Synthesis of 3,5-diaryl-4-chlorophthalates by [4+2] cycloaddition of 1-ethoxy-2-chloro-1,3-bis(trimethylsilyloxy)-1,3-diene with dimethyl acetylenedicarboxylate and subsequent site-selective Suzuki-Miyaura reactions

Article abstract of DOI:10.1016/j.tetlet.2009.11.088

The [4+2] cycloaddition of 1-ethoxy-2-chloro-1,3-bis(trimethylsilyloxy)-1,3-diene with dimethyl acetylenedicarboxylate (DMAD) afforded dimethyl 4-chloro-3,5-dihydroxyphthalate. Site-selective Suzuki-Miyaura reactions of its bis(triflate) provide a convenient approach to 3,5-diaryl-4-chlorophthalates containing two different aryl groups.

Full text of DOI:10.1016/j.tetlet.2009.11.088

Tetrahedron Letters 51 (2010) 657–660
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 3,5-diaryl-4-chlorophthalates by [4+2] cycloaddition of 1-ethoxy-2-
chloro-1,3-bis(trimethylsilyloxy)-1,3-diene with dimethyl acetylene
dicarboxylate and subsequent site-selective Suzuki–Miyaura reactions
Obaid-Ur-Rahman Abid a, Muhammad Farooq Ibad a, Muhammad Nawaz a, Muhammad Adeel a,b
,
Nasim Hasan Rama c, Alexander Villinger a, Peter Langer a,d,
*
a Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b Department of Chemistry, Gomal University, Dera Ismail Khan, N.W.F.P, Pakistan
c Department of Chemistry, Quaid-i-Azam University, Islamabad, Pakistan
d Leibniz-Institut für Katalyse e. V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The [4+2] cycloaddition of 1-ethoxy-2-chloro-1,3-bis(trimethylsilyloxy)-1,3-diene with dimethyl
acetylenedicarboxylate (DMAD) afforded dimethyl 4-chloro-3,5-dihydroxyphthalate. Site-selective
Suzuki–Miyaura reactions of its bis(triflate) provide a convenient approach to 3,5-diaryl-4-chlorophtha-
lates containing two different aryl groups.
Received 13 October 2009
Revised 19 November 2009
Accepted 20 November 2009
Available online 26 November 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Cyclocondensations
Organochlorine compounds
Suzuki–Miyaura reactions
Silyl enol ethers
Aryl chlorides are of pharmacological importance and have been
isolated as natural products.1 In fact, arenes and hetarenes contain-
ing a chloride group often show a better pharmacological activity
compared to their non-halogenated analogues.2 In addition, the
chloro group can be reacted in palladium(0)-catalyzed cross cou-
pling reactions.3 However, the synthesis of chlorinated arenes is
not straightforward. The direct chlorination of arenes often suffers
from several side-reactions, such as low regioselectivity and multi-
ple chlorination. An alternative strategy for the regioselective syn-
thesis of organochlorine compounds relies on the use of
appropriate chlorine-containing building blocks in condensation
and cyclization reactions. For example, Manzanares and co-workers
reported the synthesis of a 4-chlorophenol by [4+2] cycloaddition of
a chlorinated thiophene with dimethyl acetylenedicarboxylate.4
1,3-Bis(trimethylsilyloxy)-1,3-butadienes (e.g., Chan’s diene)5,6
represent useful synthetic building blocks.7 Recently, we reported
the application of these dienes to the synthesis of chlorinated are-
nes and hetarenes.8
boxylate (DMAD). Suzuki–Miyaura reactions of the bis(triflate) of
this product proceed with very good site-selectivity9 and provide
a
convenient approach to novel 3,5-diaryl-4-chlorophthalates
which are not readily available by other methods.
The [4+2] cycloaddition of 1-ethoxy-2-chloro-1,3-bis(trimeth-
ylsilyloxy)-1,3-diene (1), readily available from ethyl 2-chloroace-
toacetate in two steps, with DMAD afforded dimethyl 4-chloro-3,5-
Me3SiO OSiMe3
OH
OEt
Cl
CO2Me
CO2Me
Cl
1
i
+
HO
MeO2C
CO2Me
2 (50%)
DMAD
ii
OTf
Cl
CO2Me
CO2Me
Herein, we report the facile synthesis of dimethyl 4-chloro-3,5-
dihydroxyphthalate by [4+2] cycloaddition of 1-ethoxy-2-chloro-
1,3-bis(trimethylsilyloxy)-1,3-diene with dimethyl acetylenedicar-
TfO
3 (87%)
Scheme 1. Synthesis of 2 and 3. Reagents and conditions: (i) (1) 1 (1.0 equiv),
DMAD (1.5 equiv), À78?20 °C, 20 h; (2) HCl (10%); (ii) (1) and 2 (1.0 equiv),
pyridine (4.0 equiv), CH2Cl2, À78 °C, 10 min; (2) Tf2O (2.4 equiv), À78?0 °C, 4 h.
* Corresponding author. Tel.: +49 381 4986410; fax: +49 381 4986412.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.088

658
Obaid-Ur-Rahman Abid et al. / Tetrahedron Letters 51 (2010) 657–660
dihydroxyphthalate (2) in 50% yield (Scheme 1).10 The latter was
transformed into bis(triflate) 3 in high yield.11
The Suzuki reaction of 3 with boronic acids 4a–f (2.4 equiv)
afforded the novel 3,5-diaryl-4-chlorophthalates 5a–f in good
yields (Scheme 2, Table 1). The best yields were obtained when
using the arylboronic acid (2.4 equiv), Pd(PPh3)4 (0.03 equiv) cata-
lyst and K3PO4 (3.0 equiv) base in 1,4-dioxane (110 °C, 6 h).12,13
1) Ar1B(OH)2
Ar2
4e
OTf
2) Ar2B(OH)2
4a,k
Cl
CO2Me
CO2Me
Cl
CO2Me
CO2Me
TfO
i
Ar1
7a,b
3
Scheme 4. One-pot synthesis of 7a,b. Reagents and conditions: (1) 3 (1.0 equiv), 4e
(1.1 equiv), K3PO4 (1.5 equiv), Pd(PPh3)4 (3 mol %), 1,4-dioxane, 90 °C, 8 h; (2) 4a,k
(1.3 equiv), K3PO4 (1. 5 equiv), 110 °C, 6 h.
The S–M coupling of
3 with arylboronic acids 4a,b,g–j
(1.1 equiv) afforded the 5-aryl-4-chloro-3-(trifluoromethylsulfo-
nyloxy)phthalates 6a–f in good yields and with very good site-
selectivity (Scheme 3, Table 2).12,14 The formation of the opposite
regioisomers was not observed. The site-selectivity can be ex-
plained by steric reasons. 3,5-Diaryl-4-chlorophthalates 7a,b, con-
taining two different aryl groups Ar1 and Ar2, were prepared
directly from bis(triflate) 3 by the application of a one-pot proce-
dure (Scheme 4, Table 3). The Suzuki reaction of 3 with arylboronic
acid 4e (1.1 equiv, 90 °C) and subsequent addition of arylboronic
acids 4a,k (1.3 equiv, 110 °C) to the in situ formed mono-coupling
product afforded products 7a,b in acceptable yields.15,16
The structures of products 5–7 were established by 2D NMR
experiments (NOESY, and HMBC). The structures of 5a and 7a were
independently confirmed by X-ray crystal structure analyses (Figs.
1 and 2).17
Table 3
Synthesis of 7a,b
4
7
Ar1
Ar2
7a (%)
e, a
e, k
a
b
4-EtC6H4
4-EtC6H4
4-(CF3)C6H4
3-FC6H4
57
53
a
Yields of isolated products.
Ar
OTf
ArB(OH)2
Cl
CO2Me
CO2Me
Cl
Ar
CO2Me
CO2Me
4a-f
TfO
i
3
5a-f
Scheme 2. Synthesis of 5a–f. Reagents and conditions: (i) 3 (1.0 equiv), 4a–f
(2.4 equiv), K3PO4 (3.0 equiv), Pd(PPh3)4 (3 mol %), 1,4-dioxane, 110 °C, 6 h.
Table 1
Synthesis of 5a–f
4,5
Ar
5a (%)
a
b
c
d
e
f
4-(CF3)C6H4
C6H5
4-ClC6H4
3-(CF3)C6H4
4-EtC6H4
4-MeC6H4
77
75
63
49
67
72
Figure 1. Crystal structure of 5a.
a
Yields of isolated products.
OTf
OTf
ArB(OH)2
CO2Me
CO2Me
Cl
Ar
Cl
CO2Me
CO2Me
4a,b,g-j
i
TfO
3
6a-f
Scheme 3. Synthesis of 6a–f. Reagents and conditions: (i) 3 (1.0 equiv), 4a,b,g–j
(1.1 equiv), K3PO4 (1.5 equiv), Pd(PPh3)4 (3 mol %), 1,4-dioxane, 90 °C, 8 h.
Table 2
Synthesis of 6a–f
4
6
Ar
6a (%)
g
b
h
a
i
a
b
c
d
e
f
2-(MeO)C6H4
C6H5
3,4-(MeO)2C6H3
4-(CF3)C6H4
3,5-(Me)2C6H3
2,6-(MeO)2C6H3
47
65
47
63
61
48
j
a
Yields of isolated products.
Figure 2. Crystal structure of 7a.

Obaid-Ur-Rahman Abid et al. / Tetrahedron Letters 51 (2010) 657–660
659
3 was isolated as viscous colourless oil (3.65 g, 87%). 1H NMR (300 MHz,
CDCl3): d = 3.86 (s, 3 H, OCH3), 3.88 (s, 3H, OCH3), 7.92 (s, 1H, ArH). 13C NMR
In conclusion, we reported a convenient approach to dimethyl
4-chloro-3,5-dihydroxyphthalate by [4+2] cycloaddition of 1-eth-
oxy-2-chloro-1,3-bis(trimethyl-silyloxy)-1,3-diene with dimethyl
acetylenedicarboxylate (DMAD). The Suzuki–Miyaura coupling of
the bis(triflate) of the product proceeds with very good site-selec-
tivity and provides a convenient approach to 3,5-diaryl-4-chlor-
ophthalates containing two different aryl groups. The preparative
scope of the methodology is currently being studied.
1
(62.90 MHz, CDCl3): d = 52.6 (OCH3), 52.7 (OCH3), 117.5 (q, JCF = 321 Hz, CF3),
1
117.6 (q, JCF = 321 Hz, CF3), 123.0 (CH), 126.5, 128.7, 130.0, 142.4. 145.8 (C),
167.7 (2C, C@O). 19F NMR (282.4 MHz. CDCl3): d = À71.99 (CF3), À73.20 (CF3).
IR (ATR, cmÀ1): v = 3103 (w), 2960 (w), 2850 (w), 2054 (w), 1980 (w), 1739 (s),
1599 (w), 1567 (w), 1429 (s), 1395 (m), 1305 (m), 1277 (m), 1206 (s), 1129 (s),
1113 (s), 1005 (s), 961 (s), 919 (w), 859 (w), 820 (m), 787 (s), 751 (s), 732 (s),
698 (m), 651 (m), 593 (s), 574 (m). MS (EI, 70 eV): m/z (%): 524 (M+, 30), 493
(100), 460 (13), 429 (39), 391 (4), 365 (36), 299 (42), 271 (6), 238 (11), 199
(12), 171 (9), 143 (3), 84 (8), 69 (38), 59 (13). HRMS (EI) calcd for
C12H7O10ClF6S2 [M+]: 523.90679, found 523.907255.
Acknowledgements
12. General procedure for Suzuki–Miyaura reactions: A 1,4-dioxane solution (4 mL
per 0.3 mmol of 3) of 3, K3PO4, Pd(PPh3)4 and arylboronic acid 4 was stirred at
110 °C or 90 °C for 6 or 8 h. After cooling to 20 °C, a saturated aqueous solution
of NH4Cl was added. The organic and the aqueous layers were separated and
the latter was extracted with CH2Cl2. The combined organic layers were dried
(Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was
purified by column chromatography.
Financial support by the State of Pakistan (HEC scholarships for
O.-U.-R. A., M.F.I.), by the DAAD (scholarship for O.-U.-R. A. and
M.N.) and by the State of Mecklenburg-Vorpommern is gratefully
acknowledged.
13. Dimethyl 4-chloro-3,5-di(4-tolyl)phthalate (5f): Starting with
3
(157 mg,
4-
0.3 mmol), K3PO4 (191 mg, 0.9 mmol), Pd(PPh3)4 (3 mol %),
methylphenylboronic acid (98 mg, 0.72 mmol) and 1,4-dioxane (4 mL), 5f
was isolated as a colourless solid (88 mg, 72%); mp = 139–141 °C. 1H NMR
(300 MHz, CDCl3): d = 2.33 (s, 3H, CH3), 2.35 (s, 3H, CH3), 3.51 (s, 3H, OCH3),
3.82 (s, 3H, OCH3), 7.10–7.18 (m, 4H, ArH), 7.21–7.29 (m, 4H, ArH), 7.91 (s, 1H,
ArH). 13C NMR (62.89 MHz, CDCl3): d = 21.3 (ArCH3), 21.4 (ArCH3), 52.3 (OCH3),
52.6 (OCH3), 125.3 (C), 128.7 (2CH), 128.9 (2CH), 129.2 (2CH), 129.4 (2CH),
131.7 (CH), 133.4, 135.7, 136.1, 137.4, 138.0, 138.1, 140.0, 142.2 (C), 165.3
(CO), 168.0 (CO). IR (ATR, cmÀ1): v = 3026 (w), 2949 (w), 2922 (w), 2859 (w),
2253 (w), 1906 (w), 1727 (s), 1613 (w), 1584 (w), 1552 (w), 1514 (m), 1434
(m), 1373 (w), 1340 (m), 1259 (s), 1237 (s), 1213 (m), 1145 (m), 1104 (m), 1069
(m), 1021 (m), 969 (m), 909 (m), 890 (m), 814 (m), 783 (m), 730 (m), 720 (m),
634 (m), 554 (m). MS (EI, 70 eV): m/z (%): 411 (M+1, 37Cl, 9), 410 (M+, 37Cl, 36),
409 (M+1, 35Cl, 26), 408 (M+, 35Cl, 97), 380 (8), 379 (35), 378 (25), 377 (100),
347 (8), 345 (23), 318 (3), 290 (4), 289 (5), 255 (8), 239 (15), 226 (4), 204 (7),
178 (3), 126(9), 91 (2), 59 (1). HRMS (EI) calcd for C24H21O4Cl [M+]: 408.11229,
found 408.112793.
References and notes
1. For pharmacologically active chlorinated natural products and drugs, see: (a)
Gribble, G. W. Environ. Sci. Technol. 1994, 28, 310A; (b) Gribble, G. W. J. Chem.
Ed. 1994, 71, 907; (c) Gribble, G. W. Acc. Chem. Res. 1998, 31, 141; (d) Gribble, G.
W. Acc. Chem. 1996, 68, 1699; (e) Gribble, G. W. J. Nat. Prod. 1992, 55, 1353;
Griseofulvin (f) Osborne, C. S.; Leitner, I.; Hofbauer, B.; Fielding, C. A.; Favre, B.;
Ryder, N. S. Antimicrob. Agents Chemother. 2006, 50, 2234; (g) Takano, R.;
Sugano, K.; Higashida, A.; Hayashi, Y.; Machida, M.; Aso, Y.; Yamashita, S.
Pharm. Res. 2006, 23, 1144; (h) Xue, C.; Li, T.; Deng, Z.; Fu, H.; Lin, W. Pharmazie
2006, 61, 1041; (i) Phelps, J. B.; Hoffman, W. P.; Lee, C.; Murphy, G. P.; Garriott,
M. L. Mutat. Res. 2004, 561, 153; (j) Rosefort, C.; Fauth, E.; Zankl, H. Mutagenesis
2004, 19, 277; (k) Kinobe, R. T.; Dercho, R. A.; Vlahakis, J. Z.; Brien, J. F.; Szarek,
W. A.; Nakatsu, K. J. Pharmacol. Exp. Ther. 2006, 319, 277; (l) Albaugh, D.; Albert,
G.; Bradford, P.; Cotter, V.; Froyd, J. J. Antibiot. 1998, 51, 317; Dihydronidulin
(m) Finlay-Jones, P. F.; Sala, T.; Sargent, M. V. J. Chem. Soc., Perkin Trans. 1 1981,
874.
14. Dimethyl 4-chloro-3-(2-methoxyphenyl)-5-(trifluoromethylsulfonyl-oxy)phthalate
(6a): Starting with
Pd(PPh3)4 (3 mol %), 2-methoxyphenylboronic acid (50 mg, 0.33 mmol) and
1,4-dioxane (4 mL), 6a was isolated as colourless solid (68 mg, 47%),
3 (157 mg, 0.3 mmol), K3PO4 (95.4 mg, 0.45 mmol),
2. For an example from our laboratory, see: (a) Albrecht, U.; Lalk, M.; Langer, P.
Bioorg. Med. Chem. 2005, 13, 1531; (b) Nguyen, V. D.; Wolf, C.; Mäder, U.; Lalk,
M.; Langer, P.; Lindequist, U.; Hecker, M.; Antelmann, H. Proteomics 2007, 7,
1391.
3. Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A., Diederich, F., Eds.;
Springer: Weinheim, 2004.
a
mp = 103–105 °C. 1H NMR (300 MHz, CDCl3): d = 3.70 (s, 3H, OCH3), 3.82 (s,
3H, OCH3), 3.91 (s, 3H, OCH3), 6.92 (d, J = 8.4 Hz, 1H, ArH), 6.98 (dt, J = 7.4,
1.0 Hz, 1H, ArH), 7.11 (dd, J = 7.5, 1.7 Hz, 1H, ArH), 7.37 (dt, J = 7.8, 1.7 Hz, 1H,
ArH), 7.86 (s, 1H, ArH). 13C NMR (75.46 MHz, CDCl3): d = 52.0 (OCH3), 52.3
(OCH3), 54.9 (OCH3), 110.0 (CH), 117.5 (q, J = 321 Hz, CF3), 119.5 (CH), 124.7,
127.0, 128.5, (C), 129.3, 129.8, 131.2 (CH), 131.9, 141.2, 141.3, 155.4 (C), 163.1
(CO), 163.4 (CO). 19F NMR (282.4 MHz, CDCl3): d = À71.99 (CF3). IR (ATR, cmÀ1):
v = 2955 (w), 2923 (w), 2849 (W), 1738 (s), 1730 (m), 1607 (w), 1582 (w), 1501
(w), 1468 (w), 1429 (w), 1325 (w), 1270 (s), 1242 (m), 1210 (m), 1164 (w),
1135 (m), 1112 (w), 1009 (w), 926 (w), 806 (m), 755 (m), 672 (w), 639 (w), 598
(m), 572 (w), 547 (w), 573 (w). MS (EI, 70 eV): m/z (%): 484 (M+, 37Cl, 40), 482
(M+, 35Cl, 100), 451 (25), 415 (2), 387 (4), 317 (27), 289 (20), 250 (16), 229 (5),
195 (6), 168 (6), 139 (6), 69 (9), 59 (5). HRMS (EI) calcd for C18H14O8ClF3S [M+]:
482.00445, found 482.005219.
4. Corral, C.; Lissavetzky, J.; Manzanares, I. Synthesis 1997, 29.
5. For a review of 1,3-bis(silyl enol ethers), see: Langer, P. Synthesis 2002, 441.
6. (a) Chan, T.-H.; Brownbridge, P. J. Chem. Soc., Chem. Commun. 1979, 578; (b)
Krägeloh, K.; Simchen, G. Synthesis 1981, 30.
7. For a review of [3+3] cyclizations, see: Feist, H.; Langer, P. Synthesis 2007, 327.
8. For the synthesis and reactions of a 4-chloro-1,3-bis(trimethylsilyloxy)-1,3-
butadiene, see: (a) Reim, S.; Langer, P. Tetrahedron Lett. 2008, 49, 2329; For an
isolated example of a 2-chloro-1,3-bis(trimethylsilyloxy)-1,3-butadiene, see:
(b) Savard, J.; Brassard, P. Tetrahedron Lett. 1979, 20, 4911; For [3+3]
cyclizations of 1,3-bis(silyloxy)-1,3-dienes with 2-chloro-3-silyloxy-2-en-1-
ones, see: (c) Yawer, M. A.; Hussain, I.; Reim, S.; Ahmed, Z.; Ullah, E.; Iqbal, I.;
Fischer, C.; Reinke, H.; Görls, H.; Langer, P. Tetrahedron 2007, 63, 12562; For
synthetic applications of 2-chloro-1,3-bis(silyloxy)-1,3-butadienes, see: (d)
Reim, S.; Adeel, M.; Hussain, I.; Yawer, M. A.; Villinger, A.; Langer, P.
Tetrahedron Lett. 2008, 49, 4901.
15. General procedure for the synthesis of 7a,b: The reaction was carried out in a
pressure tube. To a dioxane suspension (4 mL) of 3 (236 mg, 0.45 mmol),
Pd(PPh3)4 (3 mol %) and Ar1B(OH)2 (0.5 mmol) was added K3PO4 (143 mg,
0.67 mmol), and the resultant solution was degassed by bubbling argon
through the solution for 10 min. The mixture was heated at 90 °C under Argon
atmosphere for 8 h. The mixture was cooled to 20 °C. Ar2B(OH)2 (0.6 mmol)
and K3PO4 (143 mg, 0.67 mmol) were added. The reaction mixtures were
heated under an Argon atmosphere for 6 h at 110 °C. They were diluted with
water and extracted with CH2Cl2 (3 Â 25 mL). The combined organic layers
were dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The
residue was purified by flash chromatography (silica gel, EtOAc/heptanes).
16. Dimethyl 4-chloro-3-(4-ethylphenyl)-5-(4-trifluoromethylphenyl)-phthalate (7a):
Starting with 3 (236 mg, 0.45 mmol), K3PO4 (143 mg, 0.67 mmol), Pd(PPh3)4
(3 mol %), 4-ethylphenylboronic acid (75 mg, 0.5 mmol), 1,4-dioxane (4 mL)
and 4-trifluoromethylphenylboronic acid (114 mg, 0.6 mmol), 7a was isolated
as colourless crystals (122 mg, 57%), mp = 138–140 °C. 1H NMR (300 MHz,
CDCl3): d = 1.22 (d, J = 7.8 Hz, 3H, CH3), 2.65 (q, J = 7.5 Hz, 2H, CH2), 3.48 (s, 3H,
OCH3), 3.82 (s, 3H, OCH3), 7.21–7.32 (m, 4H, ArH), 7.35–7.38 (m, 2H, ArH),
7.60–7.63 (m, 2H, ArH), 7.97 (s, 1H, ArH). 13C NMR (62.89 MHz, CDCl3): d = 15.3
(CH3), 28.6 (CH2), 52.4 (OCH3), 52.7 (OCH3), 124.0 (q, J = 272 Hz, CF3), 125.0 (q,
3JCF = 3.7 Hz, 2CH), 125.7 (C), 127.8 (2CH), 129.2 (2CH), 130.2 (2CH), 130.6 (d,
2JCF = 32.5 Hz, C), 132.4 (CH), 135.4, 135.8, 136.8, 138.5 (C), 140.0 (d, J = 1.4 Hz,
C), 142.5, 144.6 (C), 165.1, 167.6 (CO). 19F NMR (282.4 MHz, CDCl3): d = À62.7
(CF3). IR (ATR, cmÀ1): v = 3026 (w), 2949 (w), 2922 (w), 2859 (w), 2253 (w),
1906 (w), 1727 (s), 1613 (w), 1584 (w), 1552 (w), 1514 (m), 1434 (m), 1373
(w), 1340 (m), 1259 (s), 1237 (s), 1213 (m), 1145 (m), 1104 (m), 1069 (m), 1021
(m), 969 (m), 909 (m), 890 (m), 814 (m), 783 (m), 730 (m), 720 (m), 634 (m),
554 (m). MS (EI, 70 eV): m/z (%): 479 (M+1, 37Cl, 9), 478 (M+, 37Cl, 36), 477
(M+1, 35Cl, 29), 476 (M+, 35Cl, 99), 461 (30), 447 (41), 445 (100), 415 (5), 387
(4), 343 (5), 309 (7), 239 (6), 215 (8), 199 (4), 163 (1), 151 (3), 119 (4), 59 (2), 29
(1). HRMS (ESI) calcd for C25H20O4ClF3 [M]+: 476.1002, calcd for [M+H]+:
9. For a review of site-selective palladium(0)-catalyzed cross-coupling reactions
of polyhalogenated substrates, see: Schröter, S.; Stock, C.; Bach, T. Tetrahedron
2005, 61, 2245.
10. Dimethyl 4-chloro-3,5-dihydroxyphthalate (2): Diene 1 (463 mg, 1.5 mmol) was
added to DMAD (319 mg, 0.27 mL, 2.25 mmol) at À78 °C. The mixture (neat)
was allowed to warm to 20 °C for 20 h with stirring. To the mixture was added
hydrochloric acid (10%) and dichloromethane (30 mL each). The organic and
the aqueous layers were separated and the latter was extracted with CH2Cl2.
The combined organic layers were dried (Na2SO4), filtered and the filtrate was
concentrated in vacuo. The residue was purified by column chromatography to
give 2 as a crystalline colourless solid (195 mg, 50%), mp = 127–129 °C. 1H NMR
(250 MHz, CDCl3): d = 3.82 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 6.57 (s, 1H, OH),
6.57 (s, 1H, ArH), 11.55 (s, 1H, OH). 13C NMR (62.90 MHz, CDCl3): d = 52.8
(OCH3), 53.0 (OCH3), 103.5 (C), 107.5 (CH), 109.3, 135.0 (C), 156.6, 158.7 (C–
OH), 168.6, 169.0 (C@O). IR (ATR, cmÀ1): v = 2984 (w), 2954 (w), 2905 (w),
2847 (w), 1792 (w), 1722 (s), 1668 (m), 1435 (m), 1328 (m), 1243 (s), 1067 (s),
844 (m). MS (EI, 70 eV): m/z (%): 262 (M+, 37Cl, 9), 260 (M+, 35Cl, 15), 228 (53),
198 (23), 170 (100), 153 (23), 89 (25). Anal. Calcd for C10H9ClO6: C 46.08, H
3.48. Found: C 46.21, H 3.31.
11. Dimethyl 4-chloro-3,5-bis(trifluoromethylsufonyloxy)phthalate (3): To a solution
of 2 (1.0 equiv) in CH2Cl2 (10 mL/mmol) was added pyridine (4.0 equiv) at
À78 °C under an argon atmosphere. After 10 min, Tf2O (2.4 equiv) was added at
À78 °C. The mixture was allowed to warm up to 0 °C and stirred for 4 h. The
reaction mixture was filtered and the filtrate was concentrated in vacuo. The
products of the reaction mixture were isolated by rapid column
chromatography (flash silica gel, heptanes/EtOAc). Starting with 2 (2.080 g,
8.0 mmol), pyridine (2.6 mL, 32.0 mmol), CH2Cl2 and Tf2O (3.2 mL, 19.2 mmol),

660
Obaid-Ur-Rahman Abid et al. / Tetrahedron Letters 51 (2010) 657–660
477.1075 found 477.10693, and calcd for C25H20ClF3NaO4 [M+Na] +: 499.08944
found 499.08927.
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
17. CCDC 754590 and CCDC 754591 contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The