Hydroiodination-Triggered Cascade Reaction with I2/PPh3/H2O: Metal-Free Access to 3-Substituted Phthalides from 2-Alkynylbenzoates

Article abstract of DOI:10.1002/ejoc.201700839

Phthalide is an important scaffold found in several biologically active compounds. Therefore, effective methods for the synthesis of phthalides are strongly desired. Herein, we describe the metal-free synthesis of 3-substituted phthalides by the reductive hydroiodination of 2-alkynylbenzoates through an I₂/PPh₃/H₂O-triggered cascade reaction. A variety of 3-substituted phthalides were synthesized in excellent yields by a one-pot reaction involving four processes: desilylation, hydroiodination, cyclization, and reduction.

Full text of DOI:10.1002/ejoc.201700839

A Journal of
Accepted Article
Title: Hydroiodination-Triggered Cascade Reaction with I₂/PPh₃/
H₂O: a Metal-Free Access to 3-Substituted Phthalides from 2-
Alkynylbenzoates
Authors: Shin-ichi Kawaguchi, Kentaro Nakamura, Kotaro Yamaguchi,
Yuki Sato, Yuhei Gonda, Masaaki Nishioka, Motohiro Sonoda,
Akihiro Nomoto, and Akiya Ogawa
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700839
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700839
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Hydroiodination-Triggered Cascade Reaction with I2/PPh3/H2O: a
Metal-Free Access to 3-Substituted Phthalides from 2-
Alkynylbenzoates
Shin-ichi Kawaguchi,*[a] Kentaro Nakamura,[b] Kotaro Yamaguchi,[b] Yuki Sato,[b] Yuhei Gonda,[b]
Masaaki Nishioka,[b] Motohiro Sonoda,[c] Akihiro Nomoto,[b] and Akiya Ogawa*[b]
Abstract: Phthalide is an important scaffold found in several
biologically active compounds. Therefore, effective synthetic methods
for phthalides are strongly desired. Herein, we describe the metal-free
synthesis of 3-substituted phthalides by the reductive hydroiodination
of 2-alkynylbenzoates via an I2/PPh3/H2O-triggered cascade reaction.
A variety of 3-substituted phthalides were synthesized in excellent
yields via a one-pot reaction involving four processes: desilylation,
hydroiodination, cyclization, and reduction.
Synthetic methods using cascade reactions[6] have garnered
considerable attention because multiple purification steps are
avoided and they produce less waste and require less time. Our
group recently reported that the hydroiodination of alkynes with I2,
PPh3, and H2O afforded iodoalkenes.[7] Furthermore, the
hydroiodination was successfully applied to a one-pot Pd-
catalyzed cross-coupling reaction; notably, the hydroiodination
residues did not prevent the subsequent cross-coupling
reactions.[7] When the hydroiodination of various alkynes was
attempted, methyl 2-(trimethylsilylalkynyl)benzoate (1a) gave 3-
methylphthalide (2a) [Eq. (2)]. This novel lactonization should
contain four steps, i.e., desilylation, hydroiodination, cyclization[8],
and reduction. Therefore, we investigated the hydroiodination-
triggered cascade reaction of 2-alkynylbenzoates using
I2/PPh3/H2O.
Phthalide (isobenzofuranone) is an important scaffold found in
many biologically active and naturally occurring substances.[1]
Therefore, numerous synthetic methods for phthalides have been
reported in the last decade. Notably, the construction of the γ-
butyrolactone scaffold is a key step in the synthesis of phthalides,
and numerous lactonization reactions were reported including the
cyclization
of
1-(1-hydroxyalkyl)benzaldehyde
and
its
derivatives,[1b],[2] cyclization of o-aroylbenzoic acids,[3] and other
methods.[4] To accomplish efficient synthesis of phthalides, a
number of transition-metal-catalyzed reactions have been
recently reported.[5] However, metal-free efficient syntheses of
phthalides were still rare. Cyclization using 2-alkynylbenzoates 1
is an attractive route for synthesizing phthalides 2, but the
reduction of intermediate alkylidene phthalides[4b] is required [Eq.
(1)]. Therefore, the metal-free synthesis of phthalides from 2-
alkynylbenzoates is unexplored.
[a]
[b]
Dr. S-i. Kawaguchi
Center for Education and Research in Agricultural Innovation
Faculty of Agriculture, Saga University
152-1 Shonan-cho, Karatsu, Saga 847-0021, Japan
E-mail: skawa@cc.saga-u.ac.jp
K. Nakamura, K. Yamaguchi, Y. Sato, Y. Gonda, M. Nishioka, Dr. A.
Nomoto, Dr. Prof. A. Ogawa
First, we optimized the reaction conditions of the lactonization
of methyl 2-(trimethylsilylalkynyl)benzoate 1a with I2, PPh3, and
H2O (Table 1). When equimolar amounts of I2, PPh3, and H2O (0.1
mmol) were used, 3-methylidene phthalide (3a) was obtained in
19% yield (Entry 1).[9] When the amounts of I2, PPh3, and H2O
were increased (from 1 to 2 equiv.), 2a was obtained as the major
product in 70％ yield (Entry 2). Further increases in the amounts
of I2, PPh3 (3 equiv.), and H2O improved the yield of 2a (Entry 3).
With higher concentrations of 1a (0.25 M), 2a was obtained in an
excellent yield (95%) (Entry 4). When HI aq.(hydroiodic acid 57%,
6 equiv.) was used instead of I2 / PPh3 / H2O, the yields of 2a and
3a were low (0%, and 23%). Comparatively, I2 / PPh3 / H2O system
is efficient for the desired cascade reaction.
Department of Applied Chemistry
Graduate School of Engineering, Osaka Prefecture University
1-1 Gakuen-cho, Nakaku, Sakai, Osaka 599-8531, Japan
E-mail: ogawa@chem.osakafu-u.ac.jp
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Table 1. Optimization of reaction conditions.[a]
2g, 74%
2h, 0%
2i, 0%
Yield [%][b]
I2/ PPh3/ H2O [equiv.],
Entry
1j
2j, 80%[d]
concentration of 1a
2a
3a
[a] Reaction conditions: methyl 2-(trimethylsilyl)ethynyl benzoate (1, 0.3
mmol), I2 (0.9 mmol), PPh3 (0.9 mmol), H2O (0.9 mmol), CDCl3 (1.2 mL). [b]
Isolated yield. [c] 10 mmol scale in CHCl3. [d] 1j (0.3 mmol), I2 (1.8 mmol),
PPh3 (1.8 mmol), and H2O (1.8 mmol) were used.
1
2
1 / 1 / 1, 0.17 M
2 / 2 / 2, 0.17 M
3 / 3 / 3, 0.17 M
3 / 3 / 3, 0.25 M
HI 6 equiv., 0.17 M
0
19
0
70
81
95
0
3
0
4[c]
5[d]
0
Ethyl ester 1k was also a viable substrate in the cascade
reaction [Eq. (3)].
23
[a] Reaction conditions: substrate 1a (0.1 mmol), CDCl3 (0.6 mL). [b]
Determined by 1H NMR analysis. [c] Substrate 1a (0.3 mmol), CDCl3 (1.2
mL). [d] HI (3 equiv.) was used instead of I2/ PPh3/ H2O.
Next, the scope and limitations of the cyclization of methyl 2-
(trimethylsilyl)ethynyl benzoates 1 were investigated (Table 2).
First, the cascade reaction was carried out on the gram scale and
2a was successfully obtained. When methyl-, methoxy-, chloro-,
trifluoromethyl-, and fluoro-substituted 2-(trimethylsilyl)ethynyl
benzoates 1b–g were used, the cascade reaction gave the
corresponding 3-methylphthalides 2b–g in good to excellent
yields (74–91%). Nitro groups and pyridyl rings prevented the
cascade reaction. In the case of 1j, which has two cyclization sites,
the corresponding double cyclization product, 3,7-dimethyl-3,7-
dihydro-1H,5H-benzo[1,2-c:4,5-c']difuran-1,5-dione (2j), was
obtained in 80% yield.
When methyl 2-ethynylbenzoate (1l) without a silyl group was
used, 2a was obtained successfully [Eq. (4)].
As shown in Scheme 1, several methyl 2-ethynylbenzoates
with aliphatic or aromatic groups instead of trimethylsilyl groups
were subjected to the lactonization under the same conditions.
When methyl 2-(1-hexynyl)benzoate (1m) was employed, 3-
pentyl phthalide (2m) and 3-butyl isocoumarin (4m) were
obtained in 20% and 70% yields, respectively. With methyl 5-
Table 2. Synthesis of 3-methyl phthalides via cyclization of 2-
(trimethylsilyl)ethynyl benzoates.[a],[b]
chloro-2-(1-hexynyl)benzoate
(1n),
the
corresponding
isocoumarin 4n was obtained as the major product. Benzoate
substituted with a methoxy group at the 5-position 1o afforded the
corresponding phthalide 2o as the major product. Methyl 2-
(arylethynyl)benzoates 1p and 1q afforded the corresponding
isocoumarins with excellent selectivities (2/4 = 0/100). The
phthalide/isocoumarine
selectivity
depended
on
the
regioselectivity of the hydroiodination of the internal alkyne;[10] 2-
(1-alkynyl)benzoates bearing electron donating group on
aromatic ring preferentially afford phthalides, and 2-(2-
arylethyny)lbenzoates are converted to isocoumarins with
excellent selectivities.
2a, 89%,
85% (1.3 g)[c]
2b, 76%
2c, 91%
2d, 77%
2e, 82%
2f, 91%,
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phenyl-2-(trimethylsilyl)acetylene (5) was treated with excess I2,
PPh3, and H2O (3 equiv.), sequential desilylation,[12]
hydroiodination, and reduction occurred to give (1-
iodoethyl)benzene (6) in 98% yield [Eq. (5)].[13] Notably, the
reaction from phenylacetylene to (1-iodoethyl)benzene directly
has never been reported.
Scheme 1. Cyclization of 2-ethynyl benzoates. Isolated yields are shown. The
values in parentheses are corresponded to 1H NMR yields.
On the other hand, treatment of 3-methylidene phthalide (3a)
with PPh3, I2, and H2O led to a reduction and 3-methylphthalide
(2a) was obtained in a good yield (83%) [Eq. (6)].
Table 3 shows the scope of 2-ethynyl benzoates that gave
phthalides as the major product. Chloro, nitro, phenyl, and ester
groups were tolerated, and the corresponding phthalides 2r–2x
were obtained in good yields with good phthalide selectivity.
Notably, an aliphatic hydroxy group was displaced with an iodo
group under the reaction conditions,[11] affording 3-
(iodoalkyl)phthalide (2y).
To confirm the hydrogen source, the cascade reaction of 1c
was conducted using D2O (>99 atom% D) instead of H2O [Eq. (7)].
This reaction afforded 2c-D, deuterated at benzylic proton (86
atom% D) and 3-methyl proton (89 atom% D), respectively, in
56% yield. This result indicates that the reductive hydrogen
source comes from H2O in the cascade reaction. However, the
details for reduction mechanism with I2, PPh3, and H2O is still
unclear.
Table 3. Synthesis of 3-substituted phthalides[a],[b]
2r: 78%, 4r: (0%)
2s: 76%, 4s: (2%)
2t: 77%, 4t: (0%)
The proposed reaction pathway for the synthesis of 3-
substuituted phthalides 2 from methyl 2-(trimethylsilyl)ethynyl
benzoates 1 via the hydroiodination-triggered cascade reaction is
[7] [14]
shown in Scheme 2. As previously reported,
I2, PPh3, and
H2O gives HI and [Ph3POH]+[I]−, quantitatively. The generated
species can cause the hydroiodination of alkynes. First, the
desilylation of 1a occurs to give terminal alkyne 1. Subsequently,
hydroiodination of 1l proceeds to give vinyl iodide 7.[12b] Next, vinyl
iodide 7 is quickly cyclized with the elimination of MeI to give 3-
methylidene phthalide (3a). The eliminated MeI is observed by 1H
NMR analysis after the cascade reaction. Finally, 3a is reduced to
give the desired product 2a where reductive hydrogens are
derived from H2O. Although an alternative pathway via reduction
of 7, which generates alkyl iodide 8, followed by cyclization to give
2a can be also considered, 8 is not observed by 1H NMR analysis.
2u: 81%, 4u: (0%)
2w: 64%, 4w: (12%)
2v: 64%, 4v: 30%
2x: 75%, 4x: (8%)
1y
2y: 75%, 4y: (5%)
[a] Reaction conditions: 2-ethynyl benzoate (1, 0.3 mmol), I2 (0.9 mmol),
PPh3 (0.9 mmol), H2O (0.9 mmol), CDCl3 (1.2 mL), 30 °C, 17 h. [b] Isolated
yield. The values in parentheses correspond to 1H NMR yields.
To obtain further insight into this cascade reaction, the
following three additional reactions were examined. When 1-
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Scheme 2. a) Hydroiodination of alkynes with I2, PPh3, and H2O. b) Proposed
reaction pathway of the cascade reaction for the synthesis of phthalides
[9]
A few products which are not identified were also observed. We
attempted to isolate them, but they were lost during operation. They may
be reactive intermediates.
In conclusion, we developed a hydroiodination-triggered
cascade reaction of 2-alkynylbenzoates. This one-pot cascade
reaction involves four processes: desilylation, hydroiodination,
cyclization, and reduction. Metal-free and readily available
reagents (I2/PPh3/H2O) are utilized in the cascade reaction, which
offers a considerable advantage over conventional approaches.
[10] We reported the regioselectivity of the hydroiodination of several internal
alkynes, see ref 7.
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Tetrahedron 2012, 68, 9818-9825.
[13] In
our
previous
report
(ref
7),
1-(4-methyphenyl)-2-
(trimethylsilyl)acetylene with equivalent amount of I2, PPh3, and H2O
gave the corresponding vinyl iodide.
Acknowledgements
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Deplano, S. M. Godfrey, F. Lsaia, C. A. McAuliffe, M. L. Mercurp, E. F.
Trogu, Chem. Ber. 1997, 130, 299-305.
This research was supported by JSPS KAKENHI Grant Number
(16K14049, A.O., 26860168, S.K.) and the Society of Iodine
Science (SIS).
Keywords: Domino reactions • Cyclization • Reduction • Iodine •
…
Phosphorus
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Title
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Shin-ichi Kawaguchi,* Kentaro
Nakamura, Kotaro Yamaguchi, Yuki
Sato, Yuhei Gonda, Masaaki Nishioka,
Motohiro Sonoda, Akihiro Nomoto, and
Akiya Ogawa*
Page No. – Page No.
Hydroiodination-Triggered Cascade
Reaction with I2/PPh3/H2O: a Metal-
Free Access to 3-Substituted
Phthalides are synthesized in excellent yields by a metal-free cascade reaction
from 2-alkynylbenzoates with I2/PPh3/H2O, which are easy-aviable reagents. This
reaction incluldes 4 steps: desilylation, hydroiodination, cyclization, and reduction.
Phthalides from 2-Alkynylbenzoates
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