Facile synthesis of phthalides from methyl ortho-iodobenzoates and ketones via an iodinemagnesium exchange reaction using a silylmethyl Grignard reagent

Article abstract of DOI:10.1246/cl.170211

Phthalides have been easily prepared by the treatment of methyl o-iodobenzoates with a silylmethyl Grignard reagent in the presence of ketones. The electron-withdrawing ester moiety of methyl o-iodobenzoates and the low nucleophilicity of the silylmethyl Grignard reagent prompted a smooth iodinemagnesium exchange reaction, at room temperature, without affecting the ester moiety or resulting in an undesired reaction with electrophilic ketones. This simple method, wherein special control of the reaction temperature was unnecessary, has allowed the synthesis of various phthalides, including a phenolphthalein derivative.

Full text of DOI:10.1246/cl.170211

Advance Publication Cover Page
Facile Synthesis of Phthalides from Methyl ortho-Iodobenzoates and Ketones
via an Iodine–Magnesium Exchange Reaction Using a Silylmethyl Grignard Reagent
Yu Nakamura, Suguru Yoshida,* and Takamitsu Hosoya*
Advance Publication on the web March 25, 2017
doi:10.1246/cl.170211
© 2017 The Chemical Society of Japan
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Publication manuscripts.

Facile Synthesis of Phthalides from Methyl ortho-Iodobenzoates and Ketones
via an Iodine–Magnesium Exchange Reaction Using a Silylmethyl Grignard Reagent
Yu Nakamura, Suguru Yoshida,* and Takamitsu Hosoya*
Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering,
Tokyo Medical and Dental University (TMDU), 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062
(E-mail: s-yoshida.cb@tmd.ac.jp, thosoya.cb@tmd.ac.jp)
Phthalides have been easily prepared by the treatment of
methyl o-iodobenzoates with a silylmethyl Grignard reagent
in the presence of ketones. The electron-withdrawing ester
moiety of methyl o-iodobenzoates and the low nucleophilicity
of the silylmethyl Grignard reagent prompted a smooth
iodine–magnesium exchange reaction, at room temperature,
without affecting the ester moiety or resulting an undesired
reaction with electrophilic ketones. This simple method,
wherein special control of the reaction temperature was
unnecessary, has allowed the synthesis of various phthalides,
including a phenolphthalein derivative.
which could be produced via the iodine–magnesium exchange
of 1 followed by reaction of the resulting phenylmagnesium
chloride with ketone 2a, was not obtained. Instead, 1,1-
diphenyl-2-(trimethylsilyl)ethanol (4) was obtained in low
yield. This result clearly showed that the iodine–magnesium
exchange of simple iodobenzene (1) did not occur and the
addition of the silylmethyl Grignard reagent to ketone 2a
proceeded. Given that the ortho-triflyloxy group facilitated
the iodine–magnesium exchange in the generation of arynes
from o-iodoaryl triflates, we conceived of introducing an
electron-withdrawing and chelating directing group to
iodobenzene to promote the iodine–magnesium exchange
reaction. Based on this idea, we treated a mixture of methyl o-
Keywords: Iodine–magnesium exchange | Grignard
reagent| Phthalide
iodobenzoate
(5a)
and
ketone
2a
with
Aryl anions are useful intermediates for the syntheses of
various aromatic compounds.1 Halogen–metal exchange
reactions are widely used methods to generate aryl anions
from aryl halides.1–4 In particular, halogen–metal exchange
(trimethylsilyl)methylmagnesium chloride, which afforded
3,3-diphenylphthalide (6a) in 40% yield (Figure 1C and Table
1, entry 1). This result indicated that an aryl anion species was
generated via the iodine–magnesium exchange of 5a and
nucleophilic addition of the resulting aryl anion to ketone 2a
followed by cyclization afforded phthalide 6a.
using
magnesium
ate
complexes,
including
isopropylmagnesium chloride lithium chloride complex (turbo
Grignard reagent)3 and lithium tributylmagnesate,4 which
facilitate the rapid halogen–magnesium exchange of aryl
iodides or bromides, have been commonly used. However, the
high nucleophilicity of these reagents requires the reaction to
be performed in a controlled manner at low temperature,
limiting the substrate scope and making the experimental
handling cumbersome and complicated. Herein, we report that
the use of a low-nucleophilic silylmethyl Grignard reagent
allowed for the efficient iodine–magnesium exchange of
methyl o-iodobenzoates at room temperature without
affecting the ester moiety even in the presence of ketones to
afford phthalides.
During the course of our recent studies on aryne
chemistry,5–7 we have demonstrated that aryne species are
generated efficiently from o-iodoaryl triflates via an iodine–
magnesium exchange reaction using a silylmethyl Grignard
reagent (Figure 1A).7 Based on this method, various arynes
bearing a transformable functional group,6e,6i,7,8 such as a
terminal alkyne moiety,7a azido group,7d ester moiety,7c
triflyloxy group,7b,7f,7g or halogeno group,7j were generated
efficiently, via which a variety of aromatic compounds were
synthesized. These studies disclosed the potential usefulness
of the moderately nucleophilic silylmethyl Grignard reagent
in synthetic organic chemistry.7,9
A Previous work
O
OTf
Me3SiCH2MgCl
O
MeO
MeO
THF, rt
I
O
O
iodine–magnesium
exchange
cycloaddition
OTf
ß-elimination
MeO
MeO
MgCl
O
O
B
Me3SiCH2MgCl
(1.2 equiv)
SiMe3
O
OH
+
OH
+
+
1
91%
recovery
THF
rt, 12 h
Ph
Ph
I
Ph Ph
Ph Ph
1
2a
(1.5 equiv)
3
not detected
4
28%
C
This work
(based on 2a)
O
O
Me3SiCH2MgCl
(1.2 equiv)
O
OMe
+
+
5a
54%
O
THF, rt, 12 h
Ph
Ph
2a
(1.5 equiv)
I
Ph
6a
40%
recovery
5a
Ph
iodine-magnesium
exchange
O
O
O
Ph
Ph
OMe
MgCl
OMe
O
MgCl
We were interested in the unique reactivity that the
silylmethyl Grignard reagent showed; and thus, explored its
general applicability for the iodine–magnesium exchange
reaction. When iodobenzene (1) was treated with
(trimethylsilyl)methylmagnesium chloride in tetrahydrofuran
(THF) at room temperature in the presence of benzophenone
(2a), 1 was mostly recovered (Figure 1B). Trityl alcohol (3),
Ph Ph
Figure 1. Transformations via the iodine–magnesium exchange reaction
triggered by a silylmethyl Grignard reagent. (A) Our previous study
involving the generation of arynes from o-iodoaryl triflate-type precursors.
(B) Attempted iodine–magnesium exchange of iodobenzene (1). (C)
Phthalide synthesis from ester 5a and ketone 2a.

2
Table 1. Optimization of the reaction conditions
O
(entry 1). Halogeno group-containing substrates, such as 4-
fluorophenyl-, chloro-, or bromo-substituted methyl o-
iodobenzoates 5c–5e, also reacted smoothly with ketone 2a to
afford phthalides 6c–6e, leaving non-iodine halogeno groups
untouched (entries 2–4).
O
R–Mtl
(x equiv)
O
OMe
+
O
THF, rt, 12 h
Ph
Ph
I
5a
Ph
Ph
6a
2a
(1.5 equiv)
Entry
R–Mtl
x
Conversion/%a Yield/%a
Table 3. Reactions between ester 5a and various ketones 2
O
1
2
Me3SiCH2MgCl
n-BuLi
1.2
1.2
1.2
1.2
1.2
3.0
46
63
40
10
5
O
Me3SiCH2MgCl
(3.0 equiv)
O
OMe
O
+
3
i-PrMgCl·LiCl
n-Bu3MgLi
17
R
R
THF, rt, 12 h
I
R
R
5a
2
(1.5 equiv)
4
5b
100
61
0
6
Me3SiCH2MgCl
Me3SiCH2MgCl
58
87c
Entry
1
Ketone
2
Phthalide
6
Yield/%a
6
100
O
aYields determined by 1H NMR analysis, unless otherwise noted.
bThe reaction was performed at 60 °C for 12 h. c Isolated yields.
O
O
2b
6f
66
OMe
Because phthalides are an important class of molecules10
often found in natural products, drug candidates, and
functional molecules, we embarked on optimization studies
for this transformation (Table 1). In contrast to the silylmethyl
Grignard reagent (entry 1), the use of n-butyllithium (entry 2),
turbo Grignard reagent (entry 3), or lithium tributylmagnesate
(entry 4) as an activator for iodine–metal exchange were
entirely unsatisfactory. Based on the good material balance
observed when 1.2 equiv of silylmethyl Grignard reagent was
used (entry 1), we examined the reaction using this reagent.
Although simply performing the reaction at higher
temperature (60 °C) improved the yield of phthalide 6a,
significant amount of 5a still remained (entry 5). Increasing
the amount of Grignard reagent to 3.0 equiv in order to
consume 5a completely resulted in a significant improvement
in the yield of 6a (entry 6).11
MeO
OMe
MeO
O
O
O
2
2c
6g
38
79
Cl
Cl
Cl
Cl
O
O
O
3
4
2d
2e
6h
6i
O
O
O
0b
O
O
O
O
O
5
6
2f
6j
0
Ph
Me
Me
Table 2. Reactions between various esters 5 and benzophenone (2a)
Ph
O
Me3SiCH2MgCl
O
O
O
R
(3.0 equiv)
R
O
OMe
Me
Me
O
+
O
2g
6k
78
Ph
Me
Me
Ph
Ph
THF, rt, 12 h
I
Ph
Ph
Ph
5
2a
(1.5 equiv)
aIsolated yields. bA complex mixture of products was obtained.
6
Entry
1
Ester
5
Phthalide
6
Yield/%a
69
Various ketones were also applicable to the phthalide
synthesis (Table 3). Reactions of ester 5a with 4,4’-
dimethoxybenzophenone (2b) or 4,4’-dichlorobenzophenone
(2c) afforded the corresponding phthalides 6f or 6g,
respectively (entries 1 and 2).12 The reaction with dibenzo-
fused cycloheptadienone 2d proceeded efficiently to afford
spiro-phthalide 6h in high yield (entry 3). Unfortunately, the
reaction of 5a with xanthone (2e) was unsuccessful and
phthalide 6i was inaccessible by this method (entry 4).
Acetophenone (2f) was also an unfavorable substrate for this
transformation, possibly due to the preceding deprotonation of
the acidic α-proton of 2f, leading to an aldol reaction (entry 5).
In contrast, isobutyrophenone (2g) with a bulkier alkyl group
O
O
Me
Me
OMe
O
5b
6b
Ph
I
Ph
F
F
O
O
I
2
5c
6c
51
OMe
O
Ph
Ph
O
O
Cl
Cl
OMe
O
3
4
5d
5e
6d
6e
53
51
Ph
I
Ph
O
O
Br
Br
OMe
O
Ph
reacted
smoothly
with
the
o-
I
Ph
aIsolated yields.
(methoxycarbonyl)phenylmagnesium intermediate, generated
in situ via the iodine–magnesium exchange of 5a, to afford
the corresponding phthalide 6k in high yield (entry 6).
To gain insight into the effect of the ester moiety in the
iodine–magnesium exchange reaction, we examined the
reactions of methyl m-iodobenzoate (7) or methyl p-
iodobenzoate (9) with benzophenone (2a) under the optimized
conditions for phthalide synthesis (eqs 1 and 2). From these
The optimized conditions were successfully applied to
the synthesis of functionalized phthalides in only one step
from functionalized methyl o-iodobenzoates (Table 2). For
example, the iodine–magnesium exchange of methyl-
substituted ester 5b in the presence of ketone 2a under the
optimized conditions afforded phthalide 6b in good yield

3
reactions, only a small amount of alcohol 8 or none of 10 was
obtained. Also the deiodinated methyl benzoate was not
obtained, suggesting that these substrates were unsuitable for
the iodine–magnesium exchange reaction. Alternatively,
alcohol 4, which was formed by addition of the Grignard
reagent to ketone 2a, was obtained along with significant
recovery of the iodobenzoates. These results indicate that the
electron-withdrawing and directing effect by the ortho-ester
moiety play a critical role for facilitating the iodine–
magnesium exchange reaction using the silylmethyl Grignard
reagent. We also found that iodobenzene derivative 11, with
an electron-withdrawing and directing chloro group at the
ortho-position, also lead to magnesiation to afford alcohol 12
in moderate yield (eq 3).
In summary, we have shown that an ortho-ester moiety
on iodoarenes prompts a smooth iodine–magnesium exchange
reaction with
a silylmethyl Grignard reagent at room
temperature, even in the presence of ketones. This method
enabled the preparation of various phthalides from o-
iodobenzoic acid esters and ketones without special attention
to the reaction temperature. Further studies, involving the
synthetic applications of these arylmagnesium intermediates
generated using a silylmethyl Grignard reagent, are now in
progress.
The authors thank Central Glass Co., Ltd. for providing
Tf2O. This work was supported by Platform for Drug
Discovery, Informatics, and Structural Life Science of MEXT
and AMED, Japan; JSPS KAKENHI Grant Numbers
15H03118 (B; T.H.), 16H01133 (Middle Molecular Strategy;
T.H.), 26350971 (C; S.Y.); Suntory Foundation for Life
Sciences (S.Y.); Naito Foundation (S.Y.).
2a
(1.5 equiv)
Me3SiCH2MgCl
(3.0 equiv)
MeO
O
MeO
O
SiMe3
OH
(1)
+
+
7
47%
recovery
OH
Ph Ph
THF
rt, 12 h
I
Ph Ph
7
Supporting Information is available on http://dx.doi.org/
10.1246/cl.xxxxxx.
8
10%
4
52%
(based on 2a)
2a
(1.5 equiv)
O
O
Me3SiCH2MgCl
(3.0 equiv)
References and Notes
SiMe3
MeO
MeO
OH
(2)
+
+
1
a) Arene Chemistry, Reaction Mechanisms and Methods for
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9
36%
recovery
OH
Ph Ph
THF
rt, 12 h
I
Ph Ph
9
10
0%
4
46%
(based on 2a)
2
For selected examples, see: a) G. Wittig, U. Pockels, H. Droge, Ber.
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2a
(1.5 equiv)
Me3SiCH2MgCl
(3.0 equiv)
Cl
I
Cl
(3)
OH
THF
rt, 12 h
11
Ph Ph
12
32%
The facile method for phthalide synthesis rendered
functionalized phenolphthalein derivatives13 easily accessible.
For example, treatment of methyl 5-bromo-2-iodobenzoate
(5e) with the silylmethyl Grignard reagent in the presence of
4,4’-bis(silyloxy)benzophenone 2h afforded phthalide 6l in
moderate yield. Subsequent desilylation of 6l successfully
provided bromo-substituted phenolphthalein derivative 6m13b
in high yield. This simple two-step procedure would allow for
the synthesis of a wide range of phenolphthalein derivatives
by changing the ester and ketone to other substrates.
3
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2h
(1.5 equiv)
O
Br
O
I
Me3SiCH2MgCl
(3.0 equiv)
O
Br
OMe
THF, rt, 12 h
OTBS
5e
6l
47%
TBSO
O
Br
TBAF
(4.0 equiv)
O
THF, rt, 3 h
OH
6m
88%
HO
7
Scheme 1. Synthesis of bromo-substituted phenolphthalein 6m.

4
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8
11
Competition
experiment
for
metalation
using
(trimethylsilyl)methylmagnesium chloride between methyl o-
iodobenzoate (5a) and o-iodophenyl triflate revealed that the
triflyloxy group more significantly enhanced the iodine–
magnesium exchange reaction than the ester moiety. See,
Supporting Information for the detail.
12
13
Performing the reaction between 5a and 2c using
(trimethylsilyl)methylmagnesium chloride at 60 °C for 12
h
afforded 6g in 38% yield, indicating that raising the reaction
temperature is ineffective.
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