Palladium(0)-catalyzed 5-exo-dig O-cyclization/coupling of ethyl 3-(2-alkynylphenyl)-3-oxopropanoates with aryl iodides to 1,3-dihydroisobenzofurans

Article abstract of DOI:10.1016/j.tetlet.2015.10.040

Palladium-catalyzed highly regioselective 5-exo-dig O-cyclization/coupling of a series of ethyl 3-(2-alkynylphenyl)-3-oxopropanoates with aryl iodides has been developed for the synthesis of (Z)-alkylidene-1,3-dihydroisobenzofuran derivatives. Reactions o

Full text of DOI:10.1016/j.tetlet.2015.10.040

Tetrahedron Letters 56 (2015) 6629–6632
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Palladium(0)-catalyzed 5-exo-dig O-cyclization/coupling of
ethyl 3-(2-alkynylphenyl)-3-oxopropanoates with aryl
iodides to 1,3-dihydroisobenzofurans
a,c,
Li-Lan Wei b, Li-Mei Wei b, Po-Yang Lin c, Chin-Chau Chen a, Wen-Bin Pan b, , Ming-Jung Wu
⇑
⇑
a Department of Chemistry, National Sun Yat-sen University, Kaohsiung, Taiwan, ROC
b Department of Applied Chemistry and Materials Science, Fooyin University, Kaohsiung, Taiwan, ROC
c Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
Palladium-catalyzed highly regioselective 5-exo-dig O-cyclization/coupling of a series of ethyl 3-(2-alky-
nylphenyl)-3-oxopropanoates with aryl iodides has been developed for the synthesis of (Z)-alkylidene-
1,3-dihydroisobenzofuran derivatives. Reactions of ethyl 3-(2-alkynylphenyl)-3-oxopropanoates and aryl
iodides are carried out in DMSO at 80 °C with 5 mol % Pd(PPh3)4 and 2 equiv of Et3N as a base for 4 h in
modest yields.
Received 7 September 2015
Revised 8 October 2015
Accepted 10 October 2015
Available online 22 October 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
1,3-Dihydroisobenzofurans
Palladium-catalyzed
5-exo-dig
O-Cyclization/coupling
The dihydroisobenzofurans (phthalans), as useful building
blocks1 as well as key structural units in a broad range of natural
products2 and biologically important active compounds,3 have
attracted much attention in organic chemistry. As a result, much
effort has focused on the synthesis of the functionalized phthalan
derivatives. Over the years numerous routes available have been
described to synthesize these compounds, with most of them
requiring cyclization reactions of disubstituted alkynes through
iodocyclization,4 intramolecular Michael addition,5 or intramolecu-
lar addition/cyclization involving the use of palladium,6 and other
metal- and metal-free catalyzed cyclization.7 Therefore, the chal-
lenge remains to develop one-pot procedures for the production
of highly functionalized alkylidene phthalans with high efficiency
and regioselectivity. The palladium-catalyzed sequential
intramolecular cyclization and coupling reactions of acetylenic
molecules containing a heteronucleophile with organic halides or
triflates are a well-established strategy that has led to the success-
ful synthesis of a variety of heterocyclic compounds.8 We have
already disclosed several approaches to the palladium-catalyzed
synthesis of heterocycles starting from acetylenic substrates.9
In 2000, we have established a novel pathway to synthesize
3,4-disubstituted isoquinolines and diarylmethyleneisoindoles by
the palladium-mediated coupling of 2-alkynylbenzonitriles
with aryl iodides.9a In this Letter, the cyclization/coupling of
3-(2-alkynylphenyl)-3-keto esters with aryl iodides to give 1,3-
dihydroisobenzofurans is particularly attractive because ethyl
2-alkynylbenzoyl acetates can be readily prepared from the
corresponding ethyl 2-iodobenzoyl acetates with terminal
alkynes. Cyclization reactions of this type, however, can be
challenging because ethyl 3-(2-alkynylphenyl)-3-oxopropanoates
can undergo both 6-endo-dig or 5-exo-dig cyclization modes
which compete with each other, and the regioselectivity of these
reactions must therefore be well-controlled to avoid the
formation of intractable mixtures of five- and six-membered
rings. In the case of the 5-exo-dig process, it is also necessary to
control the nature of the addition to the triple bond (i.e., carbon-
vs oxygen addition) to avoid the production of a mixture of
isomeric phthalans and indanones (Scheme 1). Herein, we
described
a
one-pot and regioselective synthesis of (Z)-
alkylidenephthalan derivatives from 3-(2-alkynylphenyl)-3-
oxopropanoates and aryl iodides through Pd(0)-promoted
successive annulation/coupling reaction (Eq. 1).
⇑
Corresponding authors.
http://dx.doi.org/10.1016/j.tetlet.2015.10.040
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

6630
L.-L. Wei et al. / Tetrahedron Letters 56 (2015) 6629–6632
Ar
R
Ar
R
OEt
O
OEt
+
R
O
OH
O
O
ArI, Pd(0)
5-exo-dig C-cyclization
6-endo-dig C-cyclization
OEt
Ar
R
Ar
R
O
O
+
O
OEt
OEt
O
O
6-endo-dig O-cyclization
5-exo-dig O-cyclization
Scheme 1.
Ar
R
O
R
Table 1
Pd(PPh3)4
Palladium-catalyzed sequential cyclization/coupling reaction under various
+
Ar
I
O
conditionsa
OEt
Et3N, DMSO
ð1Þ
OEt
O
Ph
n-Am
n-Am
O
2
3
1
Pd(PPh3)4, Et3N
solvent
+
O
Ph
I
R=n-Am, i-Bu, t-Bu
OEt
OEt
O
The synthesis of starting material, ethyl 3-(2-hept-1-ynyl)phenyl)-
3-oxopropanoate 1a, from the palladium-catalyzed coupling reac-
tion of ethyl 2-iodobenzoyl acetate with 1-heptyne was outlined
in Eq. 2.
O
O
3aa
2a
1a
Entry
Solvent
Temperature (°C)
Reaction time (h)
Productb (%)
1
2
3
4
5
6
DMSO
DMSO
THF
DMF
DMSO
DMSO
rt
24
12
12
12
4
NRc
50
42
45
56
27
R
50
50
50
80
120
I
Pd(PPh3)4, CuI
Et3N, THF, 50 o
+
R
OEt
OEt
C
O
O
1
O
O
1a, R = nAm (92%)
1b, R = iBu (94%)
1c, R = tBu (86%)
a
All the reactions were carried out by using 1a (0.17 mmol), 2a (0.21 mmol),
5 mol % Pd(PPh3)4 (0.0085 mmol), 2 equiv Et3N (0.34 mmol), solvent (1 mL).
b
Isolated yields.
NR = no reaction.
c
ð2Þ
The initial attempt for the cyclization/coupled reaction of ethyl 3-
(2-hept-1-ynyl)phenyl)-3-oxopropanoate 1a and iodobenzene 2a
was carried out using 5 mol % Pd(PPh3)4 as the catalyst and
2 equiv of Et3N as a base at room temperature in DMSO for
24 h, and no desired product phthalan 3aa was observed (Table 1,
entry 1). However stirring the reaction mixture at 50 °C for 12 h,
the expected product 3aa was obtained in 50% yield (Table 1, entry
2). To optimize the reaction conditions, the cascade reactions were
carried out with different solvents and at various temperatures.
When the reaction of alkynyl ester 1a with iodobenzene 2a was
conducted in THF at 50 °C for 12 h, the yield of product phthalan
3aa was decreasing to 42% (Table 1, entry 3). Changing the reaction
solvent from THF to DMF led to the 1,3-dihydroisobenzofuran pro-
duct 3aa in 45% yield (Table 1, entry 4). We demonstrated that polar
aprotic solvent DMSO was most effective for the product formation.
Upon heating the reaction mixture at 80 °C for 4 h, the yield of pro-
duct 3aa increased to 56% yield (Table 1, entry 5).10 However upon
increase of reaction temperature to 120 °C, the reaction started get-
ting messy and the yield of 3aa dropped to 27% (Table 1, entry 6).
With the optimized reaction conditions in hand, various aryl
iodides bearing electron-donating or electron-withdrawing groups
on the phenyl ring were reacted with ethyl 3-(2-hept-1-ynyl)phe-
nyl)-3-oxopropanoate 1a in the presence of 5 mol % Pd(PPh3)4 and
2 equiv Et3N at 80 °C in DMSO for 4 h to give the cyclization prod-
ucts 3aa–3ag in modest yields. The results are summarized in
Table 2. 4-Iodoanisole 2b and 4-trifluoromethylphenyl iodide 2c
afforded the corresponding phthalans 3ab and 3ac in 55% and
58% yields, respectively, (Table 2, entries 2 and 3). 2-Iodothiophene
2d gave 3ad in 46% yield (Table 2, entry 4), which indicated that
the electron rich aryl iodides gave the cyclization products in lower
yields. 4-Iodobenzonitrile 2e produced 3ae in 53% yield (Table 2,
entry 5). 4-Iodonitrobenzene 2f was conducted with 1a to produce
3af in a higher yield (75%, Table 2, entry 6), indicating that 4-
iodonitrobenzene 2f with a strong electron-withdrawing group
on the phenyl ring may accelerate the rate of the cyclization reac-
tion. 4-Iodophenol 2g only gave 3ag in 20% yield (Table 2, entry 7).
To further examine the generality of this cyclization/coupling reac-
tion, other acetylenic b-keto esters 1b–c bearing different alkyl
substituents on the terminus alkyne are prepared from the appro-
priate ethyl o-iodobenzoyl acetate and corresponding terminal
alkynes by the above palladium/copper-catalyzed coupling
method (Eq. 2). More interestingly, the Sonogashira coupling reac-
tion of ethyl 2-iodobenzoyl acetate with phenyl acetylene afforded

L.-L. Wei et al. / Tetrahedron Letters 56 (2015) 6629–6632
6631
Table 2
Palladium-catalyzed coupling reactions of ethyl 3-(2-alkynylphenyl)-3-oxopropanoates 1 with aryl iodides 2
Ar
R
R
Pd(PPh3)4, Et3N
DMSO
+
O
Ar
I
OEt
OEt
O
O
O
3
2
1
Entry
R
Aryl iodides
Products (Yield %)
1
2
3
4
5
6
7
8
1a (R = nAm)
1a
1a
1a
2a (Ar = phenyl)
2b (Ar = 4-methoxyphenyl)
2c (Ar = 4-trifluoromethylphenyl)
2d (Ar = thiophen-2-yl)
2e (Ar = 4-cyanophenyl)
2f (Ar = 4-nitrophenyl)
2g (Ar = 4-hydroxyphenyl)
2a
2b
2c
2d
2a
2b
2c
2d
3aa (56)
3ab (55)
3ac (58)
3ad (46)
3ae (53)
3af (75)
3ag (20)
3ba (38)
3bb (20)
3bc (31)
3bd (47)
3ca (38)
3cb (27)
3cc (37)
3cd (35)
1a
1a
1a
1b (R = iBu)
9
1b
1b
1b
10
11
12
13
14
15
1c (R = tBu)
1c
1c
1c
unexpected cyclization product, (Z)-ethyl 2-((Z)-3-benzylidene)
isobenzofuran-1(3H)-ylidene)acetate 4, in 82% yield (Eq. 3).6d
I
I
R
O
Ar Pd
Ar Pd
R
R
O
H
base
Ph
OEt
I
OH
O
Pd(PPh3)4, CuI
O
Ph
O
+
OEt
Et3N, THF, 50 o
C
O
1
OEt
O
O
OEt
B
OEt
A
4
O
Ar Pd
I
ð3Þ
Ar
Pd
Treatment of ethyl 3-(2-(4-methylpent-1-ynyl)phenyl)-3-oxo-
propanoate 1b with various aryl iodides 2a–2d under the standard
reaction conditions also gave the same coupling phthalan deriva-
tives 3ba–3bd in the 20–47% yields (Table 2, entries 8–11).
Iodobenzene 2a and 4-iodoanisole 2b afforded the corresponding
phthalans 3ba and 3bb in 38% and 20% yields, respectively, (Table 2,
entries 8 and 9). Aryl iodides with an electron-withdrawing group
such as 4-iodotrifluoromethylbenzene 2c and 2-iodothiophene 2d
produced the cyclization products 3bc and 3bd in 31% and 47%
yields, respectively, (Table 2, entries 10 and 11). Finally, the same
reaction conditions apply to ethyl 3-(2-(3,3-dimethylbut-1-ynyl)
phenyl)-3-oxopropanoate 1c with various aryl iodides 2a–2d gave
the same cyclization products 3ca–3cd in the 27–38% yields
(Table 2, entries 12–15). Iodobenzene gave the cyclization product
3ca in the yield of 38% (Table 2, entry 12). 4-Methoxyphenyl iodide
produced the coupled product 3cb in the 27% yield (Table 2, entry
13). Aryl iodides 2c and 2d yielded the cyclization products 3cc
and 3cd in the yields of 37% and 35%, respectively, (Table 2, entries
14 and 15). According to the above results, substrates 1b–1c with a
bulky group such as isobutyl and t-butyl groups on the terminal
alkynes may interfere the cyclization reaction and reduce the yield
of the desired products. The chemical structure of the novel alkyli-
dene-phthalan 3aa was characterized by spectroscopic analysis.11
According to the above results and our previous work, we pro-
posed a mechanism for this tandem process as shown in Scheme 2.
This reaction pathway involves: (a) the oxidative addition of aryl
iodide to Pd(0) to give an arylpalladium intermediate, (b) coordina-
Ar
Ar
I
R
2
R
+
O
Pd(0)
O
OEt
OEt
C
O
3
O
Scheme 2.
complex to produce the
nation of the -position of palladium complex A by Et3N to yield an
g
2-palladium intermediate A, (c) deproto-
a
palladium enolate ion B, followed by 5-exo-trig intramolecular
nucleophilic O-attack of the enolate ion B to the activated car-
bon–carbon triple bond to give the vinylpalladium complex C
and (d) reductive elimination of Pd0 species from the palladium
complex C to give the five-membered ring coupled product 3. It
is worthy to note that the tandem process proceeds in a steric-
and regioselective manner.
In conclusion, we have demonstrated an efficient synthesis of
the highly functionalized (Z)-alkylidene phthalans via palladium
(0)-catalyzed sequential 5-exo-trig O-cyclization/coupling reac-
tions of ethyl 3-(2-(substituted ethynyl)phenyl)-3-oxopropanoates
with aryl iodides in DMSO. The stereochemistry was controlled by
anti-addition of the electrophilic palladium and the nucleophilic
oxygen to the alkyne. Currently, the synthetic application to phar-
maceutical important phthalan derivatives is under investigation.
tion of the carbon–carbon triple bond of 1 to
r-Csp2-palladium

6632
L.-L. Wei et al. / Tetrahedron Letters 56 (2015) 6629–6632
Li, J.-H. J. Org. Chem. 2009, 74, 3569; (f) Dell’Acqua, M.; Facoetti, D.; Abbiati, G.;
Supplementary data
Rossi, E. Tetrahedron Lett. 2011, 67, 1552; (g) Fan, Y. C.; Kwon, O. Org. Lett. 2012,
14, 3264; (h) Mancuso, R.; Ziccarelli, I.; Armentano, D.; Marino, N.; Salerno, G.;
Gabriele, B. J. Org. Chem. 2014, 79, 3506.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.10.
040.
7. (a) Chai, Z.; Xie, Z. F.; Liu, X.-Y.; Zhao, G.; Wang, J.-D. J. Org. Chem. 2008, 73,
2947; (b) Pawar, S. K.; Wang, C. D.; Bhunia, S.; Jadhav, A. M.; Liu, R. S. Angew.
Chem., Int. Ed. 2013, 52, 7559; (c) Shen, Y. C.; Kwon, O. Org. Lett. 2014, 16, 5588;
(d) Li, D. Y.; Shi, K. J.; Mao, X. F.; Chen, G. R.; Liu, P. N. J. Org. Chem. 2014, 79,
4602.
8. (a) Asao, N.; Nogami, T.; TaKahashi, K.; Yamamoto, Y. J. Am. Chem. Soc. 2002,
124, 764; (b) TsuKamoto, H.; Kondo, Y.; Ueno, T. Org. Lett. 2007, 9, 3033; (c)
Liang, Z.; Ma, S.; Yu, J.; Xu, R. J. Org. Chem. 2007, 72, 9219; (d) Gabriele, B.;
Mancuso, R.; Salerno, G. J. Org. Chem. 2008, 73, 7336.
9. (a) Wei, L. M.; Lin, C. F.; Wu, M. J. Tetrahedron Lett. 2000, 41, 1215; (b) Wu, M. J.;
Lin, C. F.; Duh, T. H.; Lu, W. D.; Lee, J. L.; Lee, C. Y. J. Chin. Chem. Soc. 2004, 51,
183; (c) Wei, L. L.; Wei, L. M.; Pan, W. B.; Wu, M. J. Synlett 2004, 1497.
10. General procedure of the preparation of (Z)-alkylidene-1,3-dihydroisobenzofuran
derivatives: A slurry of the ethyl 3-(2-hept-1-ynyl)phenyl)-3-oxopropanoate 1a
(0.05 g, 0.17 mmol), iodobenzene 2a (0.043 g, 0.21 mmol), 5 mol % Pd(PPh3)4
(0.01 g, 0.0085 mmol) and 2 equiv Et3N (0.34 mmol) in DMSO (1 mL) was
stirred at 80 °C for 4 h. After cooling to room temperature, the reaction mixture
was quenched with saturated aqueous NH4Cl solution and extracted with
EtOAc (3 ꢀ 5 mL). The combined organic extracts were dried over anhydrous
MgSO4. After filtration and removal of solvent, the residue was purified by
column chromatography on silica gel using n-hexane–EtOAc (v/v, 50:1) as
eluent to give the product 3aa (56%).
References and notes
1. (a) Meegalla, S. K.; Rodrigo, R. J. Org. Chem. 1991, 56, 1882; (b) Azzena, U.;
Demartis, S.; Fiori, M. G.; Melloni, G.; Pisano, L. Tetrahedron Lett. 1995, 36, 8123;
(c) Azzena, U.; Demartis, S.; Melloni, G. J. Org. Chem. 1996, 61, 4913; (d) Mikami,
K.; Ohmura, H. Org. Lett. 2002, 4, 3355; (e) Siyang, H. X.; Wu, X. R.; Liu, H. L.;
Wu, X. Y.; Liu, P. N. J. Org. Chem. 2014, 79, 1505.
2. (a) Strobel, G.; Ford, E.; Worapong, J.; Harper, J. K.; Arif, A. M.; Grant, D. M.;
Fung, P. C. W.; Chau, R. M. W. Phytochemistry 2002, 60, 179; (b) Harper, J. K.;
Arif, A. M.; Ford, E. J.; Strobel, G. A., Jr.; Porco, J. A.; Tomer, D. P.; Oneill, K. L.;
Heider, E. M.; Grant, D. M. Tetrahedron 2003, 59, 2471; (c) Pahari, P.; Senapati,
B.; Mal, D. Tetrahedron Lett. 2004, 45, 5109.
3. (a) Martin, C.; Mailliet, P.; Maddaluno, J. J. Org. Chem. 2001, 66, 3797; (b) Yang,
H.; Hu, G. Y.; Chen, J.; Wang, Y.; Wang, Z. H. Bioorg. Med. Chem. Lett. 2007, 17,
5210.
4. Mancuso, R.; Mehta, S.; Gabriele, B.; Salerno, G.; Jenks, W. S.; Larock, R. C. J. Org.
Chem. 2010, 75, 897.
5. (a) Mukhopadhyay, R.; Kundu, N. G. Tetrahedron 2001, 57, 9475; (b) Duan, S.;
Cress, K.; Waynant, K.; Ramos-Miranda, E.; Herndon, J. W. Tetrahedron 2007, 63,
2959.
11. Compound 3aa (56%) as a yellow liquid: 1H NMR (CDCl3, 400 MHz): d 7.55 (d, 1H,
J = 8.0 Hz), 7.45–7.38 (m, 3H), 7.32–7.23 (m, 3H), 7.13 (t, 1H, J = 7.2 Hz), 6.42 (d,
1H, J = 8.0 Hz), 5.55 (s, 1H), 4.30 (q, 2H, J = 6.8 Hz), 2.86 (t, 2H, J = 7.2 Hz), 1.46–
1.22 (m, 6H), 0.85 (t, 6H, J = 7.2 Hz); 13C NMR (CDCl3, 100 MHz): 166.1, 161.8,
148.1, 138.1, 133.8, 133.6, 131.0, 129.2, 129.2, 128.9, 128.9, 128.4, 127.8, 123.5,
122.6, 120.9, 88.5, 59.8, 33.4, 31.6, 27.1, 22.5, 14.5, 14.0; HMRS(EI); m/z calcd
for C24H26O3: 362.1882; found: 362.1881.
6. (a) Gabriele, B.; Salerno, G.; Fazio, A.; Pittelli, R. Tetrahedron 2003, 59, 6251; (b)
Bacchi, A.; Costa, M.; Cà, N. D.; Fabbricatore, M.; Fazio, A.; Gabriele, B.; Nasi, C.;
Salerno, G. Eur. J. Org. Chem. 2004, 574; (c) Lemhadri, M.; Doucet, H.; Santelli,
M. Tetrahedron 2005, 61, 9839; (d) Kobayashi, K.; Hashimoto, K.; Fukamachi, S.;
Konishi, H. Synthesis 2008, 7, 1094; (e) Peng, P.; Tang, B.-X.; Pi, S.-F.; Liang, Y.;