Critical Ligand and Salt Effects in Organomagnesiate-Promoted 3,3-Disubstituted Phthalides Synthesis from 2-Iodobenzoate Derivatives

Article abstract of DOI:10.1002/ejoc.202100899

Phthalides, also called isobenzofuranones, are widespread in many biologically active compounds and natural products. To date, most of their synthetic routes are non-convergent. Herein we report a convergent route using a metal halogen exchange (MHE) strategy. Indeed MHE of easily available 2-iodobenzoate derivatives, using the bimetallic organomagnesiate complex (rac)-(BIPHEN)BuMgLi, where (rac)-BIPHEN is (rac)-5,5′,6,6′-tetramethyl-3,3′-di-t-butyl-1,1′-biphenyl-2,2′-diol, followed by addition of a ketone which lead to an intramolecular cyclisation, and the formation of a series of diverse 3,3-disubstituted isobenzofuranones in good yield. Among the several MHE agents investigated, (rac)-(BIPHEN)BuMgLi was the only one to make such a process possible with full tolerance of various reactive functional substituents useful for subsequent transformations. The synthetic pathway to access the magnesiate has been found to play a prominent role in its reactivity. Therefore, the bimetallic magnesiate complex has been characterized by solution-state ¹H, ⁷Li and ¹H DOSY NMR experiments.

Full text of DOI:10.1002/ejoc.202100899

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Very Important Paper
Critical Ligand and Salt Effects in Organomagnesiate-
Promoted 3,3-Disubstituted Phthalides Synthesis from
2-Iodobenzoate Derivatives
Sabrina Touchet,*[a] Callum Yeardley,[b] Charles T. O’Hara,[b] and Philippe C. Gros[a]
Phthalides, also called isobenzofuranones, are widespread in
many biologically active compounds and natural products. To
date, most of their synthetic routes are non-convergent. Herein
we report a convergent route using a metal halogen exchange
(MHE) strategy. Indeed MHE of easily available 2-iodobenzoate
derivatives, using the bimetallic organomagnesiate complex
(rac)-(BIPHEN)BuMgLi, where (rac)-BIPHEN is (rac)-5,5’,6,6’-
tetramethyl-3,3’-di-t-butyl-1,1’-biphenyl-2,2’-diol, followed by
addition of a ketone which lead to an intramolecular cyclisation,
and the formation of a series of diverse 3,3-disubstituted
isobenzofuranones in good yield. Among the several MHE
agents investigated, (rac)-(BIPHEN)BuMgLi was the only one to
make such a process possible with full tolerance of various
reactive functional substituents useful for subsequent trans-
formations. The synthetic pathway to access the magnesiate
has been found to play a prominent role in its reactivity.
Therefore, the bimetallic magnesiate complex has been charac-
1
7
1
terized by solution-state H, Li and H DOSY NMR experiments.
Introduction
Phthalides are prevalent in biologically active compounds and
natural products.[1–5] In addition, these heterocycles can serve as
versatile building blocks for the synthesis of natural and
pharmaceutically-important products. Indeed, many patents
deal with the syntheses and biological activity of these
compounds. Among them, 3,3-disubstituted phthalides have
demonstrated the broad applicability in medicinal chemistry as
Figure 1. Bioactive 3,3-disubstituted isobenzofuranones.
anti-HIV[6–8] and anticancer agents,[9] protein kinase
C
modulators[10] or cytosolic phospholipase A2α inhibitor[11] (Fig-
ure 1). They can also have an influence on the innate immune
system[12] or as vasodilators.[13]
Given their important bioactivities, efforts have been
dedicated to the development of new methodologies to
prepare 3,3-disubstituted phthalide derivatives. Many of these
methods are non-convergent synthetic routes and rely on
intramolecular cyclization, requiring relatively complex synthe-
ses of the starting materials in order to bring diversity to the
final phthalides. For instance, as shown in Scheme 1, the first
route involved ortho-alkyl benzoic acids followed by oxidation
of the alkyl chain and ring closing (Scheme 1A[14]).[15–17] The
second was a copper-catalyzed cyclization of ortho-bromo-
benzylalcohols (Scheme 1B).[18] The third methodology (Sche-
me 1C) can be classified as a convergent synthetic route as a
part of the hydrocarbon chain (R2) of the product comes from a
second reagent. However, R1 of the product come from the
[a] Dr. S. Touchet, Dr. P. C. Gros
Université de Lorraine, CNRS, L2CM
54000, Nancy, France
E-mail: sabrina.touchet@univ-lorraine.fr
[b] Dr. C. Yeardley, Dr. C. T. O’Hara
WestCHEM, University of Strathclyde
295 Cathedral Street, Glasgow, G1 1XL, UK
Scheme 1. Routes to access 3,3-disubstituted isobenzofuranones.
Supporting information for this article is available on the WWW under
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starting material. This route used ortho-carboxy styrene as
starting material via a copper-catalyzed reaction involving
bromo-derivatives[19] or organotrifluoroborates[20] as coupling
partner or via an arylation-lactonization sequence involving
primary amines.[21]
The fourth methodology (Scheme 1E) is the only convergent
route allowing the introduction of R2 and R3 by the second
reagent; however, unlike the other strategies, generally a lower
level of chemical diversity is possible. These involve metal
halogen exchange (MHE) of easily available 2-iodobenzoates
followed by addition of a few ketones from the pool and
intramolecular addition of the transiently formed alkoxide to
the ester function (Scheme 1D).[22,23] However, these reactions
suffer from limitations regarding the starting materials and
carbonyl electrophiles. Indeed, in case of the use of a lithium
derivative,[22] the ester itself had to be sterically hindered
enough to avoid nucleophilic attack prior to the cyclization
process. Due to the basicity of the organometallic intermedi-
ates, these reactions were generally restricted to the use of
non-enolizable ketones.[23]
Scheme 2. Study of the magnesation-lactonization reaction and preparation
of reagents containing alkoxide.
Thus, it appears that a convergent strategy allowing a
general access to various 3,3-disubstituted phthalides is not yet
available (Scheme 1E). Our group has shown that the incorpo-
Table 1. Screening of MHEA in the magnesation-lactonization process.[a]
[b]
Entry
MHEA (eq.)
T1 [ C]
T1 [ C]
2e %c
°
°
ration of an anionic dialkoxide ligand within
a lithium
1
2
3
4
5
6
7
8
nBuLi (1)
À 78
À 78[d]
0
0
0
0
0
7
10
75
0
magnesiate conferred interesting properties to the metalation
agent and formed intermediates with an increased chemo-
selectivity and reactivity towards electrophiles. Subsequently,
this gave rise to the possibility of performing the syntheses of
enantioselective secondary alcohols using chiral ligands.[24–26]
More recently, we reported that the bimetallic (S)-(BIPHEN)
BuMgLi reagent promoted the chemo- and enantioselective
magnesiation-lactonization of 2-iodo-ethylbenzoate leading to
a panel of chiral 3-substituted isobenzofuranones with a good
level of enantioselectivity. Among the carbonyl electrophiles
used, it was interesting to note that enolizable aldehydes
reacted efficiently.[27]
Herein we report our investigation on the synthesis of 3,3-
disubstituted phthalides from enolizable ketones using organo-
magnesiates bearing dialkoxides ligands. We showed that the
homoleptic alkyl bimetallic complex nBu3MgLi is inefficient in
such a reaction; however, when the heteroleptic (rac)-(BIPHEN)
BuMgLi was employed a wide set of 3,3-disubstituted isobenzo-
furanones were formed in good yields.
MesLi (1)
À 78
À 78[e]
nBu3MgLi (1.2)g
À 78
À 78[f]
nBu3MgLi (1.2)g
À 10 to r.t.
À 10 to r.t.
À 10 to r.t.
À 10 to r.t.
À 10 to r.t.
À 10 to r.t.
À 10 to r.t.
À 10 to r.t.
À 60 to r.t.[f]
(rac)-(BIPHEN)BuMgLi (2)
(rac)-(BIPHEN)BuMgLi (2)
(rac)-(BIPHEN)BuMgLi (2)
(rac)-(BIPHEN)BuMgLi (2)
(R,R)-(TADDOL)BuMgLi (2)
T1-(TADDOL)BuMgLi (2)
(S)-(BINOL)BuMgLi (2)
À 60[d]
À 40[d]
À 20[d]
À 60 to r.t.[d]
À 60 to r.t.[d]
À 60 to r.t.[d]
À 60 to r.t.[d]
9
10
11
0
0
[a] Reactions performed on 0.5 mmol of 1a. [b] Iodine-metal exchange
was complete in every case. [c] Isolated yield. The amounts of ketone
were as follows: [d] 2 eq., [e] 1.5 eq., [f] 3 eq. [g] Synthesized from 2 eq. of
°
nBuLi and 1 eq. of nBuMgCl at À 10 C.
confirmed by TLC monitoring. In contrast, noticeable differences
were found regarding the second step of the reaction where
the arylorganometallic intermediate reacts with the ketone. In
the case of nBuLi and 2,4,6-trimethylphenyllithium (MesLi)
(Entry 1and 2 Table 1), no formation of lactone was observed;
instead a complex mixture of degradation products was
obtained, including ethyl 2-benzoylbenzoate resulting from the
self-reaction of the arylorganometallic intermediate (see SI 1.a.).
The reaction also failed when using the homoleptic nBu3MgLi
Results and Discussion
°
In this work, we investigated the magnesiation-lactonization
process for the synthesis of 3,3-disubstituted isobenzofura-
nones, employing heteroleptic lithium magnesiates. In our first
reaction, we studied the reactivity of 2-ethyliodobenzoate and
the enolizable p-methoxyacetophenone and several potential
MHE agents in the presence or absence of dialkoxy/diphenoxy
ligands (Scheme 2). The reaction conditions and results are
reported in Table 1.
reagent under Oshima’s conditions at À 78 C (Entry 3–Ta-
ble 1)[28] leading to mainly the formation of ethylbenzoate as a
result of protonation of the unreacted aryl magnesiate after
aqueous work-up. Addition of a n-butyl moiety from the aryl
magnesiate intermediate was also observed leading to the
formation of 1-phenylpentan-1-one (see SI 1.b.). Suspecting an
insufficient nucleophilicity of the intermediate aryl magnesiate
under cryogenic conditions, the reaction was then attempted at
room temperature (Entry 4–Table 1) resulting unfortunately
only in the formation of degradation products. These first
No matter which MHE agent or conditions were employed,
the iodine-metal exchange reaction proceeded quantitively as
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experiments revealed a lack of reactivity of the intermediate
arylorganometallic species towards the ketone and a non-
tolerance of the ester functionality.
magnesiate after the metal-halogen exchange step. Applying
such a stoichiometry (1:2ethyl-2-iodobenzoate:LBuMgLi A), we
were pleased to see that the introduction of the (rac)-BIPHEN
ligand produced the target lactone 2e in 75% isolated yield
when used at room temperature (Entry 8–Table 1). However,
attempts to decrease the temperature of the ketone quenching
step (Entries 5–7–Table 1) dramatically reduced the reaction
yield showing that magnesiate can be easily used in non-
cryogenic conditions. Other dialkoxide type ligands were also
investigated (Entries 9–11–Table 1) but these led to mainly
ethylbenzoate after the work-up instead of 2e signifying an
insufficient nucleophilicity of the aryl magnesiate towards the
ketone.
Encouraged by the excellent chemoselectivity and efficiency
of (rac)-(BIPHEN)BuMgLi (A1) as a MHE agent, we next examined
the scope of the magnesiation-lactonization process with
several iodobenzoates derivatives and enolizable ketones
(Table 2).
As shown in Table 2, the expected lactones 2a–n and 3a–
n were obtained in good to excellent yields. The reaction
proceeded smoothly with aromatic, heteroaromatic and
We then considered the introduction of alkoxide ligands,
which were expected to favor the release of the aromatic
intermediate via a modification of the metal coordination
sphere and to have a better tolerance of sensitive functional
groups. Thus, we examined the reactivity of magnesiate
complex LBuMgLi A [L=(rac)-BIPHEN, (R,R)-TADDOL, T1-TAD-
DOL or (S)-BINOL] reagents. The reagents were obtained by
reacting the doubly lithiated dialkoxide with nBuMgCl
(Scheme 2).
From previous works, it has been reported that the iodine-
magnesium exchange required two equivalents of magnesiate
complex LBuMgLi A for its completion. This was explained by
the reaction of one equivalent of LBuMgLi A with the reactive
iodobutane formed during the exchange process leading to the
formation of a molecule of octane.[27] Indeed, we showed that
one equivalent of aldehyde (relative to ethyl-2-iodobenzoate)
was found sufficient to trap the intermediate arylmagnesiate
quantitatively. This is only possible in the absence of free butyl
Table 2. Scope of the magnesiation-lactonization from 1a–f: Synthesis of unsymmetrical 3,3-disubstituted phthalides.[a]
2a, 77%
2b, 78%
2c, 80%
2d, 79%
2e, 75%
2f, 70%
2g, 73%
2h, 76%
2i, 73%
2j, 75%
2k, 70%
2l, 80%
2m, 65%
2n, 61%
3a, 73%
3b, 71%
3c, 68%
3d, 58%
3e, 65%
3f, 70%
3g, 70%
3h, 69%
3i, 78%
3j, 68%
3k, 78%
3l, 65%
3m, 73%
3n, 79%
[a] Reaction conditions: ethyl-2-iodobenzoate derivatives (0.25 mmol, 0.5 equiv), ketone (0.8 equiv), (rac)-(BIPHEN)BuMgLi A1 (1 equiv), THF (3.5 mL).
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aliphatic ketones most of the latter being enolizable. In
From this study, we were able to show that (rac)-(BIPHEN)
BuMgLi A1 was the best choice for performing the magnesia-
tion-lactonization reactions.
particular, the lactone 2n was obtained in a 61% yield from
the highly enolizable aliphatic 2-pentanone. This indicated a
high nucleophilicity versus basicity of the organometallic aryl
intermediate. Moreover, various reactive functional substitu-
ents, which may be useful for subsequent transformations,
were tolerated either on ethyl-2-iodobenzoate derivatives 1
or ketones. This included the sensitive C-bromine bond in
2d, 2k, 3g and 3 h and C-iodine bound in 2h. Reactive
heterocycles as the electrophilic pyridine (2l, 3n, 3k) and
thiophene (2j, 2k, 3c, 3l) nucleus were also well tolerated.
Table 2 also illustrates the diversity of the benzoates
employed in the reactions. Electron-withdrawing and elec-
tron-donating groups were tolerated with no influence on
the reactivity of the organometallic aryl intermediate.
Moreover, C-halogen bonds were also tolerated including
the CÀ Br one (3g–h) demonstrating the chemoselectivity of
(rac)-(BIPHEN)BuMgLi (A1) towards iodinated substrates and
allowing further transformation of the lactone. Interestingly,
a wide range of fluorine-containing lactones (3i–l) have been
obtained in good yields which could be useful from the
biological point of view for structure-activity relationship
studies when molecular design requires strong electron-
withdrawing effects without affecting the steric hindrance in
the compound. A spiro lactone (3d) was also obtained in
moderate yield (58%) from the enolizable 2,2,6-trimeth-
ylcyclohexanone.
As structure is inextricably linked to reactivity, the solution-
state structure of the magnesiate complex (rac)-(BIPHEN)
BuMgLi A1 was investigated by 1H, 7Li and 1H DOSY NMR
spectroscopy in d8-THF. For that, magnesiate complex was
prepared as usual (Scheme 4), then solvents were removed
under vacuum and the residue was dissolved in d8-THF.
The formation of the magnesiate complex A1, described in
1
7
Scheme 4, was clearly evidenced by solution H and Li NMR
spectroscopy which were in agreement with previously re-
ported data (Figure 2 and supporting information).[30] Indeed,
the magnesiate complex A1 showed two distinct singlets for
aromatic protons of the ligand at 6.82 and 6.79 ppm, indicating
two non-equivalent phenyl rings as expected (i.e., one phenolic
ring bridges between a Li and Mg center, while the other is
terminally bound to only Mg). The hydrogen atoms on the
carbon α to the magnesium center (CH2Mg), appear upfield as
two multiplets at À 0.77 and À 0.98 ppm, displaying the
diastereotopic nature of these protons.
As shown in Scheme 4, the magnesiate synthetic route
formally releases a molecule of LiCl. LiCl is well known to
coordinate to organometallic species and often plays a pivotal
role in the reactivity of these reagents. As such it is frequently
not an innocent bystander.[31–37] In our case, it could be
envisaged a direct association of a LiCl molecule to the
magnesiate to yield a higher order species or its presence as a
solvated Li+(THF)xClÀ species. In an attempt to ascertain the
solution behavior, we prepared the magnesiate complex (rac)-
(BIPHEN)BuMgLi via a LiCl free route (Scheme 5–B1) and then
involved it in a metal-halogen-exchange reaction with substrate
1a.
However, under these conditions, MHE didn’t occur at all
and 1a was fully recovered. In an attempt to understand this
phenomenon, LiCl (as LiCl 0.5 M in THF) has been added to the
reaction at different stage: firstly, immediately after the addition
of nBuLi (stage 1–Scheme 5); secondly, after nBu2Mg (stage 2–
Scheme 5) or thirdly, after 1a (stage 3–Scheme 5). Unfortu-
This methodology was successfully applied to the synthesis
of an anti-HIV molecule 2o[6] (Figure 1 and Scheme 3) with 65%
yield using commercially available 1a and enolizable chloro-
ketone 4 easily synthesized in one step by α-chlorination[29] of
the commercially available 4’-chloropropiophenone with 82%
yield. Our methodology allows the synthesis of 2o with a better
yield than that described in the literature (45%) which uses
chlorolactonization reaction of a non-commercial styrene-type
carboxylic acid in the presence of DABCO (1,4-diazabicyclo
[2,2,2]octane).[6]
Scheme 3. Preparation of an anti-HIV molecule 2o.
Scheme 4. Preparation of the magnesiate complex A1 from 1 equiv. of (rac)-
BIPHEN+2 equiv. nBuLi+1 equiv. nBuMgCl).
Figure 2. 1H NMR spectrum (in d8-THF) of magnesiate complex A1 from
1 equiv. of (rac)-BIPHEN+2 equiv. nBuLi+1 equiv. nBuMgCl.
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Table 3. ECCDSE was used to determine molecular weight of magnesiate
complex in d8-THF, the accuracy of the ECCDSE is in the range � �9%.[38,39]
Complexes
Complex + Complex + Complex + Complex +
possibilities
1 THF
2 THF
MWdif (%)
3 THF
MWdif (%)
4 THF
MWdif (%)
MWdet (g.molÀ 1
)
MWdif (%)
(Biphen)BuMgLi
440.88
À 23
À 12
À 6
À 1
10
16
(Biphen)BuMgLi2Cl À 16
5
483.27
483 g molÀ 1. Thus, it turns out that three complexes were
possible: i) (BIPHEN)BuMgLi+3 THF, ii) (BIPHEN)BuMgLi2Cl+2
THF or iii) (BIPHEN)BuMgLi2Cl+3 THF (Table 3). Mulvey and co-
workers showed that three THF molecules are incorporated in
the structure of the turbo-Hauser reagent (THF)2Li(μ-Cl)2Mg-
(THF) (TMP).[37] Combining those results (Table 3) with the LiCl
study (Scheme 5), it is suggested that two or three molecules of
THF are coordinated to the magnesiate complex (rac)-(BIPHEN)
BuMgLi plus one molecule of LiCl. So the DOSY data on its own
does not allow us to conclude whether or not LiCl is associated
to the magnesiate complex. However, coupled with the LiCl
experiment described above (Scheme 5) it can be tentatively
suggested that LiCl is involved in the magnesiate suggesting an
active species of the structure (rac)-(BIPHEN)BuMgLi(THF)x Li+
ClÀ .
Scheme 5. Study of the magnesiation-lactonization reaction while using
magnesiate complex B1 from 1 equiv. of (rac)-BIPHEN+1 equiv. nBuLi
+1 equiv. nBu2Mg.
nately, no MHE has been observed under any of those
conditions.
Control reactions have been performed using optimized
conditions previously determined (Table 1–Entry 8). Firstly, 1
equivalent of LiCl has been added to the reaction mixture and
no influence on the reaction was observed, lactone 2a was
obtained as previously. Secondly, because nBu2Mg is in heptane
while nBuMgCl is in THF, heptane has been added and again no
influence on the reaction was observed.
Collectively these data suggest that the route to synthesize
the magnesiate is crucial and that LiCl is probably part of the
magnesiate complex and has to come with the magnesium Conclusion
species (ie nBuMgCl).
In order to support this structural assumption 1H DOSY NMR
spectroscopy in d8-THF has been performed on the magnesiate
complex (rac)-(BIPHEN)BuMgLi A1 (Figure 3). This study sug-
gested that the molecular weight for the species that contains
the (rac)-(BIPHEN)BuMgLi is approximately 665 g molÀ 1 (External
Calibration Curve ECCDSE was used to determine molecular
weight of the magnesiate complex in d8-THF, the accuracy of
the ECCDSE is in the range � �9%) (see supporting
information).[38,39]
In summary, a wide range of new functional 3,3-disubstituted
isobenzofuranones has been prepared in good yield applying a
straightforward strategy using the magnesiate complex (rac)-
(BIPHEN)BuMgLi (A1). Moreover various reactive functional
substituents were tolerated which may be useful for subse-
quent transformations and allowed the preparation of a known
biological active molecule, anti-HIV, 2o. It is worthy of note that
the BIPHENÀ H2 was recovered safely after the reaction,
recrystallized and reused with success. Studies of the synthetic
pathway and salt effect on the magnesiate complex A as well as
The molecular weight for a THF-free and LiCl-free framework
should be 441 g molÀ 1 and for a THF-free with LiCl framework,
solution-state experiments (1H, Li and H DOSY NMR in d8-THF)
suggest an active species of the structure (rac)-(BIPHEN)BuMgLi
(THF)xLi+ClÀ (with x=2 or 3).
7
1
Experimental Section
General experimental methods: Tetrahydrofuran (THF) was dry
and dispense using a MBRAUN Solvent Purification System (MB-
SPS-800). All chemicals were used as received otherwise notice.
nBuLi and nBuMgCl from sigma Aldrich were titrated prior to use
with respectively Diphenylacetic acid or Diiode/Lithium chloride. All
the NMR spectra were recorded on a Bruker Advance III 400. 1H, 13C,
and 19F NMR spectra were recorded respectively at 400 MHz,
1
101 MHz and 376 MHz. H and 13C chemical shifts were reported in
ppm and referenced to Me4Si as internal reference. 19F NMR
chemical shifts were reported in ppm and referenced to external
CFCl3 (0.0 ppm). Data are presented as follows: chemical shift
(ppm), multiplicity (s=singlet, d =doublet, t=triplet, q=quadru-
Figure 3. 1H DOSY NMR spectrum of magnesiate complex A1 and the
°
standards tetramethylsilane (TMS) and ferrocene in d8-THF at 25 C.
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plet, dd=doublet of doublet, dt=doublet of triplet, ddd=doublet
Ethyl-4,5-dimethyl-2-iodobenzoate (1c): Compound 1c was pre-
pared according to the general procedure A using 4,5-dimethyl-2-
iodobenzoic acid (1.10 g, 4 mmol). The title compound was
obtained without purification as a yellow oil; yield 95% (1.16 g); Rf
=0.58 (petroleum ether/EtOAc 90/10); 1H NMR (400 MHz, CDCl3)
δ=7.75 (s, 1H), 7.59 (s, 1H), 4.37 (q, J=7.1 Hz, 2H), 2.23 (s, 6H), 1.40
(t, J=7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ=166.4 (C), 142.3 (C),
142.1 (CH), 136.7 (C), 132.3 (C), 132.1 (CH), 90.7 (C), 61.4 (CH2), 19.3
(2*CH3), 14.3 (CH3); HRMS (ESI positive): m/z calcd. for C11H14IO2 [M+
H]+: 305.0033 found 305.0012 and for C11H13IO2Na [M+Na]+:
326.9852 found 326.9881.
of doublet of doublet, m=multiplet,br=broad), coupling constant
J (Hz) and integration. High-resolution mass spectra (HMRS) were
recorded on a Bruker micrOTOFÀ Q spectrometer. Flash chromatog-
raphy purifications were performed on a Grace RevelerisTM with
RevelerisTM flash cartridges silica 40 μM. Analytical thin layer
chromatography was performed on Merck Silica Gel 60 F254 plates.
Preparative thin layer chromatography was performed on Merck
Silica Gel 60 F254 Glass plates (layer thickness 1 mm). Melting
temperatures were recorded with a thermostatic oil bath device.
General procedure A for the synthesis of ethyl-2-iodobenzoates
derivatives 1c–f: In a round-bottom flask under argon atmosphere,
2-iodobenzoic acid derivative (4 mmol, 1 eq.) was dissolved in DMF
(10 mL) at r.t. Iodoethane (354 μL, 4.4 mmol, 1.1 eq.) and potassium
carbonate (608 mg, 4.4 mmol, 1.1 eq.) was added dropwise and the
mixture was stirred for 16 h r.t.. The reaction was diluted with
addition of AcOEt (25 mL). The organic phase was washed with
NH4Cl (50 mL×4) to remove the DMF, then dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The
desired ethyl-2-iodobenzoate derivatives was obtained pure and
used without further purification.
Ethyl-4-chloro-2-iodobenzoate (1d): Compound 1d was prepared
according to the general procedure A using 4-chloro-2-iodobenzoic
acid (1.12 g, 4 mmol). The title compound was obtained without
purification as
a
yellow solid; yield 95% (1.22 g); Rf =0.58
1
°
(petroleum ether/EtOAc 90/10); m.p.: 28–29 C; H NMR (400 MHz,
CDCl3) δ=7.98 (d, J=2.1 Hz, 1H), 7.74 (d, J=8.3 Hz, 1H), 7.37 (dd,
J=8.4, 2.1 Hz, 1H), 4.38 (q, J=7.1 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H); 13
C
NMR (101 MHz, CDCl3) δ=165.6 (C), 140.8 (CH), 138.0 (C), 133.5 (C),
131.7 (CH), 128.2 (CH), 94.4 (C), 61.9 (CH2), 14.2 (CH3); HRMS (ESI
positive): m/z calcd. for C9H8ClIO2Na [M+Na]+: 332.9150 found
332.9113.
General procedure B for the synthesis of 3,3-disubstituted-(3H)-
isobenzofuran-1one 2a–o and 3a–n: In a flamed dried schlenk
under argon atmosphere, (rac)-BIPHEN-H2 (177 mg, 0.50 mmol,
Ethyl-5-fluoro-2-iodobenzoate (1e): Compound 1e was prepared
according to the general procedure A using 5-fluoro-2-iodobenzoic
acid (1.06 g, 4 mmol). The title compound was obtained without
purification as a yellow oil. Yield 90% (1.06 g); Rf =0.80 (petroleum
ether/EtOAc 90/10); 1H NMR (400 MHz, CDCl3) δ=8.02–7.82 (m, 1H),
7.65–7.43 (m, 1H), 6.99–6.85 (m, 1H), 4.40 (q, J=7.1 Hz, 2H), 1.41 (t,
J=7.1 Hz, 3H).; 13C NMR (101 MHz, CDCl3) δ=165.3 (d, JC-F =2.4 Hz)
(C), 162.4 (d, JC-F =249.3 Hz) (C), 142.6 (d, JC-F =7.2 Hz) (CH), 136.9 (d,
J=7.0 Hz) (C), 120.1 (d, JC-F =21.5 Hz) (CH), 118.3 (d, JC-F =24.1 Hz)
(CH), 87.0 (d, JC-F =3.6 Hz) (C), 62.1 (CH2), 14.2 (CH3); 19F NMR
(376 MHz, CDCl3) δ=-113.4; HRMS (ESI positive) m/z calcd. for
C9H9FIO2 [M+H]+: 294.9626 found 294.9608 and for C9H8FIO2Na [M
+Na]+: 316.9445 found 316.9410.
°
1 eq.) was dissolved in THF (3.5 mL) and cooled to À 5 C. n-BuLi
(1.0 mmol, 2 eq.) was added dropwise and the mixture was stirred
°
for 45 min at À 5 C. n-BuMgCl (0.50 mmol, 1 eq.) was added
°
dropwise and the mixture was stirred for 45 min at À 5 C. Ethyl-2-
iodobenzoate derivatives (0.25 mmol, 0.5 eq.) in 1 mL THF was
°
added at À 5 C and the resulting mixture was allowed to warn to
RT and stir for 1 h. The reaction was check by TLC to verify that
metalation occurred and it’s done. Then the reaction was cold
°
down to À 60 C and ketone (0.40 mmol, 0.8 eq.) in 1 mL THF was
added slowly. The reaction mixture was allowed to warn to RT and
stir for 2 h. The reaction was quenched with addition of saturated
NH4Cl and AcOEt. The aqueous phase was extracted with AcOEt
(10 mL×3). Then acidified with HCl 0.4 N (check with pH paper) and
extracted one more time with AcOEt (10 mL). The combined
organic phases were washed with brine (20 mL), dried over
anhydrous MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography using
silica cartridge to afford the desired product.
Ethyl-4-chloro-2-iodo-6-methylbenzoate (1f): Compound 1f was
prepared according to the general procedure A using 4-chloro-2-
iodo-6-methylbenzoic acid (0.99 g, 3.7 mmol). The title compound
was obtained after flash chromatography as a yellow oil; yield 95%
(1.22 g); Rf =0.60 (petroleum ether/EtOAc 90/10); 1H NMR (400 MHz,
CDCl3) δ=7.66 (s, 1H), 7.18 (s, 1H), 4.45–4.39 (m, 2H), 2.32 (s, 3H),
1.41 (t, J=7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ=168.4 (C), 138.8
(C), 137.8 (C), 135.9 (CH), 135.3 (C), 129.9 (CH), 91.9 (C), 62.0 (CH2),
19.9 (CH3), 14.1 (CH3); HRMS (ESI positive): m/z calcd. for C10H11ClIO2
[M+H]+: 324.9487 found 324.9507 and for C10H10ClIO2Na [M+Na]+
: 346.9306 found 346.9274; Flash chromatography conditions:
column 24 g, flow rate=20 mL/min, petroleum ether/EtOAc 100/0
to 90/10.
Ethyl-5-bromo-2-iodobenzoate (1b):[40] Ethyl-5-bromo-2-iodoben-
zoate 1b was prepared according to the literature method. To a
stirred solution of ethyl-2-iodobenzoate (2 g, 7.2 mmol, 1 eq.) and
N-bromosuccinimide (1.5 g, 8.0 mmol, 1.1 eq.) in acetic acid (4 mL)
was added concentrated H2SO4 (4 mL) dropwise while keeping the
°
temperature at 20–40 C. The mixture was stirred at room temper-
°
ature for 88 hours and then heated at 50 C for 4 hours. The mixture
3-Ethyl-3-phenyl-(3H)-isobenzofuran-1-one (2a): Compound 2a
was prepared according to the general procedure B using ethyl-2-
iodobenzoate 1a (69 mg, 0.25 mmol) and propiophenone (54 mg,
0.40 mmol). The title compound was obtained after flash chroma-
tography as yellow oil; yield 77% (46 mg); Rf =0.23 (petroleum
ether/EtOAc 90/10); 1H NMR (400 MHz, CDCl3) δ=7.92 (d, J=7.5 Hz,
1H), 7.68 (ddd, J=7.5, 7.5, 1.1 Hz, 1H), 7.56–7.51 (m, 4H), 7.39 (dd,
J=7.4, 7.4 Hz, 2H), 7.33 (dd, J=7.2, 7.2 Hz, 1H), 2.53 (dq, J=14.6,
7.3 Hz, 1H), 2.29 (dq, J=14.6, 7.3 Hz, 1H), 0.84 (t, J=7.3 Hz, 3H); 13C
NMR (101 MHz, CDCl3) δ=170.2 (C), 152.7 (C), 140.4 (C), 134.2 (CH),
129.1 (CH), 128.7 (2*CH), 128.1 (CH), 125.8 (CH), 125.7 (C), 125.0
(2*CH), 122.1 (CH), 90.5 (C), 33.3 (CH2), 8.1 (CH3); HRMS (ESI positive):
m/z calcd. for C16H15O2 [M+H]+: 239.1067 found 239.1118 and for
C16H14O2Na [M+Na]+: 261.0886 found 261.0942; Flash chromatog-
raphy conditions: column 12 g, flow rate=20 mL/min, petroleum
ether/EtOAc 100/0 to 90/10.
°
was cooled to 10 C then treated with 10 mL of ice water and
extracted 2*15 mL of CH2Cl2. The combined organic phases were
washed with 2*15 mL of 5% NaHCO3, dried over MgSO4 and
concentrated under vacuum. The title compound was obtained
after silica gel chromatography as a white solid. Yield 74% (1.90 g);
Rf =0.71 (petroleum ether/EtOAc 90/10); m.p.: 41–43 C; 1H NMR
°
(400 MHz, CDCl3) δ=7.83 (d, J=2.4 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H),
7.18 (dd, J=8.4, 2.4 Hz, 1H), 4.32 (q, J=7.1 Hz, 2H), 1.33 (dd, J=8.3,
6.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ=165.2 (C), 142.6 (CH),
136.9 (C), 135.5 (CH), 133.8 (CH), 122.2 (C), 92.1 (C), 62.1 (CH2), 14.2
(CH3); HRMS (ESI positive): m/z calcd. for C9H8BrIO2Na [M+Na]+:
376.8645 found 376.8632; Flash chromatography conditions: col-
umn 40 g, flow rate=20 mL/min, petroleum ether/EtOAc 100/0 to
95/5.
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3-Isopropyl-3-phenyl-(3H)-isobenzofuran-1-one (2b): Compound
oxyacetophenone (60 mg, 0.40 mmol). The title compound was
obtained after flash chromatography as white solid; yield 70%
2b was prepared according to the general procedure B using ethyl-
2-iodobenzoate 1a (69 mg, 0.25 mmol) and isobutyrophenone
(56 mg, 0.40 mmol). The title compound was obtained after flash
chromatography as yellow oil; yield 78% (49 mg); Rf =0.21 (petro-
°
(43 mg); Rf =0.17 (petroleum ether/EtOAc 90/10); m.p.: 136–138 C;
1H NMR (400 MHz, CDCl3) δ=7.90 (d, J=7.6 Hz, 1H), 7.62–7.55 (m,
3H), 7.51–7.47 (m, 1H), 7.35–7.30 (m, 1H), 6.98 (ddd, J=7.7, 7.7,
1.1 Hz, 1H), 6.90 (d, J=8.2 Hz, 1H), 3.73 (s, 3H), 2.11 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ=170.5 (C), 157.2 (C), 154.8 (C), 133.8 (CH), 130.1
(CH), 128.7 (CH), 128.3 (C), 126.8 (CH), 126.0 (C), 125.2 (CH), 122.1
(CH), 120.6 (CH), 112.1 (CH), 87.2 (C), 55.3 (CH3), 26.4 (CH3); HRMS
(ESI positive): m/z calcd. for C16H15O3 [M+H]+: 255.1016 found
255.1019 and for C16H14O3Na [M+Na]+: 277.0835 found 277.0835;
Flash chromatography conditions: column 24 g, flow rate=20 mL/
min, petroleum ether/EtOAc 100/0 to 90/10.
1
leum ether/EtOAc 90/10); H NMR (400 MHz, CDCl3) δ=7.86 (d, J=
7.6 Hz, 1H), 7.68–7.55 (m, 4H), 7.48 (ddd, J=7.6, 7.6, 1.1 Hz, 1H),
7.36 (dd, J=7.5, 7.5 Hz, 2H), 7.29 (d, J=7.3 Hz, 1H), 2.77 (p, J=
6.8 Hz, 1H), 0.94 (d, J=6.8 Hz, 3H), 0.73 (d, J=6.8 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ=170.4 (C), 152.7 (C), 140.7 (C), 134.2 (CH), 128.9
(CH), 128.7 (2*CH), 127.8 (CH), 125.8 (CH), 125.6 (C), 124.8 (2*CH),
122.1 (CH), 92.8 (C), 36.9 (CH), 17.4 (CH3), 16.4 (CH3); HRMS (ESI
positive): m/z calcd. for C17H17O2 [M+H]+: 253.1223 found
253.1269; Flash chromatography conditions: column 12 g, flow
rate=20 mL/min, petroleum ether/EtOAc 100/0 to 90/10.
3-(4-Chlorophenyl)-3-methyl-(3H)-isobenzofuran-1-one
(2g):
Compound 2g was prepared according to the general procedure B
using ethyl-2-iodobenzoate 1a (69 mg, 0.25 mmol) and 4’-chloroa-
cetophenone (62 mg, 0.40 mmol). The title compound was ob-
tained after flash chromatography as colorless oil; yield 73%
(47 mg); Rf =0.20 (cyclohexane/EtOAc 80/20); 1H NMR (400 MHz,
CDCl3) δ=7.93 (ddd, J=7.6, 0.9, 0.9 Hz, 1H), 7.69 (ddd, J=7.5, 7.5,
1.1 Hz, 1H), 7.56 (ddd, J=7.5, 7.5, 0.9 Hz, 1H), 7.46 (ddd, J=7.7, 0.8,
0.8 Hz, 1H), 7.40 (d, J=8.9 Hz, 2H), 7.34 (d, J=8.8 Hz, 2H), 2.04 (s,
3H); 13C NMR (101 MHz, CDCl3) δ=169.6 (C), 153.7 (C), 139.3 (C),
134.5 (CH), 134.4 (C), 129.3 (CH), 128.9 129.3 (2*CH), 126.6 (2*CH),
126.0 (CH), 125.0 (C), 121.9 (CH), 87.0 (C), 27.3 (CH3); HRMS (ESI
positive): m/z calcd. for C15H12ClO2 [M+H]+: 259.0520 found
259.0536 and for C15H11ClO2Na [M+Na]+: 281.0340 found 281.0442;
Flash chromatography conditions: column 24 g, flow rate=20 mL/
min, petroleum ether/EtOAc 100/0 to 90/10.
3-(tert-Butyl)-3-phenyl-(3H)-isobenzofuran-1-one (2c): Compound
2c was prepared according to the general procedure B using ethyl-
2-iodobenzoate 1a (69 mg, 0.25 mmol) and 2,2-dimeth-
ylpropiophenone (65 mg, 0.40 mmol). The title compound was
obtained after flash chromatography as yellow oil; yield 80%
(53 mg); Rf =0.55 (cyclohexane/EtOAc 80/20); 1H NMR (400 MHz,
CDCl3) δ=7.91 (ddd, J=7.9, 0.8, 0.8 Hz, 1H), 7.80 (ddd, J=7.6, 1.2,
0.8 Hz, 1H), 7.67–7.62 (m, 3H), 7.45 (ddd, J=7.5, 7.5, 0.8 Hz, 1H),
7.30–7.19 (m, 3H), 0.94 (s, 9H); 13C NMR (101 MHz, CDCl3) δ=169.9
(C), 151.4 (C), 138.2 (C), 133.7 (CH), 129.2 (CH), 127.8 (CH), 127.7
(2*CH+C), 127.7 (2*CH+C), 126.1 (CH), 124.4 (CH), 94.7 (C), 25.7
(3*CH3); HRMS (ESI positive): m/z calcd. for C18H19O2 [M+H]+:
267.1380 found 267.1365 and for C18H18O2Na [M+Na]+: 289.1199
found 289.1187; Flash chromatography conditions: column 12 g,
flow rate=20 mL/min, petroleum ether/EtOAc 100/0 to 90/10.
3-(4-Iodophenyl)-3-methyl-(3H)-isobenzofuran-1-one (2h): Com-
pound 2h was prepared according to the general procedure B
using ethyl-2-iodobenzoate 1a (69 mg, 0.25 mmol) and 4’-iodoace-
tophenone (98 mg, 0.40 mmol). The title compound was obtained
after flash chromatography as colorless oil; yield 76% (67 mg); Rf =
3-(1-Bromo)ethyl-3-phenyl-(3H)-isobenzofuran-1-one (2d): Com-
pound 2d was prepared according to the general procedure B
using ethyl-2-iodobenzoate 1a (69 mg, 0.25 mmol) and 2-bromo-
propiophenone (85 mg, 0.40 mmol). The title compound was
obtained after flash chromatography as yellow oil; yield 79%
(62 mg); Rf =0.28 (cyclohexane/EtOAc 80/20); 1H NMR (400 MHz,
CDCl3) δ=7.86 (d, J=7.6 Hz, 1H), 7.70–7.64 (m, 2H), 7.58–7.49 (m,
3H), 7.36–7.27 (m, 3H), 7.19 (s, 1H), 4.81 (q, J=6.9 Hz, 1H), 1.52 (d,
J=6.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ=168.9 (C), 149.0 (C),
138.1 (C), 134.1 (CH), 130.0 (CH), 128.8 (CH), 128.8 (2*CH), 126.8 (C),
126.3 (CH), 125.6 (2*CH), 123.1 (CH), 90.5 (C), 52.7 (CH), 20.6 (CH3);
HRMS (ESI positive): m/z calcd. for C16H13BrO2Na [M+Na]+:
339.9991 found 338.9969; Flash chromatography conditions: col-
umn 12 g, flow rate=20 mL/min, petroleum ether/EtOAc 100/0 to
90/10.
1
0.33 (cyclohexane/EtOAc 80/20); H NMR (400 MHz, CDCl3) δ=7.91
(d, J=7.6 Hz, 1H), 7.71–7.65 (m, 3H), 7.53 (dd, J=7.5, 7.5 Hz, 1H),
7.43 (d, J=7.7 Hz, 1H), 7.19 (d, J=8.6 Hz, 2H), 2.01 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ=169.6 (C), 153.6 (C), 140.6 (C), 137.8 (2*CH),
134.5 (CH), 129.4 (CH), 127.0 (2*CH), 126.0 (CH), 125.0 (C), 121.9
(CH), 94.2 (C), 87.0 (C), 27.2 (CH3); HRMS (ESI positive): m/z calcd. for
C15H12IO2 [M+H]+: 350.9877 found 350.9856 and for C15H11IO2Na
[M+Na]+: 372.9696 found 372.9773; Flash chromatography con-
ditions: column 24 g, flow rate=20 mL/min, petroleum ether/EtOAc
100/0 to 90/10.
3-(2-Chlorophenyl)-3-(4-chlorophenyl)-(3H)-isobenzofuran-1-one
(2i): Compound 2i was prepared according to the general
procedure B using ethyl-2-iodobenzoate 1a (69 mg, 0.25 mmol)
and 2,4’-dichlorobenzophenone (100 mg, 0.40 mmol). The title
compound was obtained after flash chromatography as colorless
oil; yield 73% (65 mg); Rf =0.36 (cyclohexane/EtOAc 80/20) and
3-(4-Methoxyphenyl)-3-methyl-(3H)-isobenzofuran-1-one
(2e):
Compound 2e was prepared according to the general procedure B
using ethyl-2-iodobenzoate 1a (69 mg, 0.25 mmol) and 4’-meth-
oxyacetophenone (60 mg, 0.40 mmol). The title compound was
obtained after flash chromatography as colorless oil; yield 75%
(48 mg); Rf =0.19 (petroleum ether/EtOAc 90/10); 1H NMR (400 MHz,
CDCl3) δ=7.91 (ddd, J=7.6, 0.9, 0.9 Hz, 1H), 7.65 (ddd, J=7.6, 7.6,
1.1 Hz, 1H), 7.52 (ddd, J=7.5, 7.5, 0.9 Hz, 1H), 7.42 (ddd, J=7.7, 0.8,
0.8 Hz, 1H), 7.33 (d, J=9.0 Hz, 2H), 6.86 (d, J=9.0 Hz, 2H), 3.79 (s,
3H), 2.02 (s, 3H); 13C NMR (101 MHz, CDCl3) δ=170.0 (C), 159.6 (C),
154.4 (C), 134.2 (CH), 132.6 (C), 129.0 (CH), 126.7 (2*CH), 125.9 (CH),
125.2 (C), 122.0 (CH), 114.0 (2*CH), 87.6 (C), 55.3 (CH3), 29.7 (CH3);
HRMS (ESI positive) m/z calcd. for C16H15O3 [M+H]+: 255.1016
found 255.1054 and for C16H14O3Na [M+Na]+: 277.0835 found
277.0859; Flash chromatography conditions: column 12 g, flow
rate=20 mL/min, petroleum ether/EtOAc 100/0 to 90/10.
1
0.53 (toluene/EtOAc 95/5); H NMR (400 MHz, CDCl3) δ=7.96 (d, J=
7.6 Hz, 1H), 7.73–7.65 (m, 2H), 7.58 (t, J=7.8 Hz, 1H), 7.45–7.40 (m,
1H), 7.36–7.28 (m, 4H), 7.24–7.19 (m, 3H); 13C NMR (101 MHz, CDCl3)
δ=169.4 (C), 151.0 (C), 139.2 (C), 136.8 (C), 134.4 (C), 134.3 (CH+C),
132.4 (CH), 130.6 (CH), 129.8 (CH), 129.3 (CH), 128.9 (2*CH), 127.2
(2*CH), 126.6 (CH), 126.4 (CH), 125.6 (C), 124.7 (CH), 90.7 (C); HRMS
(ESI positive): m/z calcd. for C20H12Cl2O2Na [M+Na]+: 377.0107
found 377.0210 and for C20H12Cl2O2K [M+K]+: 392.9846 found
392.9852; Flash chromatography conditions: column 24 g, flow
rate=20 mL/min, petroleum ether/EtOAc 100/0 to 90/10; Then
preparative TLC toluene / EtOAc 95/5.
3-(2-Methoxyphenyl)-3-methyl-(3H)-isobenzofuran-1-one
Compound 2f was prepared according to the general procedure B
using ethyl-2-iodobenzoate 1a (69 mg, 0.25 mmol) and 2’-meth-
(2f):
3-Methyl-3-(thiophen-2-yl)-(3H)-isobenzofuran-1-one (2j): Com-
pound 2j was prepared according to the general procedure B using
ethyl-2-iodobenzoate 1a (69 mg, 0.25 mmol) and 2-acetylthiophene
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(51 mg, 0.40 mmol). The title compound was obtained after flash
tography as yellow oil. Yield 61% (29 mg); 1H NMR (400 MHz, CDCl3)
δ=7.79 (d, J=7.7 Hz, 1H), 7.57 (dd, J=7.5, 1.1 Hz, 1H), 7.43 (dd, J=
7.5, 0.9 Hz, 1H), 7.32–7.27 (m, 1H), 1.99–1.89 (m, 1H), 1.82–1.70 (m,
1H), 1.56 (s, 3H), 1.43–1.1 (m, 1H), 1.00–0.88 (m, 1H), 0.78 (t, J=
7.3 Hz, 3H); HRMS (ESI positive): m/z calcd. for C12H14O2Na [M+Na]+
: 213.0886 found 213.0880; Flash chromatography conditions:
column 12 g, flow rate=20 mL/min, cyclohexane/EtOAc 100/0 to
90/10.
chromatography as brown oil; yield 75% (43 mg); Rf =0.30
(cyclohexane/EtOAc 80/20); 1H NMR (400 MHz, CDCl3) δ=7.92 (d,
J=7.6 Hz, 1H), 7.70 (dd, J=7.5, 7.5 Hz, 1H), 7.57 (d, J=7.5 Hz, 1H),
7.50 (d, J=7.7 Hz, 1H), 7.28 (d, J=5.0 Hz, 1H), 7.00 (d, J=3.6 Hz,
1H), 6.98–6.93 (m, 1H), 2.10 (s, 3H); 13C NMR (101 MHz, CDCl3) δ=
169.2 (C), 153.3 (C), 144.4 (C), 134.4 (CH), 129.5 (CH), 126.9 (CH),
126.2 (CH), 125.9 (CH), 125.3 (CH), 125.2 (CH), 122.1 (CH), 85.3 (C),
28.2 (CH3); HRMS (ESI positive): m/z calcd. for C13H11O2S [M+H]+:
231.0474 found 231.0490 and for C13H10O2SNa [M+Na]+: 253.0294
found 253.0316 and for C13H10O2SK [M+K]+: 269.0033 found
269.0050; Flash chromatography conditions: column 24 g, flow
rate=20 mL/min, petroleum ether/EtOAc 100/0 to 95/5.
3-(1-Chloro)ethyl-3-(4-chlorophenyl)-(3H)-isobenzofuran-1-one
(2o):[6] Compound 2o was prepared according to the general
procedure B using ethyl-2-iodobenzoate 1a (69 mg, 0.25 mmol) and
2-chloro-1-(4-chlorophenyl)propan-1-one (81 mg, 0.40 mmol). The
title compound was obtained after flash chromatography as a white
1
°
3-(5-Bromothiophen-2-yl)-3-methyl-(3H)-isobenzofuran-1-one
(2k): Compound 2k was prepared according to the general
procedure B using ethyl-2-iodobenzoate 1a (69 mg, 0.25 mmol)
and 2-acetyl-5-bromothiophene (82 mg, 0.40 mmol). The title
compound was obtained after flash chromatography as yellow oil;
yield 70% (54 mg); Rf =0.33 (cyclohexane/EtOAc 80/20); 1H NMR
(400 MHz, CDCl3) δ=7.85 (ddd, J=7.6, 1.0, 1.0 Hz, 1H), 7.64 (ddd,
J=7.5, 7.5, 1.1 Hz, 1H), 7.51 (ddd, J=7.5, 7.5, 0.9 Hz, 1H), 7.41 (ddd,
J=7.7, 0.8, 0.8 Hz, 1H), 7.19 (s, 1H), 6.84 (d, J=3.9 Hz, 1H), 6.70 (d,
J=3.9 Hz, 1H), 1.98 (s, 3H); 13C NMR (101 MHz, CDCl3) δ=169.0 (C),
152.7 (C), 146.0 (C), 134.7 (CH), 130.0 (CH), 129.9 (CH), 126.2 (CH),
125.7 (CH), 125.3 (C), 122.1 (CH), 113.5 (C), 85.0 (C), 27.9 (CH3); HRMS
(ESI positive): m/z calcd. for C13H10BrO2S [M+H]+: 308.9579 found
308.9562 and for C13H9BrO2S Na [M+Na]+: 330.9399 found
330.9388; Flash chromatography conditions: column 24 g, flow
rate=20 mL/min, petroleum ether/EtOAc 100/0 to 90/10.
solid. Yield 65% (80 mg); m.p.: 119–121 C; H NMR (400 MHz, CDCl3)
δ=7.93 (d, J=7.6 Hz, 1H), 7.79–7.72 (m, 2H), 7.62–7.58 (m, 3H), 7.37
(d, J=8.6 Hz, 2H), 4.67 (q, J=6.7 Hz, 1H), 1.43 (d, J=6.7 Hz, 3H); 13C
NMR (101 MHz, CDCl3) δ=168.9 (C), 149.1 (C), 136.1 (C), 135.1 (C),
134.5 (CH), 130.3 (CH), 129.0 (2*CH), 127.5 (2*CH), 126.5 (CH), 126.4
(C), 123.5 (C), 90.1 (CH), 61.1 (CH3), 19.82; HRMS (ESI positive): m/z
calcd. for C16H13Cl2O2 [M+H]+: 307.0287 found 307.0312 and for
C16H12Cl2O2K [M+K]+: 344.9846 found 344.9843; Flash chromatog-
raphy conditions: column 12 g, flow rate=20 mL/min, cyclohexane/
EtOAc 100/0 to 90/10.
3-Ethyl-5,6-dimethyl-3-phenyl-(3H)-isobenzofuran-1-one
(3a):
Compound 3a was prepared according to the general procedure B
using ethyl-4,5-dimethyl-2-iodobenzoate 1c (76 mg, 0.25 mmol)
and propiophenone (54 mg, 0.40 mmol). The title compound was
obtained after flash chromatography as beige solid; yield 73%
1
°
(49 mg); Rf =0.40 (petroleum ether/EtOAc 90/10); m.p.: 65–67 C; H
3-Methyl-3-(2-pyridyl)-(3H)-isobenzofuran-1-one (2l): Compound
2l was prepared according to the general procedure B using ethyl-
2-iodobenzoate 1a (69 mg, 0.25 mmol) and 2-acetylpyridine
(49 mg, 0.40 mmol). The title compound was obtained after flash
NMR (400 MHz, CDCl3) δ=7.63 (s, 1H), 7.52–7.48 (m, 2H), 7.38–7.33
(m, 2H), 7.31–7.27 (m, 1H), 7.24 (s, 1H), 2.47 (dq, J=14.6, 7.3 Hz, 1H),
2.37 (s, 3H), 2.33 (s, 3H), 2.23 (dq, J=14.5, 7.3 Hz, 1H), 0.80 (t, J=
7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ=170.5 (C), 150.9 (C), 144.3
(C), 140.8 (C), 138.2 (C), 128.6 (2*CH), 127.9 (CH), 126.0 (CH), 125.0
(2*CH), 123.6 (C), 122.8 (CH), 90.0 (C), 33.2 (CH2), 20.9 (CH3), 19.9
(CH3), 8.1 (CH3); HRMS (ESI positive): m/z calcd. for C18H19O2 [M+H]+
: 267.1380 found 267.1354 and for C18H18O2Na [M+Na]+: 289.1199
found 289.1218; Flash chromatography conditions: column 24 g,
flow rate=20 mL/min, petroleum ether/EtOAc 100/0 to 90/10.
chromatography as white solid; yield 80% (45 mg); Rf =0.22
1
°
(petroleum ether/EtOAc 90/10); m.p.: 82–84 C; H NMR (400 MHz,
CDCl3) δ=8.61 (d, J=4.7 Hz, 2H), 7.87 (dd, J=7.9, 7.9 Hz, 2H), 7.64
(d, J=7.6, 7.6 Hz, 2H), 7.55 (d, J=8.0 Hz, 1H), 7.49 (dd, J=7.5,
7.5 Hz, 1H), 7.21–7.17 (m, 1H), 2.06 (s, 3H); 13C NMR (101 MHz, CDCl3)
δ=170.1 (C), 160.1 (C), 153.5 (C), 149.2 (CH), 137.0 (CH), 134.3 (CH),
129.2 (CH), 125.4 (CH), 124.4 (C), 123.4 (CH), 122.8 (CH), 118.6 (CH),
88.0 (C), 27.3 (CH3); HRMS (ESI positive) m/z calcd. for C14H12NO2 [M
+H]+: 226.0863 found 226.0904 and for C14H11NO2Na [M+Na]+:
248.0682 found 248.0725; Flash chromatography conditions: col-
umn 12 g, flow rate=20 mL/min, cyclohexane/EtOAc 100/0 to
90/10.
3-(4-Methoxyphenyl)-3,5,6-trimethyl-(3H)-isobenzofuran-1-one
(3b): Compound 3b was prepared according to the general
procedure B using ethyl-4,5-dimethyl-2-iodobenzoate 1c (76 mg,
0.25 mmol) and 4’-methoxyacetophenone (60 mg, 0.40 mmol). The
title compound was obtained after flash chromatography as white
solid; yield 71% (50 mg); Rf =0.20 (petroleum ether/EtOAc 90/10);
1
°
3,3-Dicyclopropyl-(3H)-isobenzofuran-1-one (2m): Compound 2m
was prepared according to the general procedure B using ethyl-2-
iodobenzoate 1a (69 mg, 0.25 mmol) and dicyclopropylketone
(44 mg, 0.40 mmol). The title compound was obtained after flash
chromatography as yellow oil; yield 65% (35 mg); Rf =0.42 (petro-
m.p.: 151–153 C; H NMR (400 MHz, CDCl3) δ=7.64 (s, 1H), 7.33 (d,
J=8.8 Hz, 2H), 7.15 (s, 1H), 6.86 (d, J=8.9 Hz, 2H), 3.78 (s, 3H), 2.35
(s, 3H), 2.34 (s, 3H), 1.98 (s, 3H); 13C NMR (101 MHz, CDCl3) δ=170.3
(C), 159.4 (C), 152.7 (C), 144.4 (C), 138.2 (C), 133.0 (C), 126.6 (2*CH),
126.0 (CH), 123.1 (C), 122.7 (CH), 113.9 (2*CH), 87.1 (C), 55.3 (CH3),
27.2 (CH3), 20.8 (CH3), 19.9 (CH3); HRMS (ESI positive): m/z calcd. for
C18H19O3 [M+H]+: 283.1329 found 283.1302 and for C18H18O3Na [M
+Na]+: 305.1148 found 305.1132; Flash chromatography condi-
tions: column 24 g, flow rate=20 mL/min, petroleum ether/EtOAc
100/0 to 90/10.
1
leum ether/EtOAc 90/10); H NMR (400 MHz, CDCl3) δ=7.83 (d, J=
7.6 Hz, 1H), 7.64 (ddd, J=7.6, 7.6, 1.1 Hz, 1H), 7.50 (dd, J=7.5,
7.5 Hz, 1H), 7.43 (d, J=7.6 Hz, 1H), 1.41–1.34 (m, 2H), 0.61–0.52 (m,
2H), 0.47–0.35 (m, 6H); 13C NMR (101 MHz, CDCl3) δ=170.1 (C),
152.3 (C), 133.8 (CH), 129.0 (CH), 126.2 (C), 125.6 (CH), 121.7 (CH),
88.0 (C), 18.0 (2*CH), 1.6 (2*CH2), 0.6 (2*CH2); HRMS (ESI positive): m/
z calcd. for C14H15O2 [M+H]+: 215.1067 found 215.1079 and for
C14H14O2Na [M+Na]+: 237.0886 found 237.0928; Flash chromatog-
raphy conditions: column 12 g, flow rate=20 mL/min, cyclohexane/
EtOAc 100/0 to 90/10.
3,5,6-Trimethyl-3-(thiophen-2-yl)-(3H)-isobenzofuran-1-one (3c):
Compound 3c was prepared according to the general procedure B
using ethyl-4,5-dimethyl-2-iodobenzoate 1c (76 mg, 0.25 mmol)
and 2-acetylthiophene (51 mg, 0.40 mmol). The title compound was
obtained after flash chromatography as white solid; yield 68%
3-Methyl-3-propyl-(3H)-isobenzofuran-1-one (2n):[14] Compound
2n was prepared according to the general procedure B using ethyl-
2-iodobenzoate 1a (69 mg, 0.25 mmol) and 2-pentanone (35 mg,
0.40 mmol). The title compound was obtained after flash chroma-
(44 mg); Rf =0.18 (petroleum ether/EtOAc 90/10); m.p.: 92–94 C; H
1
°
NMR (400 MHz, CDCl3) δ=7.65 (s, 1H), 7.27 (d, J=1.2 Hz, 1H), 7.23
(s, 1H), 7.00 (dd, J=3.6, 1.3 Hz, 1H), 6.95 (dd, J=5.1, 3.6 Hz, 1H),
2.38 (s, 3H), 2.37 (s, 3H), 2.06 (s, 3H); 13C NMR (101 MHz, CDCl3) δ=
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169.7 (C), 151.8 (C), 145.1 (C), 144.7 (C), 138.9 (C), 127.0 (CH), 126.24
(400 MHz, CDCl3) δ=8.02 (d, J=2.2 Hz, 1H), 7.76 (dd, J=8.1, 1.8 Hz,
1H), 7.30–7.26 (m, 3H), 6.86 (d, J=9.0 Hz, 2H), 3.79 (s, 3H), 2.01 (s,
3H); 13C NMR (101 MHz, CDCl3) δ=168.3 (C), 159.7 (C), 153.1 (C),
137.3 (CH), 131.9 (C), 128.8 (CH), 127.3 (C), 126.6 (2*CH), 123.7 (CH),
123.0 (C), 114.1 (2*CH), 87.7 (C), 55.3 (CH3), 27.0 (CH3); HRMS (ESI
positive): m/z calcd. for C16H14BrO3 [M+H]+: 333.0121 found
333.0103 and for C16H13BrO3Na [M+Na]+: 354.9940 found 355.0003;
Flash chromatography conditions: column 24 g, flow rate=20 mL/
min, petroleum ether/EtOAc 100/0 to 90/10; Then preparative TLC
toluene/EtOAc 95/5.
(CH), 126.16 (CH), 125.3 (CH), 123.1 (C), 122.9 (CH), 85.1 (C), 28.3
(CH3), 21.0 (CH3), 20.1 (CH3); HRMS (ESI positive): m/z calcd. for
C15H15O2S [M+H]+: 259.0787 found 259.0805 and for C15H14O2SNa
[M+Na]+: 281.0607 found 281.0659; Flash chromatography con-
ditions: column 24 g, flow rate=20 mL/min, petroleum ether/EtOAc
100/0 to 90/10.
2,2,5’,6,6’-pentamethyl-spiro[cyclohexane-1,1’(3’H)-isobenzofur-
an]-3’-one (3d): Compound 3d was prepared according to the
general procedure B using ethyl-4,5-dimethyl-2-iodobenzoate 1c
(76 mg, 0.25 mmol) and 2,2,6-trimethylcyclohexanone (56 mg,
0.40 mmol). The title compound was obtained after flash chroma-
tography as yellow sticky oil; yield 58% (40 mg); Rf =0.57 (petro-
6-Bromo-3-(2-methoxyphenyl)-3-methyl-(3H)-isobenzofuran-1-
one (3h): Compound 3h was prepared according to the general
procedure
B using ethyl-5-bromo-2-iodobenzoate 1b (89 mg,
1
leum ether/EtOAc 90/10); H NMR (400 MHz, CDCl3) δ=7.61 (s, 1H),
0.25 mmol) and 2’-methoxyacetophenone (60 mg, 0.40 mmol). The
7.12 (s, 1H), 2.40 (s, 3H), 2.36 (s, 3H), 2.34–2.31 (m, 1H), 1.97–1.90 (m,
1H), 1.74–1.61 (m, 4H), 1.39–1.35 (m, 1H), 1.28 (s, 3H), 0.56 (s, 3H),
0.42 (d, J=6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ=171.2 (C),
149.0 (C), 143.1 (C), 137.6 (C), 125.8 (C), 125.7 (CH), 123.6 (CH), 94.0
(C), 38.3 (C), 37.2 (CH2), 34.5 (CH), 30.9 (CH2), 24.8 (CH3), 23.4 (CH3),
21.4 (CH2), 20.9 (CH3), 19.8 (CH3), 15.6 (CH3); HRMS (ESI positive): m/z
calcd. for C18H25O2 [M+H]+: 273.1849 found 273.1891 and for
C18H24O2Na [M+Na]+: 295.1669 found 295.1759; Flash chromatog-
raphy conditions: column 24 g, flow rate=20 mL/min, petroleum
ether/EtOAc 100/0 to 90/10.
title compound was obtained after flash chromatography as yellow
solid; yield 69% (57 mg); Rf =0.33 (petroleum ether/EtOAc 90/10);
1
°
m.p.: 122–124 C; H NMR (400 MHz, CDCl3) δ=8.01 (d, J=1.8 Hz,
1H), 7.70 (dd, J=8.2, 1.8 Hz, 1H), 7.56 (dd, J=7.8, 1.6 Hz, 1H), 7.43
(d, J=8.2 Hz, 1H), 7.34 (ddd, J=8.2, 7.5, 1.7 Hz, 1H), 6.99 (ddd, J=
7.7, 7.7 1.1 Hz, 1H), 6.89 (d, J=8.2 Hz, 1H), 3.72 (s, 3H), 2.08 (s, 3H);
13C NMR (101 MHz, CDCl3) δ=168.9 (C), 157.1 (C), 153.4 (C), 136.8
(CH), 130.4 (CH), 128.2 (C), 128.1 (CH), 127.5 (C), 126.7 (CH), 123.7
(CH), 122.5 (H), 120.7 (CH), 112.1 (CH), 87.2 (C), 55.4 (CH3), 26.3
(CH3); HRMS (ESI positive): m/z calcd. for C16H10BrO3 [M+H]+:
333.0121 found 333.0151 and for C16H13BrO3Na [M+Na]+: 354.9940
found 354.9968; Flash chromatography conditions: column 24 g,
flow rate=20 mL/min, petroleum ether/EtOAc 100/0 to 90/10.
5-Chloro-3-ethyl-3-phenyl-(3H)-isobenzofuran-1-one (3e): Com-
pound 3e was prepared according to the general procedure B
using ethyl-4-chloro-2-iodobenzoate 1d (78 mg, 0.25 mmol) and
propiophenone (54 mg, 0.40 mmol). The title compound was
obtained after flash chromatography as white solid; yield 65%
6-Fluoro-3-isopropyl-3-phenyl-(3H)-isobenzofuran-1-one
(3i):
Compound 3i was prepared according to the general procedure B
using ethyl-5-fluoro-2-iodobenzoate 1e (74 mg, 0.25 mmol) and
isobutyrophenone (56 mg, 0.40 mmol). The title compound was
obtained after flash chromatography as colorless oil; yield 78%
(53 mg); Rf =0.29 (cyclohexane/EtOAc 80/20) and 0.39 (petroleum
°
(44 mg); Rf =0.46 (petroleum ether/EtOAc 90/10); m.p.: 120–122 C;
1H NMR (400 MHz, CDCl3) δ=7.81 (d, J=8. 5 Hz, 1H), 7.50–7.45 (m,
4H), 7.41–7.36 (m, 2H), 7.35–7.30 (m, 1H), 2.50 (dq, J=14.6, 7.3 Hz,
1H), 2.25 (dq, J=14.5, 7.3 Hz, 1H), 0.83 (t, J=7.3 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ=169.0 (C), 154.5 (C), 140.9 (C), 139.7 (C), 129.9
(CH), 128.9 (2*CH), 128.4 (CH), 127.0 (CH), 124.9 (2*CH), 124.1 (C),
122.6 (CH), 90.0 (C), 33.1 (CH2), 8.0 (CH3); HRMS (ESI positive): m/z
calcd. for C16H14ClO2 [M+H]+: 273.0677 found 273.0605 and for
C16H13ClO2Na [M+Na]+: 295.0496 found 295.0433; Flash chroma-
tography conditions: column 24 g, flow rate=20 mL/min, petro-
leum ether/EtOAc 100/0 to 90/10.
1
ether/dichloromethane 50/50); H NMR (400 MHz, CDCl3) δ=7.60–
7.47 (m, 4H), 7.39–7.27 (m, 4H), 2.77 (dq, J=13.6, 6.8 Hz, 1H), 0.93
(d, J=6.8 Hz, 3H), 0.74 (d, J=6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3)
δ=169.1 (d, JC-F =3.9 Hz) (C), 163.0 (d, JC-F =249.7 Hz) (C), 148.2 (d,
J
C-F =2.4 Hz) (C), 140.3 (C), 128.8 (CH), 128.0 (CH), 127.7 (d, JC-F
=
=
8.8 Hz) (C), 124.7 (CH), 123.8 (d, JC-F =8.4 Hz) (CH), 122.1 (d, JC-F
23.8 Hz) (CH), 112.1 (d, JC-F =23.5 Hz) (CH), 92.8 (C), 36.9 (CH), 17.3
(CH3), 16.4 (CH3); 19F NMR (376 MHz, CDCl3) δ=À 111.8; HRMS (ESI
positive): m/z calcd. for C17H15FO2Na [M+Na]+: 293.0948 found
293.1079; Flash chromatography conditions: Petroleum ether/EtOAc
100/0 to 90/10; Then preparative TLC petroleum ether / dichloro-
methane 50/50.
5-Chloro-3-(4-methoxyphenyl)-3-methyl-(3H)-isobenzofuran-1-
one (3f): Compound 3f was prepared according to the general
procedure
B using ethyl-4-chloro-2-iodobenzoate 1d (78 mg,
0.25 mmol) and 4’-methoxyacetophenone (60 mg, 0.40 mmol). The
title compound was obtained after flash chromatography as white
solid; yield 70% (51 mg); Rf =0.45 (toluene / EtOAc 95/5); m.p.: 106–
3-(4-Chlorophenyl)-6-fluoro-3-methyl-(3H)-isobenzofuran-1-one
(3j): Compound 3j was prepared according to the general
procedure B using ethyl-5-fluoro-2-iodobenzoate 1e (74 mg,
1
°
108 C; H NMR (400 MHz, CDCl3) δ=7.83 (dd, J=8.2, 0.5 Hz, 1H),
7.49 (dd, J=8.2, 1.7 Hz, 1H), 7.38 (dd, J=1.7, 0.5 Hz, 1H), 7.31 (d, J=
9.0 Hz, 2H), 6.88 (d, J=9.0 Hz, 2H), 3.80 (s, 3H), 2.02 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ=168.8 (C), 159.8 (C), 156.1 (C), 140.9 (C), 131.8
(C), 129.8 (CH), 127.1 (CH), 126.6 (2*CH), 123.7 (C), 122.5 (CH), 114.1
(2*CH), 87.1 (C), 55.3 (CH3), 27.0 (CH3); HRMS (ESI positive): m/z
calcd. for C16H14ClO3 [M+H]+: 289.0626 found 289.0668 and for
C16H13ClO3Na [M+Na]+: 311.0445 found 311.0486 and for
C16H13ClO3K [M+K]+: 327.0185 found 327.0185; Flash chromatog-
raphy conditions: column 24 g, flow rate=20 mL/min, petroleum
ether/EtOAc 100/0 to 90/10; Then preparative TLC toluene/EtOAc
95/5.
0.25 mmol) and 4’-chloroacetophenone (62 mg, 0.40 mmol). The
title compound was obtained after flash chromatography as color-
less oil; yield 68% (47 mg); Rf =0.30 (cyclohexane/EtOAc 80/20) and
1
0.48 (petroleum ether/dichloromethane 50/50); H NMR (400 MHz,
CDCl3) δ=7.48 (ddd, J=7.1, 2.2, 0.7 Hz, 1H), 7.35–7.25 (m, 6H), 1.95
(s, 3H).; 13C NMR (101 MHz, CDCl3) δ=168.3 (d, JC-F =3.8 Hz) (C),
163.2 (d, JC-F =250.4 Hz) (C), 149.3 (d, JC-F =2.3 Hz) (C), 138.9 (C),
134.6 (C), 129.0 (CH), 127.2 (d, JC-F =9.0 Hz) (C), 126.5 (CH), 123.7 (d,
J
C-F =8.5 Hz) (CH), 122.4 (d, JC-F =24.1 Hz) (CH), 112.3 (d, JC-F =
23.7 Hz) (CH), 87.0 (C), 27.3 (CH3); 19F NMR (376 MHz, CDCl3) δ=-
111.1; HRMS (ESI positive): m/z calcd. for C15H10ClFO2Na [M+Na]+:
299.0246 found 299.0338; Flash chromatography conditions: Petro-
leum ether/EtOAc 100/0 to 90/10; Then preparative TLC petroleum
ether/dichloromethane 50/50.
6-Bromo-3-(4-methoxyphenyl)-3-methyl-(3H)-isobenzofuran-1-
one (3g): Compound 3g was prepared according to the general
procedure
B using ethyl-5-bromo-2-iodobenzoate 1b (89 mg,
0.25 mmol) and 4’-methoxyacetophenone (60 mg, 0.40 mmol). The
title compound was obtained after flash chromatography as yellow
oil; yield 70% (58 mg); Rf =0.36 (toluene/EtOAc 95/5); 1H NMR
6-Fluoro-3-methyl-3-(2-pyridyl)-(3H)-isobenzofuran-1-one
(3k):
Compound 3k was prepared according to the general procedure B
Eur. J. Org. Chem. 2021, 4835–4845
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Full Papers
doi.org/10.1002/ejoc.202100899
using ethyl-5-fluoro-2-iodobenzoate 1e (74 mg, 0.25 mmol) and 2-
chromatography conditions: column 12 g, flow rate=20 mL/min,
cyclohexane/EtOAc 100/0 to 90/10.
acetylpyridine (49 mg, 0.40 mmol). The title compound was
obtained after flash chromatography as colorless oil; yield 78%
(47 mg); Rf =0.20 (cyclohexane/EtOAc 80/20) and 0.32 (toluene/
EtOAc 95/5); 1H NMR (400 MHz, CDCl3) δ=8.60 (ddd, J=4.8, 1.8,
1.0 Hz, 1H), 7.89 (dd, J=8.5, 4.4 Hz, 1H), 7.66 (ddd, J=7.8, 7.8,
1.8 Hz, 1H), 7.56 (ddd, J=8.0, 1.1, 1.1 Hz, 1H), 7.49 (ddd, J=7.2, 2.4,
0.5 Hz, 1H), 7.35 (dd, J=8.6, 8.6, 2.4 Hz, 1H), 7.21 (ddd, J=7.5, 4.8,
Acknowledgements
The authors would like to thank François Dupire (UMR 7053–
L2CM) and Fabien Lachaud (UMR 7053–L2CM) for the HRMS and
GC-MS experiments and related discussions. We gratefully
acknowledge the support of the Royal Society (IEC\R2\170207)
and the Leverhulme Trust (RPG-2016-281) for funding. They thank
also the Université de Lorraine, the CNRS and the University of
Strathclyde for their support. Data associated with this study can
be accessed at https://doi.org/10.15129/4c342ff2-8f1f-4a69-aad4-
ff2f93cff686.
1.2 Hz, 1H), 2.04 (s, 3H); 13C NMR (101 MHz, CDCl3) δ=168.77 (d, J
F =4.0 Hz) (C), 163.27 (d, JC-F =249.4 Hz) (C), 159.83 (C), 149.27 (CHC),-
149.07 (d, JC-F =2.3 Hz) (C), 137.10 (CH), 126.47 (d, JC-F =9.1 Hz) (C),
125.38 (d, JC-F =8.4 Hz) (CH), 122.87 (CH), 122.18 (d, JC-F =23.8 Hz)
(CH), 118.51 (CH), 111.53 (d, JC-F =23.6 Hz) (CH), 87.94 (C), 27.59
(CH3); 19F NMR (376 MHz, CDCl3) δ=-111.8; HRMS (ESI positive): m/z
calcd. for C14H11FNO2 [M+H]+: 244.0768 found 244.0694 and for
C14H10FNO2Na [M+Na]+: 266.0588 found 266.0512; Flash chroma-
tography conditions: Petroleum ether/EtOAc 100/0 to 90/10; Then
preparative TLC toluene/EtOAc 95/5.
6-Fluoro-3-methyl-3-(thiophen-2-yl)-(3H)-isobenzofuran-1-one
(3l): Compound 3l was prepared according to the general
Conflict of Interest
procedure
B using ethyl-5-fluoro-2-iodobenzoate 1e (74 mg,
0.25 mmol) and 2-acetylthiophene (51 mg, 0.40 mmol). The title
compound was obtained after flash chromatography as yellow oil;
yield 65% (40 mg); Rf =0.20 (Cyclohexane/EtOAc 80/20); 1H NMR
(400 MHz, CDCl3) δ=7.56 (dd, J=7.1, 2.3 Hz, 1H), 7.47 (dd, J=8.4,
4.4 Hz, 1H), 7.40 (td, J=8.5, 2.4 Hz, 1H), 7.30 (dd, J=5.0, 1.3 Hz, 1H),
7.00 (dd, J=3.7, 1.3 Hz, 1H), 6.96 (dd, J=5.0, 3.6 Hz, 1H), 2.09 (s,
3H); 13C NMR (101 MHz, CDCl3) δ=167.9(d, JC-F =3.9 Hz) (C), 163.33
(d, JC-F =250.5 Hz) (C), 148.93 (d, JC-F =2.4 Hz) (C), 144.0 (C), 127.40
(d, JC-F =8.9 Hz) (C), 127.0 (CH), 126.4 (CH), 125.5 (CH), 123.88 (d, JC-
The authors declare no conflict of interest.
Keywords: BIPHEN-H2 · Cyclization · Lactones · Magnesiate ·
Metal-halogen exchange
F =8.6 Hz) (CH), 122.28 (d, JC-F =24.1 Hz) (CH), 112.16 (d, JC-F
=
23.7 Hz) (CH), 85.3 (C), 28.2 (CH3); 19F NMR (376 MHz, CDCl3) δ=-
110.8; HRMS (ESI positive): m/z calcd. for C13H10FSO2 [M+H]+:
249.0380 found 249.0380 and for C13H9FSO2Na [M+Na]+: 271.0199
found 271.0242; Flash chromatography conditions: Petroleum
ether/EtOAc 100/0 to 90/10.
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CN103980238 A.
5-Chloro-3,7-dimethyl-3-(4-methoxyphenyl)-(3H)-isobenzofuran-
1-one (3m): Compound 3m was prepared according to the general
procedure
B using ethyl-4-chloro-2-iodo-6-methylbenzoate 1f
(85 mg, 0.25 mmol) and 4’-methoxyacetophenone (60 mg,
0.40 mmol). The title compound was obtained after flash chroma-
tography as yellow oil; yield 73% (55 mg); Rf =0.36 (petroleum
ether/EtOAc 90/10); 1H NMR (400 MHz, CDCl3) δ=7.31 (d, J=8.9 Hz,
2H), 7.25 (s, 1H), 7.17 (s, 1H), 6.87 (d, J=8.9 Hz, 2H), 3.79 (s, 3H), 2.69
(s, 3H), 1.99 (s, 3H).; 13C NMR (101 MHz, CDCl3) δ=169.1 (C), 159.7
(C), 156.6 (C), 141.5 (C), 140.2 (C), 132.3 (C), 131.0 (CH), 126.6 (2*CH),
121.2 (C), 119.8 (CH), 114.1 (2*CH), 86.0 (C), 55.3 (CH3), 27.1 (CH3),
17.3 (CH3); HRMS (ESI positive): m/z calcd. for C17H16ClO3 [M+H]+:
303.0782 found 303.0812 and for C17H15ClO3Na [M+Na]+: 325.0602
found 325.0634; Flash chromatography conditions: column 24 g,
flow rate=20 mL/min, petroleum ether/EtOAc 100/0 to 90/10.
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5-Chloro-3,7-dimethyl-3-(2-pyridyl)-(3H)-isobenzofuran-1-one
(3n): Compound 3n was prepared according to the general
procedure
B using ethyl-4-chloro-2-iodo-6-methylbenzoate 1f
(85 mg, 0.25 mmol) and 2-acetylpyridine (49 mg, 0.40 mmol). The
title compound was obtained after flash chromatography as white
solid; yield 79% (54 mg); Rf =0.42 (petroleum ether/EtOAc 90/10);
1
°
m.p.: 153–155 C; H NMR (400 MHz, CDCl3) δ=8.61 (d, J=4.8 Hz,
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8.0 Hz, 1H), 7.24–7.17 (m, 2H), 2.65 (s, 3H), 2.02 (s, 3H).; 13C NMR
(101 MHz, CDCl3) δ=169.1 (C), 159.8 (C), 155.5 (C), 149.4 (CH), 141.0
(C), 140.3 (C), 137.0 (CH), 131.1 (CH), 122.9 (CH), 121.2 (CH), 120.5
(C), 118.6 (CH), 86.5 (C), 27.5 (CH3), 17.3 (CH3); HRMS (ESI positive):
m/z calcd. for C15H13ClNO2 [M+H]+: 274.0629 found 274.0658 and
for C15H12ClNO2Na [M+Na]+: 296.0449 found 296.0430; Flash
9265–9269.
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Manuscript received: September 9, 2021
Revised manuscript received: August 15, 2021
Accepted manuscript online: August 18, 2021
Eur. J. Org. Chem. 2021, 4835–4845
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4845
© 2021 Wiley-VCH GmbH