IrCl3 or FeCl3-catalyzed convenient synthesis of 3-hydroxyphthalates

Article abstract of DOI:10.1016/j.tetlet.2011.09.068

IrCl₃·3H₂O or FeCl₃-catalyzed convenient synthesis of 3-hydroxyphthalates has been achieved by a Diels-Alder reaction of furans with dimethyl acetylenedicarboxylate, followed by ring-opening aromatization reaction of the D

Full text of DOI:10.1016/j.tetlet.2011.09.068

Tetrahedron Letters 52 (2011) 6238–6241
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Tetrahedron Letters
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IrCl3 or FeCl3-catalyzed convenient synthesis of 3-hydroxyphthalates
⇑
Hiroyuki Shinohara, Motohiro Sonoda , Shingo Atobe, Haruna Masuno, Akiya Ogawa
Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuencho, Nakaku, Sakai, Osaka 599-8531, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 July 2011
Revised 9 September 2011
Accepted 15 September 2011
Available online 22 September 2011
IrCl3Á3H2O or FeCl3-catalyzed convenient synthesis of 3-hydroxyphthalates has been achieved by a Diels–
Alder reaction of furans with dimethyl acetylenedicarboxylate, followed by ring-opening aromatization
reaction of the Diels–Alder adducts, 7-oxabicyclo[2.2.1]hepta-2,5-diene derivatives. In addition,
7-azabicyclo[2.2.1]hepta-2,5-diene derivative, derived from N-Boc-pyrrole and dimethyl acetylenedicar-
boxylate, also converted into 3-aminophthalate derivative.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
3-Hydroxyphthalate
Iridium trichloride
Diels–Alder reaction
One-pot reaction
It has been well known that phthalic acid derivatives are impor-
tant starting materials or building blocks for the syntheses of
various dyes,1 typical resin paints,2 various pharmaceuticals, and
biologically active agents.3 Therefore, a development of convenient
synthetic approach to phthalic acid derivatives has still been the
current interest. The conventional syntheses of phthalic acid deriv-
atives have been performed mainly using phthalic acid or phthalic
acid anhydride.4 According to the recent letters, a dimethyl
acetylenedicarboxylate (DMAD) (1) is used as the starting com-
pound for the syntheses of phthalates via Diels–Alder reactions5
or transition-metal catalyzed [2+2+2] cycloaddition reactions.6 In
particular, a two-step synthesis consisting of Diels–Alder reaction
of furans with 1 and a subsequent ring-opening reaction by
Brønsted acids,7 Lewis acids,8 or nucleophiles,9 could open access
to the synthesis of 3-hydroxyphthalate derivatives, which are also
attractive as salicylate derivatives (Scheme 1).10
phenylfurans were performed by ZnI2 catalyst to give monohydroxy
biaryls.11 Moreno et al. reported that the use of silica-supported
Lewis acid catalysts under microwave irradiation promoted the sim-
ilar one-pot reactions.12 Ram et al.13 and Marque and co-workers14
showed the one-pot methods under thermal conditions using
3-chlorofurans and 2-amino-5-hydroxymethylfurans, respectively.
Herein, we report that IrCl3Á3H2O and FeCl3 were found to be excel-
lent catalysts for theone-pot reaction to afford 3-hydroxyphthalates.
To begin with, we have examined a ring-opening aromatization
reaction of dimethyl 1-methyl-7-oxabicyclo[2.2.1]hepta-2,5-diene-
2,3-dicarboxylate (3a), which was derived quantitatively from the
Diels–Alder reaction of 2-methylfuran (2a) with 1 in toluene,15
under the similar condition of the Diels–Alder reaction of 2a in
the presence of various Lewis acids (Table 1).
When a 10 mol % of IrCl3Á3H2O was used as a catalyst at the
lower temperature, a small amount of dimethyl 3-hydroxy-6-
methylphthalate (4a) was obtained and the starting materials were
recovered (entries 1 and 2). We were pleased to observe that the
desired ring-opening aromatization of 3a proceeded smoothly to
afford 4a in 68% yield at 70 °C (entry 3). Moreover, when FeCl3
was employed as a catalyst, the reaction proceeded quantitatively
(entry 7) though other Lewis acids such as CoCl2Á6H2O, FeCl3Á6H2O,
NiCl2, PdCl2, CuCl2, ZnI2, and Pd(OAc)2 had no effect (entries 5, 6, 8,
9, 10, 11, and 14). In the cases of metal triflates such as Cu(OTf)2
and Zn(OTf)2, the product 4a was obtained in moderate yields
(entries 12 and 13). On the basis of these results, next we planned
to carry out the one-pot reaction using 1 and 2a (Table 2).
R2
R3
OH
Ring-opening
aromatization
Diels-Alder
reaction
R2
R3
O
R2
R3
+
R1
O
R1
R1
3
4
2
Scheme 1. A two-step synthesis of 3-hydroxyphthalate derivatives.
Toward the development of a more efficient and convenient
method, only a few one-pot methods, which are important from a
green chemical viewpoint, for the synthesis of 3-hydroxyphthaletes
have been reported. Brun et al. showed that one-pot reactions of
In the presence of IrCl3Á3H2O catalyst, the reaction of 2a with 1
in toluene at 70 °C under air proceeded to give 4a in 68% yield. It
implied that IrCl3Á3H2O catalyst has an insignificant effect on the
first Diels–Alder reaction step. Unfortunately, in the case of FeCl3
or Cu(OTf)2 as a catalyst, the lower reactivity was observed than
⇑
Corresponding author.
E-mail address: sonoda@chem.osakafu-u.ac.jp (M. Sonoda).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.068

H. Shinohara et al. / Tetrahedron Letters 52 (2011) 6238–6241
6239
Table 1
Ring-opening aromatization of 3aa
OH
CO2Me
CO2Me
CO2Me
CO2Me
cat. [M] (10 mol%)
toluene, 24 h
O
3a
4a
Entry
Catalyst
Temp (°C)
Yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
IrCl3Á3H2O
IrCl3Á3H2O
IrCl3Á3H2O
IrCl3Á3H2O
CoCl2Á6H2O
FeCl3Á6H2O
FeCl3
NiCl2
PdCl2
CuCl2
ZnI2
rt
Trace
10
68
65
N.D.
6
Quant.
N.D.
N.D.
N.D.
Trace
58
50
70
110
70
70
70
70
70
70
70
70
70
70
Cu(OTf)2
Zn(OTf)2
Pd(OAc)2
44
N.D.
a
Reaction conditions: 3a (0.5 mmol), catalyst (0.05 mmol), toluene (1 mL), under air.
b
Determined by 1H NMR.
Table 2
Synthesis of 3-hydroxyphthalate 4a in one-pot methoda
OH
CO2Me
IrCl3 3H2O
(10 mol%)
CO2Me
CO2Me
O
+
toluene, 70oC
CO2Me
1
CO2Me
O
2a
4a
CO2Me
3a
Entry
Solvent
Time (h)
Yield (%)b,c
3a
4a
1
2
3
4
5
6
toluene
CH3CN
THF
CHCl3
1,2-dichloroethane
toluene
24
24
24
24
24
48
30
16
17
48
94
15
68
7
14
36
2
83
a
b
c
Reaction conditions: 2a (0.6 mmol), 1 (0.5 mmol), IrCl3Á3H2O (0.05 mmol), under air.
Based on 1.
Determined by 1H NMR.
that in the case of IrCl3Á3H2O. Further optimization of the reaction
conditions was examined. The other solvents such as CH3CN, THF,
CHCl3, and 1,2-dichloroethane were unfavorable for this reaction
(entries 2, 3, and 4). The yield of 4a increased to 83% by extension
of the reaction time to 48 h (entry 5).
yields, respectively (entries 5, 6, and 7). In contrast, in the case of
2-arylfurans bearing a strong electron-withdrawing group such
as nitro, cyano, or trifluoromethyl group, a significant decrease in
the reactivity was observed (entries 8, 9, and 10). We attempted
to perform the reaction of pure 3h in the presence of IrCl3Á3H2O
in toluene, however, the desired ring-opening reaction did not
proceed at all. The reaction of 2-(4-fluorophenyl)furan (2k)
proceeded to give the corresponding product 4k in 97% yield (entry
11). The reaction of methyl 2-furoate (2l), bearing an unfavorable
substituent as a diene for Diels–Alder reaction, did not take place
(entry 12). Unfortunately, in the cases of furan (2m) and 2,3-
dimethylfuran (2n), Diels–Alder adducts 3m and 3n were ob-
tained, respectively (entries 13 and 14).
Then, we reviewed the experimental procedure and have found
another one-pot method using FeCl3 instead of IrCl3Á3H2O as a cat-
alyst. After the Diels–Alder reaction of 2h with 1 in the absence of
catalyst at 70 °C for 12 h under nitrogen atmosphere, a 10 mol % of
FeCl3 was added and stirred at 110 °C for 36 h to give the desired
product 4h in 62% yield (entry 2 in Table 4). Using this procedure,
The similar one-pot reactions of various furans (2a–n) with 1
were examined and the results are summarized in Table 3. The
reaction of furans bearing an electron-donating group, such as
methyl, n-pentyl, or methoxy group at 2-position, proceeded to
give the corresponding 3-hydroxyphthalates in good to excellent
yields, respectively (entries 1, 2, and 4). In the case of furfuryl alco-
hol (2c), the latter-half of the reaction did not take place and a
Diels–Alder adduct 3c was formed in 90% yield as a sole product
(entry 3).16 Interestingly, when pure 3c was used for the ring-
opening reaction in the presence of IrCl3Á3H2O in toluene, the reac-
tion proceeded to afford an intramolecular lactonization product
5c in 65% yield (Scheme 2).17 2-Phenylfuran (2e), 2-(4-methyl-
phenyl)furan (2f), and 2-(4-methoxyphenyl)furan (2g) were also
applicable for this one-pot reaction to give 4e, 4f, and 4g in good

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H. Shinohara et al. / Tetrahedron Letters 52 (2011) 6238–6241
Table 3
Synthesis of 3-hydroxyphthalates 4 in one-pot methoda
OH
CO2Me
IrCl3 3H2O
(10 mol%)
CO2Me
CO2Me
O
R1
CO2Me
CO2Me
O
+
toluene, 70 o
C
R2
R2
R2
48 h
CO2Me
R1
R1
4
2
1
3
Entry
Furans
R1
R2
Yield (%)b,c
3
4
1
2
3
4
5
6
7
8
9
10
11
12
13
14
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
Me
C5H11
CH2OH
OMe
Ph
4-Me-C6H4
4-MeO-C6H4
4-NO2-C6H4
4-CN-C6H4
4-CF3-C6H4
4-F-C6H4
CO2Me
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
15
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
83 (82)
98 (85)
0
2
90
8
10
7
92 (82)
90 (90)
93 (93)
90 (89)
Trace
25 (21)
62 (62)
97 (97)
0
9
95
74
35
2
0
92
98
H
Me
2
trace
a
b
c
Reaction conditions: 2 (0.6 mmol), 1 (0.5 mmol), IrCl3Á3H2O (0.05 mmol), under air.
Based on 1.
Determined by 1H NMR. Isolated yield in parentheses.
OH
IrCl3 3H2O
(10 mol%)
toluene, 70oC
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
O
O
65%
O
N
+
Boc
N
toluene, reflux
24 h
Boc
7 55%
CO2Me
OH
3c
6
1
5c
Boc
HN
Scheme 2. Ring-opening aromatization of 3c using IrCl3Á3H2O.
Pd(OAc)2 (10 mol%)
toluene, 70 o
48 h
CO2Me
C
CO2Me
Table 4
8 75%
a
Synthesis of 3-hydroxyphthalates 4 using FeCl3
Scheme 3. Synthesis of 3-aminophthalate derivative.
CO2Me
O
R1
+
Next we planned to apply the similar method to other five-
membered heteroaromatic compounds such as pyrroles and thio-
phenes. There are a few report on the ring-opening aromatization
reactions of 7-azabicyclo[2.2.1]hepta-2,5-dienes.8e,18 Very inter-
estingly, however, the desired ring-opening aromatization of a
N-Boc-7-azabicyclo[2.2.1]hepta-2,5-diene 7, which was synthe-
sized from the Diels–Alder reaction of N-Boc-pyrrole (6) with 1
in toluene at 110 °C in 55% yield, was transformed in the presence
of a 10 mol % of Pd(OAc)2 to give a 3-aminophthalate 8 in 75% yield
(Scheme 3). In this case, an attempt to perform the one-pot
reaction was not successful. The use of other catalysts such as MCln
listed in Table 1 resulted in no reaction. On the other hand,
thiophenes were found to be unfavorable substrates because of a
difficulty of initial Diels–Alder reaction.19
R2
CO2Me
2
1
OH
R1
FeCl3
(10 mol%)
CO2Me
CO2Me
toluene
70 oC, 12 h
toluene
R2
reflux, 36 h
4
Entry
Furans
R1
R2
Yield (%)b,c
1
2
3
4
2a
2h
2i
Me
4-NO2-C6H4
4-CN-C6H4
H
Me
Me
H
H
H
H
Me
Me
4a
4h
4i
4m
4n
4n
86 (80)
62 (60)
84 (80)
Trace
89 (83)
39 (32)
2m
2n
2n
5
6d
a
Reaction conditions: 2 (0.6 mmol), 1 (0.5 mmol), FeCl3 (0.05 mmol), under
nitrogen atmosphere.
In summary, we have developed an efficient method for the
synthesis of 3-hydroxyphthalates via Diels–Alder reaction of fur-
ans with 1 and the subsequent ring-opening aromatization reac-
tion catalyzed by IrCl3Á3H2O in one-pot method. Further studies
of these reactions are now in progress.
b
Based on 1.
Determined by 1H NMR. Isolated yield in parentheses.
Under air condition.
c
d
2a, 2i, and 2n also converted into the corresponding products 4a,
4i, and 4n in good yields, respectively (entries 1, 3 and 5), though
a formation of 4m from 2m did not take place (entry 4). The reac-
tion of 2n with 1 under air condition resulted in the formation of
4n in 39% yield (entry 6).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.09.068.

H. Shinohara et al. / Tetrahedron Letters 52 (2011) 6238–6241
6241
K.; Tam, W. J. Am. Chem. Soc. 2006, 128, 3514; (g) Sugahara, M.; Moritani, Y.;
Terakawa, Y.; Ogiku, T.; Ukita, T.; Iwasaki, T. Tetrahedron Lett. 1998, 39, 1377;
(h) Maggiani, A.; Tubul, A.; Brun, P. Tetrahedron Lett. 1998, 39, 4485; (i) Duval,
O.; Gomès, L. M. Tetrahedron Lett. 1988, 29, 3243.
Reference and notes
1. Dawson, T. L. Color. Technol. 2006, 122, 61.
2. Taylor, J. J. Am. Paint J. 1943, 27, 51.
3. (a) Katoh, N.; Nakahata, T.; Kuwahara, S. Tetrahedron 2008, 68, 9037; (b) Keay,
B. A.; Rodrigo, R. Tetrahedron 1984, 40, 4597.
4. Santhanam, B.; Boons, G. J. e-EROS Encylopedia of Reagents for Org. Synth. 2001.
doi:10.1002/047084289X.rn00356.
9. For the selected ring-opening reaction of 7-oxabicyclo[2.2.1]hepta-2,5-dienes
using nucleophiles, see: (a) Barluenga, J.; Martínez, S.; Suárez-Sobrino, A. L.;
Tomás, M. Org. Lett. 2008, 10, 677; (b) Chen, C.-L.; Martin, S. F. J. Org. Chem.
2006, 71, 4810; (c) Chen, C.-L.; Martin, S. F. Org. Lett. 2004, 6, 3581; (d) Bailey, J.
H.; Coulter, C. V.; Pratt, A. J.; Robinson, W. T. J. Chem. Soc., Perkin Trans. 1 1995,
589.
10. (a) Dhananjeyan, M. R.; Milev, Y. P.; Kron, M. A.; Nair, M. G. J. Med. Chem. 2005,
48, 2822; (b) Fersht, A. R.; Kirby, A. J. J. Am. Chem. Soc. 1968, 90, 5833.
11. Maggiani, A.; Tubul, A.; Brun, P. Synthesis 1997, 631.
12. Moreno, A.; Gómez, M. V.; Vázquez, E.; De La Hoz, A.; Díaz-Ortiz, A.; Prieto, P.;
Mayoral, J. A.; Pires, E. Synlett 2004, 1259.
13. Ram, R. N.; Kumar, N. Tetrahedron Lett. 2008, 49, 799.
14. Medimagh, Raouf.; Marque, S.; Prim, D.; Chatti, S. Heterocycles 2009, 78, 679.
15. Constantino, M. G.; Aragão, V.; Silva, G. V. J. D. Tetrahedron Lett. 2008, 49,
1393.
16. When the reaction of pure 3c under the same condition as Scheme 2 in the
presence of 0.1 equiv of 1 or 2c was examined, the product 5c did not obtained
at all. From these results, a coordination of 1 or 2c to iridium might inhibit the
formation of 5c from 3c.
5. For the recent report on Diels–Alder reaction, see: (a) Sajna, K. V.; Kotikalapudi,
R.; Chakravarty, M.; Bhuvan, K. N. N.; Swamy, K. C. K. J. Org. Chem. 2011, 76,
920; (b) Lozama, A.; Cunningham, C. W.; Caspers, M. J.; Douglas, J. T.; Dersch, C.
M.; Rothman, R. B.; Prisinzano, T. E. J. Nat. Prod. 2011, 74, 718; (c) Yang, C.-M.;
Jeganmohan, M.; Parthasarathy, K.; Cheng, C.-H. Org. Lett. 2010, 12, 3610; (d)
Shook, B. C.; Rassnick, S.; Hall, D.; Rupert, K. C.; Heintzelman, G. R.; Hansen, K.;
Chakravarty, D.; Bullington, J. L.; Scannevin, R. H.; Magliaro, B. Bioorg. Med.
Chem. Lett. 2010, 20, 2864; (e) Yan, X.; Zhou, Y.; Xi, C. Chem. Commun. 2010, 46,
7801; (f) Kotha, S.; Khedkar, P. J. Org. Chem. 2009, 74, 5667.
6. For the recent report on [2+2+2] cycloaddition, see: (a) Zhou, P.; Huang, L.;
Jiang, H.; Wang, A.; Li, X. J. Org. Chem. 2010, 75, 8279; (b) Mitamura, T.; Ogawa,
A. Tetrahedron Lett. 2010, 51, 3538; (c) Shen, Y.; Jiang, H.; Chen, Z. J. Org. Chem.
2010, 75, 1321; (d) Kuninobu, Y.; Nishi, M.; Kawata, A.; Tanaka, H.; Hanatani,
Y.; Salprima, Y. S.; Iwai, A.; Takai, K. J. Org. Chem. 2010, 75, 334; (e) Kotha, S.;
Khedkar, P. Eur. J. Org. Chem. 2009, 5, 730.
17. A similar reaction by using BF3 or H2SO4 was reported, see: McCulloch, A. W.;
Stanovnik, B.; Smith, D. G.; McInnes, A. G. Can. J. Chem. 1969, 47, 4319.
18. For the ring-opening reaction of 7-azabicyclo[2.2.1]hepta-2,5-dienes, see: (a)
Ikawa, T.; Takagi, A.; Kurita, Y.; Saito, K.; Azechi, K.; Egi, M.; Akai, S.; Kakiguchi,
K.; Kita, Y. Angew. Chem., Int. Ed. 2010, 49, 5563; (b) Altundasß, A.; Tepe, E.;
Akbulut, N.; Kara, Y. Russ. J. Org. Chem. 2009, 45, 613; (c) Tenaglia, A.; Marc, S. J.
Org. Chem. 2008, 73, 1397; (d) Cho, Y.-H.; Zunic, V.; Senboku, H.; Olsen, M.;
Lautens, M. J. Am. Chem. Soc. 2006, 128, 6837; (e) Jeevanandam, A.; Srinivasan,
P. C. J. Chem. Soc., Perkin Trans. 1 1995, 2663; (f) Vernon, J. M.; Ahmed, M.;
Kricka, L. J. J. Chem. Soc., Perkin Trans. 1 1978, 837.
19. Diels–Alder reactions of thiophenes are limited to the use of ion liquid as a
solvent or intermolecular reaction, see: (a) Hemeron, I.; DeAmicis, C.; Jenkins,
H.; Scammells, P.; Singer, R. D. Synlett 2002, 1815; (b) Ciganek, E. In Organic
Reactions; Dauben, W. G., Ed.; Wiley: New York, 1984; Vol. 32, pp 306–307
(Chapter 1).
7. For the selected ring-opening reaction of 7-oxabicyclo[2.2.1]hepta-2,5-dienes
using Brønstead acid, see: (a) Gordon, C. P.; Byrne, N.; McCluskey, A. Green
Chem. 2010, 12, 1000; (b) Lang, S.; Groth, U. Angew. Chem., Int. Ed. 2009, 48, 911;
(c) James, C. A.; Sniekus, V. J. Org. Chem. 2009, 74, 4080; (d) Morton, G. E.;
Barret, A. G. M. J. Org. Chem. 2005, 70, 3525; (e) Biland-Thommen, A. S.; Raju, G.
S.; Blagg, J.; White, A. J. P.; Barret, A. G. M. Tetrahedron Lett. 2004, 45, 3181; (f)
Maggiani, A.; Tubul, A.; Brun, P. Chem. Commun. 1999, 24, 2495; (g) Vogel, P.;
Willhalm, B.; Prinzbach, H. Helv. Chim. Acta 1969, 52, 584.
8. For the selected ring-opening reaction of 7-oxabicyclo[2.2.1]hepta-2,5-dienes
using Lewis acid, see: (a) Tang, X.; Rawson, D.; Woodward, S. Synlett 2010, 636;
(b) Sawama, Y.; Kawamoto, K.; Satake, H.; Kita, Y.; Krause, N. Synlett 2010,
2151; (c) Ballantine, M.; Menard, M.; Tam, W. J. Org. Chem. 2009, 74, 7570; (d)
Repine, J. T.; Johnson, D. S.; White, A. D.; Favor, D. A.; Stier, M. A.; Yip, J.; Rankin,
T.; Ding, Q.; Maiti, S. N. Tetrahedron Lett. 2007, 48, 5539; (e) Allen, A.; Le, M. P.;
Burton, R.; Villeneuve, K.; Tam, W. J. Org. Chem. 2007, 72, 7849; (f) Villeneuve,