
Me
O
OMe
O
OEt
O
O
O
OMe
2j; 47%
2k, 71%
2m; 63%
2l;72%
O
O
O
O
I
O
O
O
O
CH3
Ph
OEt
CH3
O
OEt
O
OEt
O
O
CH3
2n; 45%
2o; 78%
2q; 65%
2p; 51%
Scheme 2. Synthesis of isocoumarins from 2ꢀiodo enol esters.
When the (E)ꢀ2ꢀ(ethoxycarbonyl)vinyl 2ꢀbromobenzoate was treated under similar reaction
conditions, the reaction became sluggish with the production of 2a over a period of 36 h
(40% yield). Similarly, as expected, the less reactive (E)ꢀ2ꢀ(ethoxycarbonyl)vinyl 2ꢀ
chlorobenzoate did not produce 2a at room temperature over a period of 12h. However,
raising the temperature to 80°C, 2a was produced hitherto in low yield (15%). Pleasantly,
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annulation of other o-iodo vinyl benzoates having variable chain lengths occurred and
isocoumarins (2bꢀ2e) were produced in good yield (65ꢀ80%). Ketoꢀfunctionality in the enol
ester was also found to be tolerant to produce the desired isocoumarins (2l, 2q) in moderate
to good yield. Other substituents (such as iodo and methyl groups) to the aromatic ring were
also lenient to the reaction conditions by producing the corresponding isocoumarins 2m and
2n in 45% and 63% yield respectively. Most importantly, the current protocol activates the Cꢀ
I bond ortho to the carbonyl group for the cyclization whereas other CꢀI bonds remain
unaffected. Furthermore, under same reaction conditions, 3,4ꢀdisubstituted isocoumarins (2oꢀ
2q) were also obtained in moderate to good yield.
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Based on some control experiments (Scheme 3), a hypothesis was formulated to explain these
results, although no compelling evidence had yet been gathered. Notably, addition of 1 equiv.
of TEMPO to the reaction mixture did not lower the yield significantly (79% isolated yield of
2a), excludes the involvement of radical path way in the above transformation. The reaction
of enol ester 1a with DMAP in the absence of the catalyst, followed by acidification of the
reaction mixture led to the o-iodobenzoic acid and bis(transꢀ2ꢀethoxycarbonylvinyl) ether
(C).16 Furthermore, the reaction of the oꢀiodobenzoic acid with 2ꢀ(ethoxycarbonyl)vinyl 4ꢀ
methoxybenzoate (D) also produces 2a, albeit in reduced yield (75%). Besides, when enol
ester such as E was treated under similar reaction conditions, nucleophilic attack occurs to
the aldehyde group of B with the formation of benzodioxanone18 F. These observations
suggest that the enol ester 1a initially reacts with DMAP to produce the enolate (e.g. A which
rearranges to B) along with the intermediate I (Scheme 4). Subsequently, Cꢀarylation may
occur through oxidative addition of silver catalyst (e.g. II), by producing the intermediate III.
Evidently, analogous Cuꢀcatalyzed Cꢀarylation is endowed with literature precedent,16,19 and
the potential of Agꢀcatalyst in above Csp2-Csp3 bond formation is not well exploited.20 Upon
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enolization (IV) and subsequent nucleophilic attack forms the corresponding isocoumarin
(e.g. 2a) selectively.
O
O
CO2Et
O
+ H2O
DMAP, CH3CN
CO2Et
A
O
OEt
a)
O
-H2O
H
I
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OHC
CO2Et
CO2Et
1a
IC6H4CO2H
C (30% yield)
B
O
O
O
O
O
D
O
AgOAc, DMAP
CH3CN, rt
b)
c)
OH
OEt
I
MeO
COOEt
2a (75% yield)
O
O
O
O
O
AgOAc, DMAP
CH3CN, rt
O
OEt
CO2Et
OH
E
F (60% yield)
Scheme 3. Control experiments for mechanism
O
I
N
N
O
I
CO2Et
N
DMAP
O
N
I
1a
O
AgOAc
DMAP
N
O
O
OEt
A
N
O
[Ag]
O
III O
Ag
II
I
OAc
Ag
CO2Et
2a
O
O
H
OEt
O
N
H
N
B
N
N
C
O
CHO
CO2Et III
CO2Et
IV
Scheme 4. Plausible mechanism for the synthesis of 2a from 1a.
Finally, from the control experiments we recognized that our new method could be employed
for the straightforward synthesis of isocoumarins from the reaction of an oꢀhalo benzoic acid
and simple enol esters (Table 2). Thus, when oꢀiodobenzoic acids21 with different substituents
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Table 2. Isocoumarins synthesis from oꢀiodobenzoic acid and enol esters a
O
O
O
R2
COR1
O
OH
+
AgOAc
O
R2
DMAP
CH3CN
I
R
R
COR1
2/5
3
4
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Entry acid
enol ester
Isocoumarin Yield (%)
O
O
O
I
O
CO2Et
OH
O
1
79
2a
4a
3a
CO2Et
O
O
I
I
O
OH
2
42
4a
4a
I
3b
CO2Et
O
2n
O
Cl
Cl
OH
O
3
63
3c
I
5a
CO2Et
O
CH3
CH3
O
O
48
65
OH
4a
4
3d
I
2m
CO2Et
O
O
CH3
CO2Et
3a
O
5
O
4b
CH3
CO2Et
2o
O
I
O
6
48b
3b
4b
CH3
CO2Et
5b
O
Cl
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3c
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CH3
5c
CO2Et
O
O
CH3
COCH3
O
O
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3a
3b
47b
CH3
COCH3
4c
4c
2q
O
I
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45b
CH3
5d
COCH3
O
10
3c
Cl
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O
41b
CH3
5e
COCH3
O
CH3
4c
4c
O
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3d
49b
CH3
5f
COCH3
O
O
I
NC
NC
OH
O
40b
3e
CH3
5g
COCH3
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a Reaction Conditions: enol ester 4 (50 mg), oꢀiodobenzoic acid (1 equiv), AgOAc (1 equiv),
DMAP (2 equiv.), in 2 ml of CH3CN, rt for 12h. b 50°C for 12h.
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were treated with the readily prepared enol ester of benzoic acid (4a), 4ꢀsubstituted
isocoumarins were produced smoothly in good yield (see Scheme 5 for possible mechanism).
Consequently 3ꢀmethylꢀ4ꢀethylcarboxylates (entries 6ꢀ8) were achieved under the similar
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reaction conditions from oꢀiodobenzoic acids in moderate yield. Notably, earlier work on
coupling of the 2ꢀhalo benzoic acid with dicarbonyl compounds in the presence of CuI
reported to be unsuitable to afford 3ꢀsubstituted 4ꢀacryl isocoumarins. Regrettably,
deacylation occurs unambiguously through a fourꢀmembered cyclic intermediate and 3ꢀ
substituted isocoumarins are produced exclusively. However, when we treated oꢀiodobenzoic
acid with the enol ester 4c, owing to the mild reaction conditions of the current method, 3ꢀ
substituted 4ꢀacylated isocoumarins (2q, 5cꢀg) were produced smoothly without any
deacylation. In comparison to our earlier report on Cuꢀcatalyzed αꢀnaphthol synthesis,16 it
may be presumed that, the silver catalyst is more selective towards the Cꢀarylation than the
Cꢀcarbonylation reaction in isocoumarin synthesis.
O
N
Ag
O
O
N
O
O
[Ag]
CO2Et
O
OEt
O
H
OEt
O
I
DMAP
OH
O
O
O
H
O
H
O
CHO
CO2Et
O
O
O
O
OH
CHO
CO2Et
CO2Et
CO2Et
Work up
O
O
-H2O
O
O
OH
CO2Et
2a
CO2Et
Scheme 5. Plausible mechanism for the synthesis of 2a from 3a.
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Conclusion
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In summary, we have developed a simple protocol for the synthesis of less precedent 4ꢀ
substituted isocoumarins under very mild reaction conditions simply by switching the catalyst
from Cu to Ag. Potential of the Agꢀcatalysis in Csp2-Csp3 bond formation reaction was also
recognized exclusively. An alternate and complementary silverꢀmediated strategy for the
synthesis of isocoumarins from the reaction of easily accessible enol esters and oꢀhalo
benzoic acid was also demonstrated. The current method is found to be simple and mild
enough to produce 4ꢀ and 3,4ꢀsubstituted isocoumarins selectively. Unlike, earlier methods
deacylation did not occur under this reaction condition. Further synthetic application of above
methodology towards the total synthesis of natural products such as sescandelin, oosponol,
and antibiotic AGIꢀ7 is underway in our laboratory.
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EXPERIMENTAL SECTION
General information
All reactions were carried out in a closed round bottom flask. All commercial reagents were
used without purification, and all solvents were reaction grade. The reactions were monitored
by TLC and the residue was chromatographed on silica gel (Rankem, India, Mesh 60ꢀ120),
using an ethyl acetateꢀpetroleum ether (60ꢀ80°C) mixture as eluent. All the melting points are
uncorrected and measured in sulfuric acid bath. All NMR spectra were recorded on 400 MHz
(for 1H NMR, 100 MHz for13C NMR) NMR spectrometer and chemical shifts were expressed
in δ units relative to TMS signal as internal reference in CDCl3. Multiplicities are indicated as
s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet, when multiplicity is complex) for
1H NMR. Coupling constants, J were reported in Hz. IR spectra were recorded by FTIR
spectrometer (IR Affinity 1S W/L with quest ATR). Catalyst composition was analyzed via
inductively coupled plasma optical emission spectroscopy (ICPꢀOES). From ICPꢀOES
analysis it was found that the weight percent of silver in AgOAc is > 99.91%. Other
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impurities such as Cu (0.017 %), Fe (0.06%), Ni (0.01 %) are present in negligible amount
and expectedly did not contribute to the transformation.
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General procedure for preparation of enol esters16 (Method A)
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A mixture of 2ꢀiodo acid (1.0 equiv), alkyl propiolate (1.1 equiv) and pyridine (2.0 equiv) in
15 mL of toluene was stirred at room temperature. After 12 h the reaction mixture was
diluted with ethyl acetate (15 mL) followed by 1N HCl (10 mL) solution. The organic layer
was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic
layer was dried over brine, anhydrous Na SO , and then evaporated under reduced
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pressure. The crude residue was purified by column chromatography over silica gel using
a mixture of petroleum ether and ethyl acetate as eluent to give the desired enol esters.
General procedure for preparation of αꢀsubstituted enol esters (Method B)
Synthesis of αꢀsubstituted enol esters were achieved by following the slightly modified
procedure reported by Mohrig and coꢀworkers.22 To a stirred solution of 2ꢀiodo acid (500 mg,
2.02 mmol) in 5 mL of dichloromethane, oxalyl chloride (0.5 mL) was added at room
temperature under nitrogen atmosphere. Then 2 drops of DMF was added to initiate the
reaction. The resulting solution was stirred at room temperature for 8h and then solvent was
removed under reduced pressure. To the resulting slurry dry acetonitile (2 mL) was added. In
another round bottom flask 1,3ꢀdicarbonyl compound (1 equiv) was treated with DBU (1.2
equiv) in 8 mL of dry acetonitrile over a period of 15 min at room temperature. This resulting
solution was then added to the previously prepared acid chloride solution with the help of a
syringe over a period of 15 min. After 12 h the reaction mixture was diluted with ethyl
acetate (15 mL) followed by 1N HCl (10 mL) solution. The organic layer was separated,
and the aqueous layer was extracted with ethyl acetate. The combined organic layer was
dried over brine, anhydrous Na2SO4, and then evaporated under reduced pressure. The
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crude residue was purified by column chromatography over silica gel using a mixture of
petroleum ether and ethyl acetate as eluent to give the desired substituted enol esters.
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General procedure for preparation of enol esters from acid chlorides (Method C)
To a stirred solution of 1,3ꢀdicarbony compounds (1 equiv) and DBU (1.2 equiv) in 8 mL of
dry acetonitrile, benzoyl chloride (500 mg, 3.57 mmol) was added drop wise over a period of
15 min at room temperature. After 12 h the reaction mixture was then diluted with ethyl
acetate (15 mL) followed by 1N HCl (10 mL) solution. The organic layer was separated,
and the aqueous layer was extracted with ethyl acetate. The combined organic layer was
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dried over brine, anhydrous Na SO , and then evaporated under reduced pressure. The
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crude residue was purified by column chromatography over silica gel using a mixture of
petroleum ether and ethyl acetate as eluent to give the desired substituted enol esters.
(E)-2-(ethoxycarbonyl)vinyl 2-iodobenzoate16 (1a): Following method A, compound 1a was
obtained from the reaction of 2ꢀiodo benzoic acid (500 mg, 2.01mmol) and ethyl propiolate
(216 mg, 2.21mmol) as a colourless solid (590 mg, 85% yield); mp 77ꢀ78°C; IR (KBr):
3053, 2964, 2873, 1748, 1683, 1632, 1555, 1535, 1510, 1468, 1219 cmꢀ1; 1H NMR (400
MHz, CDCl3): δ 8.53 (d, 1H, J = 12.4 Hz), 8.09 (dd, 1H, J1 = 8.0 Hz, J2 = 0.8 Hz), 7.97 (dd,
1H, J1 = 7.6 Hz, J2 = 1.6 Hz), 7.52ꢀ7.46 (m, 1H), 7.28ꢀ7.23 (m, 1H), 5.92 (d, 1H, J = 12.4
Hz), 4.26 (q, 2H, J = 7.2 Hz), 1.34 (t, 3H, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3): δ 165.9,
161.9, 149.5, 142.0, 133.9, 132.0, 131.9, 128.1, 107.0, 90.1, 60.6, 14.2. MS (ESI, +ve) m/z
(relative intensity) 369.02 ([M+Na],+ 100%).
(E)-2-(propoxycarbonyl)vinyl 2-iodobenzoate16 (1b): Following method A, compound 1b
was obtained from the reaction of 2ꢀiodo benzoic acid (500 mg, 2.01mmol) and propyl
propiolate (248 mg, 2.21 mmol) as a colourless solid (566 mg, 78% yield); mp 74ꢀ75°C; IR
(KBr): 3090, 2966, 2885, 1755, 1718, 1653, 1581, 1464, 1430, 1389, 1285, 1232, 1062,
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1032, 1011cmꢀ1; 1H NMR (400 MHz, CDCl3): δ 8.53 (d, 1H, J = 12.8 Hz), 8.08 (dd, 1H, J1 =
8 Hz, J2 = 0.8 Hz), 7.97 (dd, 1H, J1 = 8.0 Hz, J2 = 1.6 Hz), 7.50ꢀ7.45 (m, 1H), 7.28ꢀ7.22 (m,
1H), 5.92 (d, 1H, J = 12.4 Hz), 4.15 (t, 2H, J = 6.8 Hz), 1.76ꢀ1.67 (m, 2H), 0.99 (t, 3H, J =
7.2 Hz); 13C NMR (100 MHz, CDCl3): δ 166.0, 161.8, 149.4, 142.1, 134.0, 131.9, 128.1,
107.0, 95.2, 66.2, 22.0, 10.4. MS (ESI, +ve) m/z (relative intensity) 742.93 ([2M+Na],+
100%), 382.90 ([M+Na],+ 80%).
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(E)-2-(butoxycarbonyl)vinyl 2-iodobenzoate16 (1c): Following method A, compound 1c was
obtained from the reaction of 2ꢀiodo benzoic acid (500 mg, 2.01mmol) and butyl propiolate
(279 mg, 2.21 mmol) as a colourless solid (573 mg, 76% yield); mp 76ꢀ78 °C; IR (KBr):
3087, 2953, 2868, 1748, 1698, 1654, 1578, 1459, 1316, 1268, 1231, 1192, 1133, 1011 cmꢀ1;
1H NMR (400 MHz, CDCl3): δ 8.52 (d, 1H, J = 12.8 Hz), 8.07 (t, 1H, J = 7.2 Hz), 7.97 (dd,
1H, J1 = 8.0 Hz, J2 = 1.6 Hz), 7.50ꢀ7.45 (m, 1H), 7.28ꢀ7.22 (m, 1H), 5.91 (d, 1H, J = 12.4
Hz), 4.19 (t, 1H, J = 6.8 Hz), 1.72ꢀ1.63 (m, 2H), 1.46ꢀ1.39 (m, 2H), 0.96 (t, 3H, J = 7.6 Hz);
13C NMR (100 MHz, CDCl3): δ 166.03, 161.8, 149.4, 142.1, 134.0, 131.9, 128.1, 107.0, 95.2,
64.5, 30.6, 19.1, 13.7. MS (ESI, +ve) m/z (relative intensity) 396.97 ([M+Na],+ 100%).
(E)-2-((pentyloxy)carbonyl)vinyl 2-iodobenzoate16 (1d): Following method A, compound 1d
was obtained from the reaction of 2ꢀiodo benzoic acid (500 mg, 2.01mmol) and pentyl
propiolate (310 mg, 2.211mmol) as a colourless liquid (563 mg, 72% yield); IR 3090, 2953,
2888, 2856, 1749, 1702, 1657, 1577, 1460, 1431, 1310, 1294, 1266, 1231, 1190, 1169, 1131,
1033, 1010 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ 8.52 (d, 1H, J = 12.4 Hz), 8.08 (dd, 1H, J1 =
8.2 Hz, J2 = 1.2 Hz), 7.97 (dd, 1H, J1 = 8.0 Hz, J2 = 1.6 Hz), 7.50ꢀ7.45 (m, 1H), 7.28ꢀ7.22 (m,
1H), 5.92 (d, 1H, J = 12.8 Hz), 4.19 (m, 2H), 1.72ꢀ1.65 (m, 2H), 1.40ꢀ1.33 (m, 4H), 0.96ꢀ
0.90 (m, 3H); 13C NMR (100 MHz, CDCl3): δ 166.0, 161.8, 149.4, 142.1, 134.0, 131.9,
131.9, 128.1, 107.0, 95.2, 64.8, 28.3, 28.0, 22.3, 13.9. MS (ESI, + ve) m/z (relative intensity)
411.00 ([M+Na],+ 100%), 799.00 ([2M+Na],+ 80%).
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(E)-2-((octyloxy)carbonyl)vinyl 2-iodobenzoate16 (1e): Following method A, compound 1e
was obtained from the reaction of 2ꢀiodo benzoic acid (500 mg, 2.01mmol) and octyl
propiolate (372 mg, 2.21mmol) as a colourless liquid (590 mg, 68% yield); IR: 3089, 2941,
2925, 2850, 1749, 1703, 1657, 1577, 1464, 1432, 1314, 1267, 1230, 1193, 1132, 1107, 1031,
1010 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ 8.49 (d, 1H, J = 12.4 Hz), 8.04 (dd, 1H, J1 = 8 Hz,
J2 = 1.2 Hz), 7.93 (dd, 1H, J1 = 8 Hz, J2 = 1.6 Hz), 7.47ꢀ7.41 (m, 1H), 7.24ꢀ7.18 (m, 1H),
5.88 (d, 1H, J = 12.4 Hz), 4.15 (t, 2H, J = 6.8 Hz), 1.69ꢀ1.61 (m, 2H), 1.36ꢀ1.24 (m, 10H),
0.85 (t, 3H, J = 6.4 Hz); 13C NMR (100 MHz, CDCl3): δ 166.0, 161.8, 149.4, 142.1, 134.0,
132.0, 131.8, 128.1, 107.0, 95.2, 64.8, 31.8, 29.2, 29.2, 28.6, 25.9, 22.6, 14.1. MS (ESI, + ve)
m/z (relative intensity) 453.09 ([M+Na], + 100%).
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(E)-2-((cyclohexyloxy)carbonyl)vinyl 2-iodobenzoate16 (1f): Following method A,
compound 1f was obtained from the reaction of 2ꢀiodo benzoic acid (500 mg, 2.01 mmol)
and cyclohexyl propiolate (336 mg, 2.21mmol) as yellow oil (588 mg, 73% yield); IR: 3282,
1
2913, 2845, 1751, 1718, 1683, 1642, 1577, 1457, 1429, 1370, 1221 cm.ꢀ1; H NMR (400
MHz, CDCl3): δ 8.49 (d, 1H, J = 12.4 Hz), 8.05 (dd, 1H, J = 8 Hz), 7.94 (dd, 1H, J = 8 Hz),
7.49ꢀ7.43 (m, 1H), 7.26ꢀ7.20 (m, 1H), 5.89 (d, 1H, J = 12.4 Hz), 4.90ꢀ4.82 (m, 1H), 1.92ꢀ
1.86 (m, 2H), 1.77ꢀ1.72 (m, 2H), 1.57ꢀ1.23 (m, 6H); 13C NMR (100 MHz, CDCl3): δ 165.3,
161.9, 149.2, 142.0, 134.0, 131.9, 131.9, 128.1, 107.5, 95.2, 72.9, 31.6, 25.3, 23.7. MS (ESI,
+ ve) m/z (relative intensity) 423.01 ([M+Na],+ 100%).
(E)-2-((benzyloxy)carbonyl)vinyl 2-iodobenzoate16 (1g): Following method A, compound 1g
was obtained from the reaction of 2ꢀiodo benzoic acid (500 mg, 2.01mmol) and benzyl
propiolate (354 mg, 2.21mmol) as a colourless liquid (658 mg, 80% yield); IR: 3086, 3053,
1
2952, 1752, 1718, 1654, 1580, 1455, 1272, 1230, 1090, 1007 cmꢀ1; H NMR (400 MHz,
CDCl3): δ 8.58 (d, 1H, J = 12.4 Hz), 8.08 (dd, 1H, J1 = 8 Hz, J2 = 0.8 Hz), 7.97 (dd, 1H, J1 =
7.6 Hz, J2 = 1.6 Hz), 7.47 (t ,1H, J = 0.8 Hz), 7.43ꢀ7.37 (m, 5H), 7.28ꢀ7.24 (m, 1H), 5.98 (d,
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1H, J = 12.4 Hz), 5.25 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 165.8, 161.8, 149.9, 142.1,
135.7, 134.1, 132.0, 131.7, 128.6, 128.3, 128.3, 128.2, 106.7, 95.3, 66.4. MS (ESI, +ve) m/z
(relative intensity) 838.84 ([2M+Na],+ 100%), 430.90 ([M+Na],+ 50%).
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(E)-2-((allyloxy)carbonyl)vinyl 2-iodobenzoate16 (1h): Following method A, compound 1h
was obtained from the reaction of 2ꢀiodo benzoic acid (500 mg, 2.01mmol) and allyl
propiolate (243 mg, 2.21mmol) as a colourless liquid (512 mg, 71% yield); IR: 3086, 2916,
1
2840, 1754, 1718, 1654, 1580, 1429, 1273, 1230, 1105, 1006 cmꢀ1; H NMR (400 MHz,
CDCl3): δ 8.56 (d, 1H, J = 12.4 Hz), 8.08 (d, 1H, J = 8.0 Hz), 7.97 (dd, 1H, J1 = 8 Hz, J2 =
1.6 Hz), 7.49 (dd, 1H, J1 = 11.2 Hz, J2 = 0.8 Hz), 7.28ꢀ7.22 (m, 1H), 6.03ꢀ5.92 (m, 2H),
5.40ꢀ5.26 (m, 2H), 4.70 (d, 2H, J = 5.6 Hz); 13C NMR (100 MHz, CDCl3): δ 165.5, 161.8,
149.8, 142.1, 134.0, 132.0, 131.9, 128.1, 118.5, 106.6, 95.2, 65.2. MS (ESI, + Ve) m/z
(relative intensity) 380.95 ([M+Na],+ 100%), 738.8 ([2M+Na],+ 40%).
(E)-2-((prop-2-ynyloxy)carbonyl)vinyl 2-iodobenzoate16 (1i): Following method A,
compound 1i was obtained from the reaction of 2ꢀiodo benzoic acid (500 mg, 2.01mmol) and
propꢀ2ꢀynyl propiolate (239 mg, 2.21mmol) as a colourless liquid (545 mg, 76% yield); IR:
3088, 2925, 2851, 2135, 1753, 1718, 1658, 1573, 1435, 1374, 1272, 1245, 1131, 1103, 1007
cmꢀ1; 1H NMR (400 MHz, CDCl3): δ 8.59 (d, 1H, J = 12.4 Hz), 8.09 (t, 1H, J = 7.6 Hz), 7.98
(dd, 1H, J1 = 8 Hz, J2 = 1.6 Hz), 7.52ꢀ7.45 (m, 1H), 7.28ꢀ7.23 (m, 1H), 5.95 (d, 1H, J = 12.4),
4.80 (d, 2H, J = 2.4 Hz), 2.53 (t, 1H, J = 2.4 Hz); 13C NMR (100 MHz, CDCl3): δ 165.1,
161.7, 150.5, 142.1, 134.1, 132.0, 131.7, 128.1, 105.9, 95.3, 77.4, 75.1, 52.1. MS (ESI, + Ve)
m/z (relative intensity) 356.11 ([M+1],+ 100%).
(E)-3-oxo-3-(p-tolyloxy)prop-1-en-1-yl 2-iodobenzoate (1j): Following method A,
compound 1j was obtained from the reaction of 2ꢀiodo benzoic acid (500 mg, 2.01mmol) and
pꢀtolyl propiolate (354 mg, 2.21 mmol) as a colourless liquid (535 mg, 65% yield); FTIR
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1430, 1464, 1507, 1583, 1653, 1730, 1756 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.74 (d, 1H, J
= 12.4 Hz), 8.11 (dd, 1H, J1 = 8 Hz, J2 = 0.8 Hz), 8.02 (dd, 1H, J1 = 8 Hz, J2 = 1.6 Hz), 7.55ꢀ
7.47 (m, 1H), 7.32ꢀ7.24 (m 1H), 7.22 (d, 2H, J = 8.4 Hz), 7.09ꢀ7.02 (m, 2H), 6.11 (d, 1H, J =
12.4 Hz), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.6, 161.7, 150.9, 148.1, 142.1,
135.6, 134.1, 132.0, 131.8, 130.0, 128.2, 121.2, 106.3, 95.3, 20.9. HRMS (ESI ꢀTOF) m/z
calcd for C17H14IO4 [M+H]+ 408.9937; Found 408.9929.
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(E)-3-(2-methoxyethoxy)-3-oxoprop-1-en-1-yl 2-iodobenzoate16 (1k): Following method A,
compound 1k was obtained from the reaction of 2ꢀiodo benzoic acid (500 mg, 2.01mmol) and
2ꢀmethoxyethyl propiolate (283 mg, 2.21mmol) as a yellow solid (568 mg, 75 % yield); mp
80°C; FTIR 1429, 1464, 1506, 1583, 1653, 1730, 1756 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ
8.55 (d, 1H, J = 12.8 Hz), 8.10ꢀ8.04 (m, 1H), 7.99ꢀ7.92 (m, 1H), 7.51ꢀ7.43 (m, 1H), 7.28ꢀ
7.20 (m, 1H), 5.95 (d, 1H, J = 12.8 Hz), 4.37ꢀ4.31 (m, 2H), 3.68ꢀ3.62 (m, 2H), 3.41 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 166.0, 161.8, 149.9, 142.1, 134.0, 132.0, 131.8, 128.1, 106.5,
95.2, 70.4, 63.7, 59.0. MS ESI m/z 399 ([M+Na] +, 100%).
(E)-3-(4-methoxyphenyl)-3-oxoprop-1-en-1-yl 2-iodobenzoate (1l): Following method A,
compound 1l was obtained from the reaction of 2ꢀiodo benzoic acid (500 mg, 2.01mmol) and
1ꢀ(4ꢀmethoxyphenyl)propꢀ2ꢀynꢀ1ꢀone (354 mg, 2.21mmol) as a yellow solid (567 mg, 69%
yield); mp 80°C; FTIR 1430, 1464, 1507, 1583, 1653, 1730, 1756 cmꢀ1; 1H NMR (400 MHz,
CDCl3) δ 8.61 (d, 1H, J = 12 Hz), 8.13ꢀ8.06 (m, 1H), 8.04ꢀ7.94 (m, 3H), 7.54ꢀ7.46 (m, 1H),
7.31ꢀ7.22 (m, 1H), 7.03ꢀ6.94 (m, 3H), 3.90 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 188.4,
163.6, 162.1, 149.7, 142.0, 134.0, 132.1, 131.9, 130.7, 130.6, 128.1, 113.9, 110.7, 95.2, 55.5.
MS ESI (GC) m/z 407 [M]+, 207 (100); HRMS (ESIꢀTOF) m/z calcd for C17H14IO4 [M+H]+
408.9937; Found 408.9930.
(E)-3-ethoxy-3-oxoprop-1-en-1-yl 2-iodo-6-methylbenzoate (1m): Following method A,
compound 1m was obtained from the reaction of 2ꢀiodoꢀ6ꢀmethylbenzoic acid (500 mg, 1.91
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mmol) and ethyl propiolate (206 mg, 2.10 mmol) as a yellow solid (563 mg, 82% yield): mp
80°C; FTIR 1430, 1464, 1507, 1583, 1653, 1730, 1756 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ
8.49 (dd, 1H, J1 = 12.4 Hz, J2 = 1.6 Hz), 7.67ꢀ7.61 (m, 1H), 7.18 (d, 1H, J = 8 Hz), 7.06ꢀ6.98
(m, 1H), 5.85 (dd, 1H, J1 = 12.4 Hz, J2 = 1.6 Hz), 4.21 (q, 2H, J = 2 Hz), 2.31 (s, 3H), 1.28 (t,
3H, J = 2 Hz); 13C NMR (100 MHz, CDCl3) δ 165.7, 164.5, 149.3, 137.5, 137.3, 136.6,
131.6, 129.9, 107.5, 91.8, 60.6, 20.1, 14.2. MS ESI (GC) m/z 359 [M]+, 207 (100). HRMS
(ESI ꢀTOF) m/z calcd for C13H14IO4 [M+H]+ 360.9937; Found 360.9991.
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(E)-3-ethoxy-3-oxoprop-1-en-1-yl 2,5-diiodobenzoate (1n): Following method A, compound
1n was obtained from the reaction of 2,5ꢀdiiodobenzoic acid (500 mg, 1.34 mmol) and ethyl
propiolate (144 mg, 1.47 mmol) as a yellow solid (473 mg, 75% yield); mp 80°C; FTIR
1430, 1464, 1507, 1583, 1653, 1730, 1756 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.48 (d, 1H, J
= 12.4 Hz), 8.23 (s, 1H), 7.77 (d, 1H, J = 8.4 Hz), 7.57ꢀ7.51 (m, 1H), 5.95 (d, 1H, J = 12.4
Hz), 4.26 (q, 2H, J = 6.8 Hz), 1.33 (t, 3H, J = 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 165.7,
160.6, 149.2, 143.3, 142.8, 140.4, 133.7, 107.5, 94.4, 93.1, 6.7, 14.2. HRMS (ESI ꢀTOF) m/z
calcd for C12H11I2O4 [M+H]+ 472.8747; Found 472.8739.
(E)-4-ethoxy-4-oxobut-2-en-2-yl 2-iodobenzoate (1o): Following method B, compound 1o
was obtained from the reaction of 2ꢀiodobenzoyl chloride (in situ prepared from 500 mg of
acid) and ethyl acetoacetate (262 mg, 2.02 mmol) as a colourless oil (474 mg, 65% yield);
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FTIR 1430, 1465, 1507, 1583, 1653, 1729, 1755 cmꢀ1; H NMR (400 MHz, CDCl3) δ 8.09ꢀ
8.03 (m, 1H), 7.90 (dd, 1H, J1 = 7.6 Hz, J2 = 1.6 Hz), 7.50ꢀ7.42 (m, 1H), 7.27ꢀ7.19 (m, 1H),
5.87 (s, 1H), 4.22 (q, 2H, J = 7.2 Hz), 2.51 (s, 3H), 1.31 (t, 3H, J = 7.2 Hz); 13C NMR (100
MHz, CDCl3) δ 165.8, 165.7, 165.6, 141.7, 133.4, 131.5, 128.1, 110.7, 94.5, 60.3, 18.2, 14.2.
HRMS (ESI ꢀTOF) m/z calcd for C13H14IO4 [M+H]+ 360.9937; Found 360.9928.
(E)-3-ethoxy-3-oxo-1-phenylprop-1-en-1-yl 2-iodobenzoate (1p): Following method B,
compound 1p was obtained from the reaction of 2ꢀiodobenzoyl chloride (in situ prepared
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from 500 mg of acid) and ethyl benzoylacetate (387 mg, 2.02 mmol) as yellow solid (538
mg, 63% yield); mp 98°C; FTIR 1430, 1464, 1507, 1583, 1653, 1730, 1756 cmꢀ1; 1H NMR
(400 MHz, CDCl3) δ 8.34 (d, 1H , J = 8 Hz), 8.10 (d, 1H, J = 8 Hz), 7.68 (d, 2H, J = 8 Hz),
7.57ꢀ7.49 (m, 1H), 7.49ꢀ7.40 (m, 3H), 7.29ꢀ7.22(m, 1H), 6.40 (s, 1H), 4.19 (q, 2H, J = 7.2
Hz), 1.24 (t, 3H, J = 7.2 Hz) ;13C NMR (100 MHz, CDCl3) δ 164.0, 162.9, 157.7, 141.7,
133.4, 133.2, 133.0, 132.3, 131.0, 128.8, 128.1, 126.1, 106.8, 95.2, 60.4, 14.1. HRMS (ESI ꢀ
TOF) m/z calcd for C18H16IO4 [M+H]+ 423.0093; Found 423.0085.
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(E)-4-oxopent-2-en-2-yl 2-iodobenzoate (1q): Following method B, compound 1q was
obtained from the reaction of 2ꢀiodobenzoyl chloride (in situ prepared from 500 mg of acid)
and acetylacetone (202 mg, 2.02 mmol) as a colourless oil in (407 mg, 61% yield); FTIR
1430, 1464, 1507, 1583, 1653, 1730, 1756 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.06 (d, 1H ,
J = 8 Hz), 7.93ꢀ7.87 (m, 1H), 7.51ꢀ7.43 (m, 1H), 7.27ꢀ7.19 (m, 1H), 6.27 (s, 1H), 2.47 (s,
1H), 2.28 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 163.5, 162.5, 141.8, 133.5, 133.4, 131.5,
128.2, 128.1, 116.7, 94.6, 32.2, 18.6. MS ESI (GC) m/z 330 [M]+, 231 (100); HRMS (ESI ꢀ
TOF) m/z calcd for C12H12IO3 [M+H]+ 330.9831; Found 330.9823.
(E)-3-ethoxy-3-oxoprop-1-en-1-yl benzoate23 (4a): Following method A, compound 4a was
obtained from the reaction of benzoic acid (500 mg, 4.09 mmol) and ethyl propiolate (441
mg, 4.50 mmol) as a colourless oil (766 mg, 85% yield); FTIR 1430, 1464, 1507, 1583, 1653,
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1730, 1756 cmꢀ1; H NMR (400 MHz, CDCl3) δ 8.55 (d, 1H, J = 12.4 Hz), 8.12 (d, 2H, J = 8
Hz), 7.67ꢀ7.61 (m, 1H), 7.51 (t, 2H, J = 8 Hz), 5.91 (d, 1H, J = 12.4 Hz), 4.25 (q, 2H, J = 7.2
Hz), 1.32 (t, 3H, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 166.2, 162.5, 149.8, 134.4,
130.3, 128.7, 127.6, 106.4, 60.5, 14.2. MS ESI (GC) m/z 220 [M]+, 105 (100).
(E)-4-ethoxy-4-oxobut-2-en-2-yl benzoate24(4b): Following method C, compound 4b was
obtained from the reaction of benzoyl chloride (500 mg, 3.57 mmol) and ethyl acetoacetate
(463 mg, 3.56 mmol) as a colourless oil (624 mg, 75 % yield); FTIR 1429, 1464, 1506, 1583,
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1653, 1730, 1755 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.07 (d, 2H, J = 7.6 Hz), 7.65ꢀ7.57 (m,
1H), 7.47 (t, 2H, J = 7.6 Hz), 5.82 (s, 1H), 4.19 (q, 2H, J = 7.2 Hz), 2.48 (s, 3H), 1.28 (t, 3H,
J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 165.9, 164.1, 163.9, 133.8, 130.0, 128.8, 128.4,
110.4, 60.2, 18.2, 14.2. MS ESI (GC) m/z 234 [M]+, 105 (100).
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4-oxopent-2-en-2-yl benzoate24 (4c): Following method C, compound 4c was obtained from
the reaction of benzoyl chloride (500 mg, 3.57 mmol) and acetylacetone (357 mg, 3.57
mmol) as a mixture (E:Z = 2:1) (530 mg, 73% yield); FTIR 1430, 1464, 1507, 1583, 1653,
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1730, 1756 cmꢀ1; For E isomer: colourless liquid; H NMR (400 MHz, CDCl3) δ 8.12ꢀ8.01
(m, 2H), 7.68ꢀ7.56 (m, 1H), 7.55ꢀ7.40 (m, 2H), 6.24 (s, 1H), 2.45 (s, 3H), 2.26 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ 197.4, 164.0, 162.9, 133.9, 130.0, 129.0, 128.6, 116.6, 32.2, 18.7.
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For Z isomer: colourless liquid; H NMR (400 MHz, CDCl3) δ8.14ꢀ8.04 (m, 2H), 7.67ꢀ7.55
(m, 1H), 7.55ꢀ7.44 (m, 2H), 5.89 (s, 1H), 2.18 (s, 3H), 2.13 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 195.5, 163.4, 158.2, 133.9, 130.1, 129.1, 128.3, 117.3, 31.0, 21.4. MS ESI (GC)
m/z 204 [M]+, 105 (100).
General procedure for preparation of isocoumarin from 2ꢀiodo enol esters (1) (Method
Ι)
A mixture of enol ester 1 (50 mg), AgOAc (1 equiv), dimethly aminopyridine (DMAP) (1.2
equiv) in CH3CN (2 mL) was stirred at room temperature for 12h. Completion of the reaction
was monitored by TLC. Then the reaction mixture was charged for column chromatography
over silica gel using a mixture of petroleum ether and ethyl acetate (9:1) as an eluent to
enable the desired isocoumarin.
General procedure for the synthesis of isocoumarin from 2ꢀiodo benzoic acid (3) at
room temperature (Method ΙΙ)
A mixture of enol ester 4a (50 mg), 2ꢀiodobenzoic acid (1 equiv), AgOAc (1 equiv), DMAP
(2 equiv) in CH3CN (2 mL) was stirred at room temperature for 12 h. Then the reaction
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mixture was charged for column chromatography over silica gel using a mixture of petroleum
ether and ethyl acetate (9:1) as an eluent to produce the desired isocoumarin.
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General procedure for the synthesis of isocoumarin from 2ꢀiodo benzoic acid (3) at 50°C
(Method ΙIΙ)
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A mixture of enol ester (4b or 4c) (50 mg), 2ꢀiodobenzoic acid (1 equiv), AgOAc (1 equiv),
DMAP (2 equiv) in CH3CN (2 mL) was heated at 50°C for 12h. Then the reaction mixture
was charged for column chromatography over silica gel using a mixture of petroleum ether
and ethyl acetate (9:1) as an eluent to afford the desired isocoumarin.
Ethyl 1-oxo-1H-isochromene-4-carboxylate (2a): Following method Ι, compound 2a was
prepared from the Agꢀmediated annulation of 1a as a white solid (30 mg, 95% yield).
Following method ΙΙ, compound 2a was also prepared from the reaction of 2ꢀiodobenzoic
acid (3a) and enolꢀester (4a) as a white solid (39 mg, 79 % yield): mp 68°C; FTIR 2940,
1744, 1728, 1492, 1483, 1468, 1442, 1418 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.69 (d, 1H, J
= 8.4 Hz), 8.35 (dd, 1H, J1 = 8 Hz, J2 = 1.2 Hz), 8.22 (s, 1H), 7.80ꢀ7.89 (m, 1H), 7.57ꢀ7.65
(m, 1H), 4.41 (q, 2H, J = 7.2 Hz), 1.43 (t, 3H, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ
164.0, 160.9, 152.4, 135.4, 133.6, 129.9, 129.0, 125.4, 120.4, 110.1, 61.2, 14.2. HRMS (ESIꢀ
TOF) m/z calcd for C12H11O4 [M+H]+ 219.0659; Found 219.0648.
Propyl 1-oxo-1H-isochromene-4-carboxylate (2b): Following method Ι, compound 2b was
prepared from 1b as colourless liquid (21 mg, 65% yield): FTIR 2940, 1744, 1736, 1728,
1492, 1483, 1468, 1459 1442, 1418 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.67 (d, 1H, J = 8.4
Hz), 8.34 (dd, 1H, J1 = 8 Hz, J2 = 1.2 Hz), 8.21 (s, 1H), 7.79ꢀ7.87 (m, 1H), 7.56ꢀ7.64 (m, 1H),
4.30 (t, 2H, J = 6.6 Hz), 1.75ꢀ1.88 (m, 2H), 1.05 (t, 3H, J = 7.2 Hz); 13C NMR (100 MHz,
CDCl3) δ 164.1, 160.8, 152.4, 135.4, 133.6, 129.9, 129.0, 125.4, 120.4, 110.1, 66.8, 22.0,
10.5. HRMS (ESIꢀTOF) m/z calcd for C13H13O4 [M+H]+ 233.0816; Found 233.0806.
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Butyl 1-oxo-1H-isochromene-4-carboxylate (2c): Following method Ι, compound 2c was
prepared from 1c as a white solid (25 mg, 76% yield): mp 57°C; FTIR 2925, 1752, 1744,
1736, 1492, 1483, 1468, 1459, 1427, 1418 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.67 (d, 1H, J
= 8 Hz), 8.34 (dd, 1H, J1 = 8 Hz, J2 = 1.2 Hz), 8.20 (s, 1H), 7.79ꢀ7.88 (m, 1H), 7.56ꢀ7.64 (m,
1H), 4.35 (t, 2H, J = 6.6 Hz), 1.71ꢀ1.82 (m, 2H), 1.43ꢀ1.53 (m, 2H), 1.00 (t, 3H, J = 7.4 Hz);
13C NMR (100 MHz, CDCl3) δ 164.1, 160.9, 152.4, 135.4, 133.6, 129.9, 129.0, 125.4, 120.4,
110.1, 65.1, 30.6, 19.2, 13.7. HRMS (ESIꢀTOF) m/z calcd for C14H15O4 [M+H]+ 247.0972;
Found 247.0962.
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Pentyl 1-oxo-1H-isochromene-4-carboxylate (2d): Following method Ι, compound 2d was
prepared from 1d as yellowish liquid (25 mg, 74% yield): FTIR 2925, 1744, 1728, 1492,
1483, 1459, 1427, 1428 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.67 (d, 1H, J = 8 Hz), 8.34 (d,
1H, J = 8 Hz), 8.20 (s, 1H), 7.83 (t, 1H, J = 7.6 Hz), 7.59 (t, 1H, J = 7.6 Hz), 4.33 (t, 2H, J =
6.8 Hz), 1.71ꢀ1.82 (m, 2H), 1.38ꢀ1.45 (m, 4H), 0.91ꢀ.098 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ 164.1, 160.9, 152.4, 135.4, 133.6, 129.9, 129.0, 125.4, 120.4, 110.1, 65.4, 28.3,
28.1, 22.3, 14.0. HRMS (ESIꢀTOF) m/z calcd for C15H17O4 [M+H]+ 261.1129; Found
261.1120.
Octyl 1-oxo-1H-isochromene-4-carboxylate (2e): Following method Ι, compound 2e was
prepared from1e as a colourless liquid (28 mg, 80% yield): FTIR 2950, 1744, 1728, 1492,
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1468, 1442, 1427, 1418 cmꢀ1; H NMR (400 MHz, CDCl3) δ 8.68 (d, 1H, J = 8Hz), 8.35 (dd,
1H, J1 = 7.8 Hz, J2 = 1 Hz), 8.21 (s, 1H), 7.80ꢀ7.89 (m, 1H), 7.57ꢀ7.65 (m, 1H), 4.34 (t, 2H, J
= 6.6 Hz), 1.73ꢀ1.84 (m, 2H), 1.24ꢀ1.48 (m, 10H), 0.86ꢀ0.94 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ 164.1, 160.9, 152.4, 135.4, 133.6, 129.9, 129.0, 125.4, 120.4, 110.2, 65.4, 31.7,
29.2, 29.1, 28.6, 26.0, 22.6, 14.1. HRMS (ESIꢀTOF) m/z calcd for C18H23O4 [M+H]+
303.1598; Found 303.1592.
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Cyclohexyl 1-oxo-1H-isochromene-4-carboxylate (2f): Following method Ι, compound 2f
was prepared from 1f as a colourless liquid (22 mg, 66% yield): FTIR 1744, 1736, 1728,
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1492, 1483, 1468, 1442, 1418 cmꢀ1; H NMR (400 MHz, CDCl3) δ 8.68 (d, 1H, J = 8 Hz),
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8.35 (dd, 1H, J1 = 7.6 Hz, J2 = 1.2 Hz), 8.20 (s, 1H), 7.80ꢀ7.88 (m, 1H), 7.56ꢀ7.64 (m, 1H),
5.01ꢀ5.11 (m, 1H), 1.37ꢀ1.66 (m, 10H); 13C NMR (100 MHz, CDCl3) δ 163.5, 160.9, 152.2,
135.3, 133.7, 129.9, 128.9, 125.4, 120.4, 110.5, 73.7, 31.6, 25.3, 23.7. HRMS (ESI ꢀTOF)
m/z calcd for C16H17O4 [M+H]+ 273.1129; Found 273.1118.
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Benzyl 1-oxo-1H-isochromene-4-carboxylate (2g): Following method Ι, compound 2g was
prepared from 1g as a white solid (18 mg, 53% yield): mp 76°C; 1H NMR (400 MHz, CDCl3)
δ 8.69 (d, 1H, J = 8 Hz), 8.34 (dd, 1H, J1 = 8 Hz, J2 = 1.2 Hz), 8.25 (s, 1H), 7.79ꢀ7.88 (m,
1H), 7.56ꢀ7.64 (m, 1H), 7.37ꢀ7.49 (m, 5H), 5.38 (s, 2H); 13C NMR (100 MHz, CDCl3) δ
163.8, 160.7, 152.8, 135.4, 135.3, 133.5, 130.0, 129.0, 128.7, 128.7, 128.6, 128.4, 125.3,
120.4, 109.9, 66.9. HRMS (ESIꢀTOF) m/z calcd for C17H13O4 [M+H]+ 281.0816; Found
281.0808.
Allyl 1-oxo-1H-isochromene-4-carboxylate (2h): Following method Ι, compound 2h was
prepared from 1h as a white solid (19 mg, 60% yield): mp 59°C; 1H NMR (400 MHz, CDCl3)
δ 8.69 (d, 1H, J = 8.4 Hz), 8.35 (dd, 1H, J1 = 8 Hz, J2 = 1.2 Hz), 8.26 (s, 1H), 7.80ꢀ7.88 (m,
1H), 7.57ꢀ7.65 (m, 1H), 5.97ꢀ6.11 (m, 1H), 5.39ꢀ5.44 (m, 1H), 5.35 (dd, 1H, J1 = 10.4 Hz,
J2=1.2 Hz), 4.81ꢀ4.87 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 163.7, 160.8, 152.7, 135.4,
133.5, 131.6, 130.0, 129.1, 125.3, 120.4, 119.1, 109.9, 65.8. HRMS (ESI ꢀTOF) m/z calcd for
C13H11O4 [M+H]+ 231.0659; Found 231.0649.
Prop-2-yn-1-yl 1-oxo-1H-isochromene-4-carboxylate (2i): Following method Ι, compound
2i was prepared from 1i as a white solid (22 mg, 70% yield): mp 104°C; FTIR 2323, 1744,
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1728, 1647, 1492, 1451, 1427, 1408 cmꢀ1; H NMR (400 MHz, CDCl3) δ 8.68 (d, 1H, J =
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8.4Hz), 8.35 (dd, 1H, J1 = 8Hz, J2 = 1.2Hz), 829 (s, 1H), 7.81ꢀ7.90 (m, 1H), 7.58ꢀ7.66 (m,
1H), 4.95 (d, 2H, J = 2.4Hz), 2.58 (t, 1H, J = 2.4Hz); 13C NMR (100 MHz, CDCl3) δ 163.2,
160.6, 153.2, 135.5, 133.2, 130.0, 129.2, 125.3, 120.3, 109.3, 77.1, 75.6, 52.5. HRMS (ESI ꢀ
TOF) m/z calcd for C13H9O4 [M+H]+ 229.0503; Found 229.0494.
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p-Tolyl 1-oxo-1H-isochromene-4-carboxylate (2j): Following method Ι, compound 2j was
prepared from 1j as a white solid (16 mg, 47% yield): mp 76°C; 1H NMR (400 MHz, CDCl3)
δ 8.72 (d, 1H, J = 8Hz), 8.51 (S, 1H), 8.39 (dd, 1H, J1 = 6.8Hz, J2 = 1.2Hz), 7.82ꢀ7.90 (m,
1H), 7.60ꢀ7.68 (m, 1H), 7.27 (d, 2H, J = 8.4Hz), 7.10 (dd, 2H, J1 = 6.4Hz, J2 = 2Hz), 2.41 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 162.8, 160.6, 153.6, 147.7, 136.1, 135.6, 133.3, 130.1,
130.0, 129.2, 125.4, 121.3, 120.3, 109.5, 20.9. HRMS (ESI ꢀTOF) m/z calcd for C17H13O4
[M+H]+ 281.0184; Found 281.0180.
2-methoxyethyl 1-oxo-1H-isochromene-4-carboxylate (2k): Following method Ι, compound
1
2k was prepared 1k as a white solid (23 mg, 71% yield): mp 58°C; H NMR (400 MHz,
CDCl3) δ 8.66 (d, 1H, J = 8.4 Hz), 8.35 (dd, 1H, J1 = 8 Hz, J2 = 2.8 Hz), 8.26 (s, 1H), 7.80ꢀ
7.88 (m, 1H), 7.57ꢀ7.65 (m, 1H), 4.47ꢀ4.53 (m, 2H), 3.71ꢀ3.77 (m, 2H), 3.45 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 164.0, 160.8, 152.7, 135.4, 133.5, 130.0, 129.0, 125.3, 120.3,
109.9, 70.3, 64.1, 59.0. HRMS (ESIꢀTOF) m/z calcd for C13H13O5 [M+H]+ 249.0765; found
249.0755.
4-(4-methoxybenzoyl)-1H-isochromen-1-one (2l): Following method Ι, compound 2l was
prepared from 1l as a white solid (25 mg, 72% yield): mp 76°C; 1H NMR (400 MHz, CDCl3)
δ 8.40 (d, 1H, J = 8 Hz), 8.0 (d, 1H, J = 8 Hz), 7.92 (dd, 2H, J1 = 6.8 Hz, J2 = 2 Hz), 7.76ꢀ
7.84 (m, 1H), 7.59ꢀ 7.67 (m, 2H), 7.01 (dd, 2H, J1 = 7 Hz, J2 = 1.8 Hz), 3.92 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 190.8, 164.2, 160.8, 149.7, 135.2, 134.3, 132.4, 130.3, 130.0,
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129.3, 125.2, 120.9, 118.2, 114.0, 55.6. HRMS (ESI ꢀTOF) m/z calcd for C17H13O4 [M+H]+
281.0814; Found 281.0806.
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Ethyl 8-methyl-1-oxo-1H-isochromene-4-carboxylate (2m): Following method Ι, compound
2m was prepared from 1m as a colourless liquid (20 mg, 63% yield). Following method ΙΙ,
compound 2m was also prepared from the reaction of 3d and 4a as a white solid (25 mg, 48%
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yield): FTIR 2925, 2877, 1744, 1728, 1492, 1483, 1468, 1435 cmꢀ1; H NMR (400 MHz,
CDCl3) δ 8.53 (d, 1H, J = 8.4 Hz), 8.16 (s, 1H), 7.67 (t, 1H, J = 7.8 Hz ), 7.39 (d, 1H, J = 7.6
Hz), 4.39 (q, 2H, J = 7.2 Hz), 2.83 (s, 3H), 1.41 (t, 3H, J = 7 Hz); 13C NMR (100 MHz,
CDCl3) δ 164.3, 160.0, 152.3, 143.8, 135.0, 134.5, 132.0, 123.2, 118.8, 110.2, 61.1, 23.8,
14.2; HRMS (ESI ꢀTOF) m/z calcd for C13H13O4 [M+H]+ 233.0816; Found 233.0804.
Ethyl 7-iodo-1-oxo-1H-isochromene-4-carboxylate (2n): Following method Ι, compound 2n
was prepared from the reaction of 1n as a white solid (16 mg, 45% yield). Following method
ΙΙ, compound 2n was also prepared from the reaction of 3b and 4a as a white solid (33 mg,
1
42% yield); mp 128°C; FTIR 2910, 1752, 1736, 1728, 1483, 1459, 1435, 1418; H NMR
(400 MHz, CDCl3) δ 8.68 (d, 1H, J = 2 Hz), 8.45 (d, 1H , J = 8.8 Hz), 8.24 (s, 1H), 8.12 (dd,
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1H, J1=8.4 Hz, J2 = 2 Hz), 4.40 (q, 2H, J = 7.2 Hz), 1.41 (t, 3H, J = 7.2 Hz); C NMR (100
MHz, CDCl3) δ 163.7, 159.3, 152.8, 144.1, 138.5, 132.8, 127.1, 121.8, 109.7, 94.0, 61.4,
14.2. HRMS (ESI ꢀTOF) m/z calcd for C12H10IO4 [M+H]+ 344.9626; Found 344.9618.
Ethyl 3-methyl-1-oxo-1H-isochromene-4-carboxylate25 (2o): Following method Ι,
compound 2o was prepared from the reaction of 1o as yellowish liquid (25 mg, 78% yield).
Following method ΙΙ, compound 2o was also prepared from the reaction of 3a and 4b as
yellowish liquid (32 mg, 65% yield): FTIR 2925, 1752, 1736, 1720, 1712, 1492, 1483, 1475,
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1459, 1442 cmꢀ1; H NMR (400 MHz, CDCl3) δ 8.29 (dd, 1H, J1 = 7.6 Hz, J2 = 0.8 Hz), 7.70ꢀ
7.81 (m, 2H), 7.48ꢀ7.56 (m, 1H), 4.46 (q, 2H, J = 7.2 Hz), 2.47 (s, 3H), 1.44 (t, 3H, J = 7.2
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Hz); 13C NMR (100 MHz, CDCl3) δ 165.8, 161.2, 157.6, 135.1, 134.6, 129.6, 128.1, 124.1,
119.4, 110.2, 61.7, 19.3, 14.2.
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Ethyl 1-oxo-3-phenyl-1H-isochromene-4-carboxylate25 (2p): Following method Ι,
compound 2p was prepared from 1p as colourless liquid (18 mg, 51% yield): FTIR 2975,
1744, 1736, 1712, 1483, 1468, 1460, 1459, 1451, 1043 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ
8.39 (dd, 1H, J1 = 7.2 Hz, J2 = 1.2 Hz), 8.03 (dd, 1H, J1 = 8.8 Hz, J2 = 1.8 Hz), 7.73ꢀ7.84 (m,
2H), 7.63ꢀ7.69 (m, 2H), 7.49 7.64 (m, 1H), 7.26ꢀ7.52 (m, 3H), 4.22 (q, 2H, J = 7.2 Hz), 1.06
(t, 3H, J = 7.0 Hz) ; 13C NMR (100 MHz, CDCl3) δ 166.3, 161.1, 155.4, 135.3, 134.6, 132.6,
130.5, 129.9, 128.8, 128.4, 128.1, 124.1, 119.8, 110.9, 61.9, 13.56.
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4-acetyl-3-methyl-1H-isochromen-1-one26 (2q): Following method Ι, compound 2q was
prepared from 1q as a white solid (20 mg, 65% yield). Following method ΙΙI, compound 2q
was also prepared from the reaction of 3a and 4c as a white solid (23 mg, 47% yield): mp
102°C; FTIR 1752, 1736, 1696, 1492, 1459, 1442, 1427, 1418 cmꢀ1; 1H NMR (400 MHz,
CDCl3) δ 8.33 (dd, 1H, J1 = 7.6 Hz, J2 = 1.0 Hz), 7.71ꢀ7.79 (m, 1H), 7.51ꢀ7.58 (m, 1H), 7.34
(d, 1H, J = 8 Hz), 2.60 (s, 3H), 2.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 201.3, 161.3,
152.6, 135.1, 134.3, 130.1, 128.3, 123.0, 119.8, 118.5, 32.4, 18.3.
Ethyl 7-chloro-1-oxo-1H-isochromene-4-carboxylate (5a): Following method ΙΙ, compound
5a was prepared from the reaction of 3c and 4a as a white solid (36 mg, 63% yield): mp
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94°C; FTIR 2925, 2901, 1736, 1720, 1712, 1483, 1468, 1451, 1435 cmꢀ1; H NMR (400
MHz, CDCl3) δ 8.66 (d, 1H, J = 8.8 Hz), 8.28 (d, 1H, J = 2.4 Hz), 8.21 (s, 1H), 7.76 (dd, 1H,
J1 = 8.8 Hz, J2 = 2.4 Hz), 4.40 (q, 2H, J = 7.2 Hz), 1.41 (t, 3H, J = 7.2 Hz); 13C NMR (100
MHz, CDCl3) δ 163.7, 159.7, 152.5, 135.6, 135.0, 132.0, 129.3, 127.2, 121.7, 109.6, 61.4,
14.2. MS ESI (GC) m/z 252 [M]+, 168 (100); HRMS (ESI ꢀTOF) m/z calcd for C12H10ClO4
[M+H]+ 253.0268; Found 253.0258.
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Ethyl 7-iodo-3-methyl-1-oxo-1H-isochromene-4-carboxylate (5b): Following method ΙIΙ,
compound 5b was prepared from the reaction of 3b and 4b as a white solid (37 mg, 48%
yield): mp 100°C; 1H NMR (400 MHz, CDCl3) δ 8.63 (d, 1H, J = 2 Hz), 8.03 (dd, 1H, J1=8.8
Hz, J2=1.8 Hz), 7.58 (d, 1H, J = 8.4 Hz), 4.46 (q, 2H, J = 7.2 Hz), 2.47 (s, 3H), 1.44 (t, 3H, J
= 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 165.3, 159.6, 158.84, 143.7, 138.2, 133.9, 125.9,
120.9, 109.7, 92.6, 61.8, 19.6, 14.2. MS ESI (GC) m/z 358 [M]+ (100); HRMS (ESI ꢀTOF)
m/z calcd for C13H12IO4 [M+H]+ 358.9780; found 358.9768.
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Ethyl 7-chloro-3-methyl-1-oxo-1H-isochromene-4-carboxylate (5c): Following method ΙIΙ,
compound 5c was prepared from the reaction of 3c and 4b as a white solid (31 mg, 55%
yield): mp 98°C; FTIR 2925, 1744, 1736, 1720, 1475, 1459, 1451, 1435, 1412, 669 cmꢀ1; 1H
NMR (400 MHz, CDCl3) δ 8.26 (d, 1H, J = 2.4 Hz), 7.80 (d, 1H, J = 8.4 Hz), 7.69 (dd, 1H, J1
= 9 Hz, J2 = 2.2 Hz), 4.46 (q, 2H, J = 7.2 Hz), 2.49 (s, 3H), 1.44 (t, 3H, J = 7 Hz); 13C NMR
(100 MHz, CDCl3) δ 165.4, 460.1, 158.5, 135.4, 134.1, 133.0, 129.0, 126.0, 120.7, 109.6,
61.9, 19.5, 14.2. MS ESI (GC) m/z 266 [M]+, 220 (100); HRMS (ESIꢀTOF) m/z calcd for
C13H12ClO4 [M+H]+ 267.0424; Found 267.0417.
4-Acetyl-7-iodo-3-methyl-1H-isochromen-1-one (5d): Following method ΙΙI, compound 5d
was prepared from the reaction of 3b and 4c as a white solid (36 mg, 45% yield): mp 128°C;
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FTIRꢀ1752, 1736, 1720, 1696, 1492, 1483, 1459, 1427, 1418cmꢀ1; H NMR (400 MHz,
CDCl3) δ 8.66 (d, 1H, J = 2 Hz), 8.02 (dd, 1H, J1 = 8.4 Hz, J2 = 2.0 Hz), 7.10 (d, 1H, J = 8.4
Hz), 2.58 (s, 3H), 2.33 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 200.6, 159.7, 153.5, 143.8,
138.7, 133.5, 124.7, 121.2, 118.11, 92.7, 32.4, 18.6. MS ESI (GC) m/z 328 [M]+ (100);
HRMS (ESIꢀTOF) m/z calcd for C12H10IO3 [M+H]+ 328.9675; Found 328.9667.
4-Acetyl-7-chloro-3-methyl-1H-isochromen-1-one (5e): Following method ΙΙI, compound
5e was prepared from the reaction of 3c and 4c as a yellow solid (24 mg, 41% yield): mp
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128°C; FTIR 1736, 1720, 1696, 1492, 1483, 1459, 1427, 1418, 669 cmꢀ1; H NMR (400
MHz, CDCl3) δ 8.26 (d, 1H, J = 2.4 Hz), 7.68 (dd, 1H, J1 = 8.8 Hz, J2 = 2.4 Hz), 7.32 (d, 1H,
J = 8.8 Hz), 2.59 (s, 3H), 2.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 200.6, 160.1, 153.2,
135.4, 134.3, 132.7, 129.5, 124.8, 121.1, 117.9, 32.4, 18.5. MS ESI (GC) m/z 236 [M]+, 221
(100); HRMS (ESIꢀTOF) m/z calcd for C12H10ClO3 [M+H]+ 237.0318; Found 237.0309.
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4-acetyl-3,8-dimethyl-1H-isochromen-1-one (5f): Following method ΙΙI, compound 5f was
prepared from the reaction of 3d and 4c as a white solid (26 mg, 49% yield): mp 102°C;
FTIR 2942, 1752, 1736, 1696, 1492, 1483, 1459, 1427, 1418 cmꢀ1; H NMR (400 MHz,
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CDCl3) δ 7.58 (t, 1H, J = 7.8 Hz), 7.32 (d, 1H, J = 7.6 Hz), 7.10 (d, 1H, J = 8.0 Hz), 2.83 (s,
3H), 2.56 (s, 3H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 202.0, 160.7, 151.7, 144.2,
135.8, 134.3, 131.2, 120.9, 118.8, 118.2, 32.4, 23.5, 18.0. MS ESI (GC) m/z 216 [M]+, 201
(100); HRMS (ESIꢀTOF) m/z calcd for C13H13O3 [M+H]+ 217.0865; Found 217.0855.
4-acetyl-3-methyl-1-oxo-1H-isochromene-7-carbonitrile (5g): Following method ΙIΙ,
compound 5g was prepared from the reaction of 3e and 4c as a white solid (22 mg, 40%
yield): mp 172°C; FTIR 2371, 1752, 1736, 1696, 1492, 1483, 1459, 1427, 1418 cmꢀ1; H
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NMR (400 MHz, CDCl3) δ 8.61 (d, 1H, J = 1.6 Hz), 7.95 (dd, 1H, J1 = 8.8 Hz, J2 = 1.8 Hz),
7.49 (d, 1H, J = 8.4 Hz), 2.61 (s, 3H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 199.9,
159.2, 156.3, 137.6, 137.3, 134.5, 124.3, 120.3, 117.8, 117.2, 112.1, 32.5, 18.9. MS ESI (GC)
m/z 227 [M]+, 212 (100); HRMS (ESIꢀTOF) m/z calcd for C13H10NO3 [M+H] 228.0661;
Found 228.0656.
ASSOCIATED CONTENT
Supporting Information
Copies of 1H and 13C NMR of enol esters and isocoumarins. This material is available free of
charge via the Internet at http://pubs.acs.org.
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