Synthesis of 3,5-Diaryl-4-fluorophthalates by [4+2]-cycloaddition and subsequent site-selective suzuki-miyaura reactions

Article abstract of DOI:10.1055/s-0029-1218556

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

Full text of DOI:10.1055/s-0029-1218556

LETTER
195
Synthesis of 3,5-Diaryl-4-fluorophthalates by [4+2]-Cycloaddition and
Subsequent Site-Selective Suzuki–Miyaura Reactions
S
ynthesis of 3,5-Diary
u
h
halates ammad Farooq Ibad,a Obaid-Ur-Rahman Abid,a Muhammad Nawaz,a Muhammad Adeel,a,b
Alexander Villinger,a Peter Langer*a,c
a
Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
Department of Chemistry, Gomal University, Dera Ismail Khan, N.W.F.P, Pakistan
Leibniz Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
b
c
Fax +49(381)4986412; E-mail: peter.langer@uni-rostock.de
Received 7 October 2009
Miyaura reactions of the bis(triflate) of this product pro-
ceeded with very good site-selectivity10 and provided a
convenient approach to novel 3,5-diaryl-4-fluorophtha-
lates which are not readily available by other methods.
Abstract: The [4+2] cycloaddition of 1-ethoxy-2-fluoro-1,3-
bis(trimethylsilyloxy)-1,3-diene with dimethyl acetylenedicarbox-
ylate (DMAD) afforded dimethyl 4-fluoro-3,5-dihydroxyphthalate.
Site-selective Suzuki–Miyaura reactions of its bis(triflate) provide
a convenient approach to 3,5-diaryl-4-fluorophthalates.
The [4+2] cycloaddition of 1-ethoxy-2-fluoro-1,3-bis(tri-
methylsilyloxy)-1,3-diene (1) with DMAD afforded di-
methyl 4-fluoro-3,5-dihydroxyphthalate (2) in 40% yield
(Scheme 1).11 The latter was transformed into bis(triflate)
3 in high yield.12 The structure of 2 was independently
confirmed by X-ray crystal structure analysis (Figure 1).13
Key words: arenes, cyclizations, organofluorine compounds, site-
selectivity, Suzuki–Miyaura reaction
In the last decade, we have witnessed a dramatic increase
of the interest in organofluorine compounds because of
their great pharmacological relevance.1 While the size of
the fluorine atom is relatively small, its high electronega-
tivity often results in an improvement of drug-receptor in-
teractions. Due to the chemical and biological stability of
the carbon–fluorine bond, undesired metabolic transfor-
mations are rather rare and the transport of the drug in
vivo is facilitated by the high lipophilicity of organofluo-
rine compounds. Fluorinated arenes and heteroarenes are
also versatile building blocks in transition-metal-cata-
lyzed cross-coupling reactions.2 In addition, organofluo-
rine compounds, such as fluorinated thioureas, are used as
organocatalysts3 and ligands.4
Me3SiO
OSiMe3
OEt
HO
F
CO2Me
CO2Me
F
i
1
+
OH
MeO2C
CO2Me
2 (40%)
DMAD
ii
TfO
CO2Me
CO2Me
F
OTf
Direct fluorination reactions of arenes often suffer from
their low chemo- and regioselectivity. Multiple fluorina-
tion represents an additional drawback. Cyclization reac-
tions of fluorinated building blocks provide a powerful
alternative for the synthesis of fluorinated arenes and
hetarenes. Schlosser et al. reported the synthesis of fluor-
inated arenes by Diels–Alder reactions of alkenes or
alkynes with fluorinated 1,3-butadienes.5 Portella et al.
developed a versatile approach to fluorinated phenols
from 2,2-difluoro-1,5-diketones.6
3 (87%)
Scheme 1 Synthesis of 2 and 3. Reagents and conditions: (i) (1) 1
(1.0 equiv), DMAD (1.5 equiv), –78 °C → 20 °C, 20 h; (2) HCl
(10%); (ii) (1) 2 (1.0 equiv), pyridine (4.0 equiv), CH2Cl2, –78 °C, 10
min; (2) Tf2O (2.4 equiv), –78 °C → 0 °C, 4 h.
The Suzuki reaction of 3 with boronic acids 4a–f (2.3
equiv) afforded the novel 3,5-diaryl-4-fluorophthalates
5a–f in good yields (Scheme 2, Table 1). The best yields
were obtained when Pd(PPh3)4 (3 mol%) was used as the
catalyst, when 2.3 equivalents of the boronic acid was em-
ployed, and when the reaction was carried out in 1,4-diox-
ane (110 °C, 8 h) using K3PO4 as the base.14,15
Recently, we studied the synthesis of fluorinated arenes
and hetarenes based on formal [3+3] and [3+2] cycliza-
tions of 1,3-bis(silyloxy)-1,3-butadienes.7–9 Herein, we
report, for the first time, the synthesis of dimethyl 4-fluo-
ro-3,5-dihydroxyphthalate by [4+2] cycloaddition of 1-
ethoxy-2-fluoro-1,3-bis(trimethylsilyloxy)-1,3-diene with
dimethyl acetylenedicarboxylate (DMAD). Suzuki–
The Suzuki–Miyaura reaction of 3 with arylboronic acids
4a,g–l (1.1 equiv) afforded the 5-aryl-4-fluorophthalates
6a–g in good yields and with very good site-selectivity
(Scheme 3, Table 2).16 The formation of the opposite
regioisomers was not observed.
SYNLETT 2010, No. 2, pp 0195–0198
x
x.
x
x.
2
0
1
0
Advanced online publication: 11.12.2009
DOI: 10.1055/s-0029-1218556; Art ID: G34009ST
© Georg Thieme Verlag Stuttgart · New York

196
M. F. Ibad et al.
LETTER
Table 2 Synthesis of 6a–g
4
g
h
i
6
a
b
c
d
e
f
Ar
6 (%)a
2-(CF3)C6H4
3-FC6H4
59
71
56
68
75
57
60
3,4-(MeO)2C6H3
4-(CF3)C6H4
3,5-Me2C6H3
3-(CF3)C6H4
2-(EtO)C6H4
a
j
k
l
g
a Yields of isolated products.
1) Ar1B(OH)2
OTf
Ar2
4a,h,l
2) Ar2B(OH)2
4e,i
Figure 1 Crystal structure of 2
F
CO2Me
CO2Me
F
CO2Me
CO2Me
TfO
Ar1
OTf
Ar
i
F
CO2Me
CO2Me
ArB(OH)2
F
CO2Me
CO2Me
7a–c
3
4a–f
i
Scheme 4 Synthesis of 7a–c. Reagents and conditions: (1) 3 (1.0
equiv), 4a,h,l (1.1 equiv), K3PO4 (1.5 equiv), Pd(PPh3)4 (3 mol%),
1,4-dioxane, 90 °C, 9 h; (2) 4e,i (1.3 equiv), K3PO4 (1.5 equiv), 110
°C, 6 h.
TfO
Ar
3
5a–f
Scheme 2 Synthesis of 5a–f. Reagents and conditions: (i) 3 (1.0
equiv), 4a–f (2.3 equiv), K3PO4 (3.0 equiv), Pd(PPh3)4 (3 mol%), 1,4-
dioxane, 110 °C, 8 h.
Table 3 Synthesis of 7a–c
4
7
a
b
c
Ar1
Ar2
7 (%)a
51
Table 1 Synthesis of 5a–f
4,5
a
Ar
5 (%)a
67
a,i
h,i
l,e
4-(CF3)C6H6
3-FC6H6
2-(EtO)C6H4
3,4-(MeO)2C6H3
3,4-(MeO)2C6H3
4-EtC6H4
49
4-(CF3)C6H4
Ph
58
b
c
83
a Yields of isolated products.
4-ClC6H4
3-ClC6H4
4-EtC6H4
3,5-Me2C6H3
75
d
e
63
72
f
77
a Yields of isolated products.
OTf
OTf
ArB(OH)2
4a,g–l
F
CO2Me
CO2Me
CO2Me
F
TfO
i
Ar
CO2Me
6a–g
3
Scheme 3 Synthesis of 6a–g. Reagents and conditions: (i) 3 (1.0
equiv), 4a,g–l (1.1 equiv), K3PO4 (1.5 equiv), Pd(PPh3)4 (3 mol%),
1,4-dioxane, 90 °C, 9 h.
3,5-Diaryl-4-fluorophthalates 7a–c, containing two dif-
ferent aryl groups, were prepared directly from bis(tri-
flate) 3 by application of a one-pot procedure (Scheme 4,
Table 3). The Suzuki reaction of 3 with arylboronic acids
Figure 2 Crystal structure of 7c
Synlett 2010, No. 2, 195–198 © Thieme Stuttgart · New York

LETTER
Synthesis of 3,5-Diaryl-4-fluorophthalates
197
(3) Reviews: (a) Wittkopp, A.; Schreiner, P. R. The Chemistry
of Dienes and Polyenes, Vol. 2; John Wiley & Sons Ltd.:
New York, 2000. (b) Schreiner, P. R. Chem. Soc. Rev. 2003,
32, 289. See also: (c) Wittkopp, A.; Schreiner, P. R. Chem.
Eur. J. 2003, 9, 407. (d) Kleiner, C. M.; Schreiner, P. R.
Chem. Commun. 2006, 4315. (e) Kotke, M.; Schreiner, P. R.
Synthesis 2007, 779. (f) Review: Tsogoeva, S. B. Eur. J.
Org. Chem. 2007, 1701.
(4) (a) Schmidbaur, H.; Kumberger, O. Chem. Ber. 1993, 126,
3. (b) Dinger, M. B.; Henderson, W. J. Organomet. Chem.
1998, 560, 233. (c) Liedtke, J.; Loss, S.; Widauer, C.;
Grützmacher, H. Tetrahedron 2000, 56, 143. (d) Schneider,
S.; Tzschucke, C. C.; Bannwarth, W. Multiphase
Homogeneous Catalysis; Cornils, B.; Herrmann, W. A.;
Horvath, I. T.; Leitner, W.; Mecking, S.; Olivier-Booubigou,
H.; Vogt, D., Eds.; Wiley-VCH: Weinheim, 2005, Chap. 4,
346. (e) Clarke, D.; Ali, M. A.; Clifford, A. A.; Parratt, A.;
Rose, P.; Schwinn, D.; Bannwarth, W.; Rayner, C. M. Curr.
Top. Med. Chem. 2004, 7, 729.
4a,h,l (1.1 equiv, 90 °C) and subsequent addition of aryl-
boronic acids 4e,i (1.3 equiv, 110 °C) to the in situ formed
monocoupling product afforded products 7a–c in accept-
able yields.17,18
The structure of products 6 and 7 were established by 2D
NMR experiments (NOESY, HMBC). The structure of 7c
was independently confirmed by X-ray crystal structure
analysis (Figure 2).13
In conclusion, we have reported the synthesis of dimethyl
4-fluoro-3,5-dihydroxyphthalate by [4+2] cycloaddition
of 1-ethoxy-2-fluoro-1,3-bis(trimethylsilyloxy)-1,3-diene
with dimethyl acetylenedicarboxylate (DMAD). Site-
selective Suzuki–Miyaura reactions of the bis(triflate) of
dimethyl 4-fluoro-3,5-dihydroxyphthalate provide a con-
venient approach to 3,5-diaryl-4-fluorophthalates.
(5) (a) Shi, G.-Q.; Cottens, S.; Shiba, S. A.; Schlosser, M. A.
Tetrahedron 1992, 48, 10569. (b) Shi, G.-Q.; Schlosser, M.
Tetrahedron 1993, 49, 1445. (c) Patrick, T. B.; Rogers, J.;
Gorrell, K. Org. Lett. 2002, 4, 3155.
(6) Lefebvre, O.; Brigaud, T.; Portella, C. Tetrahedron 1998,
54, 5939.
Acknowledgment
Financial support by the State of Pakistan (HEC scholarship for
O.-U.-R.A.), by the DAAD (scholarships for M.F.I. and M.N.) and
by the State of Mecklenburg-Vorpommern is gratefully acknowled-
ged.
(7) For a review of 1,3-bis(silyloxy)-1,3-butadienes in general,
see: Langer, P. Synthesis 2002, 441.
(8) For a review of [3+3] cyclizations, see: Feist, H.; Langer, P.
References and Notes
Synthesis 2007, 327.
(1) (a) Fluorine in Bioorganic Chemistry; Filler, R.; Kobayasi,
Y.; Yagupolskii, L. M., Eds.; Elsevier: Amsterdam, 1993.
(b) Filler, R. Fluorine Containing Drugs in Organofluorine
Chemicals and their Industrial Application; Pergamon: New
York, 1979, Chap. 6. (c) Hudlicky, M. Chemistry of
Organic Compounds; Ellis Horwood: Chichester, 1992.
(d) Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-
VCH: Weinheim, 2004. (e) Chambers, R. D. Fluorine in
Organic Chemistry; Blackwell Publishing CRC Press:
Florida, 2004. See also: (f) Ryckmanns, T.; Balancon, L.;
Berton, O.; Genicot, C.; Lamberty, Y.; Lallemand, B.;
Passau, P.; Pirlot, N.; Quéré, L.; Talaga, P. Bioorg. Med.
Chem. Lett. 2002, 12, 261. (g) Malamas, M. S.; Sredy, J.;
Moxham, C.; Katz, A.; Xu, W.; McDevitt, R.; Adebayo,
F. O.; Sawicki, D. R.; Seestaller, L.; Sullivan, D.; Taylor,
J. R. J. Med. Chem. 2000, 43, 1293. (h) Ciha, A. J.;
Ruminski, P. G. J. Agric. Food Chem. 1991, 39, 2072.
(i) Albrecht, H. A.; Beskid, G.; Georgopapadakou, N. H.;
Keith, D. D.; Konzelmann, F. M.; Pruess, D. L.; Rossman,
P. L.; Wei, C. C.; Christenson, J. G. J. Med. Chem. 1991, 34,
2857. (j) Albrecht, H. A.; Beskid, G.; Christenson, J. G.;
Deitcher, K. H.; Georgopapadakou, N. H.; Keith, D. D.;
Konzelmann, F. M.; Pruess, D. L.; Wie, C. C. J. Med. Chem.
1994, 37, 400. (k) Song, C. W.; Lee, K. Y.; Kim, C. D.;
Chang, T.-M.; Chey, W. Y. J. Pharmacol. Exp. Ther. 1997,
281, 1312. (l) De Voss, J. J.; Sui, Z.; DeCamp, D. L.; Salto,
R.; Babe, L. M.; Craik, C. S.; Ortiz de Montellano, P. R.
J. Med. Chem. 1994, 37, 665. (m) Anjaiah, S.;
(9) (a) Adeel, M.; Reim, S.; Wolf, V.; Yawer, M. A.; Hussain,
I.; Villinger, A.; Langer, P. Synlett 2008, 2629. (b)Hussain,
I.; Yawer, M. A.; Lau, M.; Pundt, T.; Fischer, C.; Reinke, H.;
Görls, H.; Langer, P. Eur. J. Org. Chem. 2008, 503.
(10) For reviews of site-selective palladium(0)-catalyzed cross-
coupling reactions of polyhalogenated substrates, see:
Schröter, S.; Stock, C.; Bach, T. Tetrahedron 2005, 61,
2245.
(11) Synthesis of Dimethyl 4-Fluoro-3,5-dihydroxyphthalate
(2): Diene 1 (9.0 g, 30.8 mmol) was added toDMAD (6.5 g,
5.5 mL, 46.2 mmol) at –78 °C. The mixture(neat) was
allowed to warm to 20 °C during 20 h with stirring. To the
mixture were added hydrochloric acid (10%) and
dichloromethane (50 mL each). The organic and the aqueous
layer 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 colorless solid (3.0 g, 40%); mp 140–142 °C. 1H
NMR (250 MHz, CDCl3): d = 3.87 (s, 3 H, OMe), 3.90 (s, 3
H, OMe), 6.15 (s, 1 H, OH), 6.60 (d, 1 H, JFH = 7.5 Hz, ArH),
10.96 (s, 1 H, OH). 13C NMR (75 MHz, CDCl3): d = 52.8
(OMe), 53.0 (OMe), 104.6 (C), 108.4 (CH), 131.6 (d, JFC
=
4.5 Hz, C), 140.5 (d, JFC = 239 Hz, CF), 148.3 (d, JFC = 11.7
Hz, COH), 151.1 (d, JFC = 11.0 Hz, COH), 168.6 (C=O),
168.8 (d, JFC = 3.0 Hz, C=O). 19F NMR (282 MHz, CDCl3):
d = –160.80 (F). IR (ATR): 3292 (m), 2962 (w), 2859 (w),
1716 (s), 1682 (s), 1621 (s), 1599 (s), 1515 (w), 1434 (s),
1325 (s), 1236 (s), 1093 (s), 933 (w) cm–1. GC–MS (EI, 70
eV): m/z (%) = 244 (24) [M+], 212 (53), 181 (11), 154 (100),
137 (4), 126 (12), 97 (9). HRMS (EI): m/z [M+] calcd for
C10H9O6F: 244.03777; found: 244.037617.
Chandrasekhar, S.; Gree, R. Adv. Synth. Catal. 2004, 346,
1329. (n) Iorio, M. A.; Paszkowska, R. T.; Frigeni, V. J.
Med. Chem. 1987, 30, 1906. (o) Popp, J. L.; Musza, L. L.;
Barrow, C. J.; Rudewicz, P. J.; Houck, D. R. J. Antibiot.
1994, 47, 411. (p) Chen, T. S.; Petuch, B.; MacConnell, J.;
White, R.; Dezeny, G. J. Antibiot. 1994, 47, 1290. (q) Lam,
K. S.; Schroeder, D. R.; Veitch, J. M. J. M.; Colson, K. L.;
Matson, J. A.; Rose, W. C.; Doyle, T. W.; Forenza, S.
J. Antibiot. 2001, 54, 1.
(12) Dimethyl 4-Fluoro-3,5-bis(trifluoromethylsulfonyloxy)-
phthalate (3): To a solution of 2 (1.0 equiv) in CH2Cl2 (10
mL/mmol) was added pyridine (4.0 equiv) at – 78 °C under
an argon atmosphere. After 10 min, Tf2O (2.4 equiv) was
added at –78 °C. The mixture was allowed to warm up to 0
°C and stirred for 4 h. The reaction mixture was filtered and
(2) Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A.;
Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004.
Synlett 2010, No. 2, 195–198 © Thieme Stuttgart · New York

198
M. F. Ibad et al.
LETTER
the filtrate was concentrated in vacuo. The products of the
reaction mixture were isolated by rapid column
mol%), 3,5-dimethylphenylboronic acid (50 mg, 0.33 mmol)
and 1,4-dioxane (4 mL), 6e was isolated as a colorless solid
(104 mg, 75%); mp 79–80 °C. 1H NMR (300 MHz, CDCl3):
d = 2.31 (br s, 6 H, 2 × Me), 3.85 (s, 3 H, OMe), 3.92 (s, 3 H,
chromatography (flash silica gel, heptanes–EtOAc). Starting
with 2 (2.00 g, 8.0 mmol), pyridine (2.6 mL, 32.0 mmol),
CH2Cl2 (80 mL), Tf2O (3.2 mL, 19.2 mmol), 3 was isolated
as a viscous colorless liquid (3.54 g, 87%). 1H NMR (300
MHz, CDCl3): d = 3.87 (s, 3 H, OMe), 3.90 (s, 3 H, OMe),
7.96 (d, 4JFH = 6.4 Hz, 1 H, ArH). 13C NMR (75 MHz,
CDCl3): d = 52.6 (OMe), 52.7 (OMe), 117.5 (q, 1JCF = 321
Hz, CF3), 117.6 (q, 1JCF = 321 Hz, CF3), 124.3 (br s, CH),
124.9 (d, 3JFC = 5.0 Hz, C), 130.9 (C), 133.8 (d, 2JFC = 13.2
Hz, C), 136.7 (d, 2J = 12.2 Hz, C), 148.0 (d, 1J = 268 Hz, CF),
161 (CO), 161.4 (d, 4JFC = 1.6 Hz, CO). 19F NMR (282 MHz,
CDCl3): d = 129.34, –72.81 (d, 5JFCF3 = 5.1 Hz, CF3), –72.51
(d, 5JFCF3 = 14.31 Hz, CF3). IR (ATR): 2960 (w), 2922 (w),
1739 (s), 1616 (w), 1595 (w), 1502 (w), 1426 (s), 1326 (m),
1209 (s), 1128 (m), 1045 (m), 1011 (s), 971 (s), 887 (m), 821
(m), 787 (s), 750 (m), 736 (m), 650 (w), 601 (s) cm–1. GC–
MS (70 eV): m/z (%) = 510 (1) [M+ + 2], 509 (2) [M+ + 1],
508 (12) [M+], 477 (100), 439 (5), 413 (44), 349 (52), 283
(33), 253 (6), 222 (19), 183 (16), 155 (14), 127 (4), 81 (8),
69 (63), 59 (15), 45 (4). HRMS (EI): m/z [M+] calcd for
C12H7O10F7S2: 507.93634; found: 507.936470.
OMe), 7.02 (s, 1 H, ArH), 7.06 (s, 2 H, ArH), 8.01 (d, 4JFH
=
6.6 Hz, 1 H, ArH). 13C NMR (62.90 MHz, CDCl3): d = 20.3
(2 × Me), 52.1 (OMe), 52.3 (OMe), 117.5 (q, 1JCF = 321 Hz,
CF3), 124.4 (d, 3JFC = 4.4 Hz, C), 125.6 (d, 4JFC = 2.75, 2 ×
CH), 128.8 (C), 130.1 (CH), 130.9 (d, 3JFC = 4.6 Hz, CH),
131.1 (d, 4J = 1.8 Hz, C), 131.9 (d, 2J = 13.0 Hz, C), 133.3
(d, 2JF,C = 17.0 Hz, C), 137.6 (s, 2 × C), 152.3 (d, 1JFC = 261
Hz, C), 162.7 (d, 4JFC = 2.7 Hz, CO). 163.1 (CO). 19F NMR
(282 MHz, CDCl3): d = –72.58 (d, J = 13.4 Hz, CF3), –
122.34 (q, J = 13.4 Hz, ArF). IR (ATR): 2959 (w), 2921 (w),
1737 (s), 1729 (s), 1620 (w), 1602 (w), 1495 (w), 1428 (s),
1408 (m), 1343 (m), 1275 (s), 1205 (s), 1133 (m), 1006 (m),
945 (m), 854 (m), 813 (s), 757 (m), 731 (m), 598 (s), 532 (s)
cm–1. GC–MS (70 eV): m/z (%) = 466 (8) [M+ + 2], 465 (21)
[M+ + 1], 464 (100) [M+], 433 (35), 395 (2), 369 (16), 331
(6), 303 (10), 272 (9), 242 (15), 214 (10), 185 (6), 160 (7),
99 (1), 69 (5), 59 (2). HRMS (ESI, +ve): m/z [M + H]+ calcd
for C19H17F4O7S: 465.06256; found: 465.06268.
(17) General Procedure for the Synthesis of 7a–c: The reaction
was carried out in a pressure tube. To a dioxane suspension
(4 mL) of 3 (228 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 an argon atmosphere for 9 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 H2O and extracted with
CH2Cl2 (3 × 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).
(13) CCDC 753087 and CCDC 753088 contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(14) General Procedure for Suzuki–Miyaura Reactions:
A 1,4-dioxane solution (4 mL per 3 mmol of 3) of 3, K3PO4,
Pd(PPh3)4 and arylboronic acid 4 was stirred at 110 °C or 90
°C for 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.
(15) Dimethyl 4-Fluoro-3,5-di(4-ethylphenyl)phthalate (5e):
Starting with 3 (152 mg, 0.3 mmol), K3PO4 (191 mg, 0.9
mmol), Pd(PPh3)4 (3 mol%), 4-ethylphenylboronic acid (105
mg, 0.7 mmol) and 1,4-dioxane (4 mL), 5e was isolated as a
colorless solid (91 mg, 72%); mp 151–153 °C. 1H NMR (300
MHz, CDCl3): d = 1.19 (t, J = 7.5 Hz, 3 H, Me), 1.20 (t, J =
7.5 Hz, 3 H, Me), 2.62 (q, J = 7.6 Hz, 2 H, CH2), 2.63 (q,
J = 7.6 Hz, 2 H, CH2), 3.56 (s, 3 H, OMe), 3.83 (s, 3 H,
OMe), 7.16–7.23 (m, 9 H, ArH). 13C NMR (75 MHz, CDCl3):
d = 15.3, 15.5 (2 × Me), 28.6 (2 × CH2), 52.4 (OMe), 52.6
(OMe), 123.6 (d, 3JCF = 4.4 Hz, C), 127.7 (2 × CH), 128.2
(2 × CH), 129.0 (d, 4JCF = 2.8 Hz, 2 × CH), 129.3 (C), 129.6
(d, 4JFC = 1.2 Hz, 2 × CH), 130.2 (d, 2JFC = 15.9 Hz, C), 131.5
(C), 131.9 (d, 3JFC = 5.5 Hz, CH), 136.6 (d, 4JFC = 3.8 Hz, C),
144.7 (d, 2JFC = 23.7 Hz, C), 159.1 (d, 1JFC = 256 Hz, CF),
165.4 (CO), 167.9 (d, 4JFC = 2.7 Hz, CO). 19F NMR (282
MHz, CDCl3): d = –111.4. IR (ATR): 3037 (w), 3002 (w),
2961 (m), 2947 (m), 2931 (m), 2671 (w), 1739 (m), 1717 (s),
1613 (w), 1514 (m), 1429 (m), 1396 (m), 1345 (m), 1274
(m), 1247 (m), 1219 (s), 1146 (m), 1118 (m), 1069 (m), 1020
(m), 1003 (m), 968 (m), 848 (m), 835 (m), 794 (m), 683 (m),
575 (m), 531 (m) cm–1. GC–MS (70 eV): m/z (%) = 421 (28)
[M+ + 1], 420 (100) [M+], 405 (20), 389 (52), 373 (3), 357
(18), 329 (7), 315 (2), 301 (4), 287 (5), 273 (6), 272 (5), 259
(4), 257 (6), 252 (2), 244 (3), 195 (7), 170 (2), 143 (3), 135
(3), 129 (2), 77 (1), 59 (1), 29 (2). HRMS (EI): m/z [M+]
calcd for C26H25O4F: 420.17314: found: 420.173423.
(16) Dimethyl 4-Fluoro-5-(3,5-dimethylphenyl)-3-(trifluoro-
methylsulfonyloxy)phthalate (6e): Starting with 3 (152
mg, 0.3 mmol), K3PO4 (95 mg, 0.45 mmol), Pd(PPh3)4 (3
(18) Dimethyl 4-Fluoro-5-(2-ethoxyphenyl)-3-(4-ethylphenyl)-
phthalate (7c): Starting with 3 (228 mg, 0.45 mmol), K3PO4
(286 mg, 1.34 mmol), Pd(PPh3)4 (3 mol%), 2-ethoxyphenyl-
boronic acid (82 mg, 0.5 mmol), 1,4-dioxane (4 mL), and
4-ethylphenylboronic acid (85 mg, 0.6 mmol), 7c was
isolated as transparent crystals (114 mg, 58%); mp 104–106
°C. 1H NMR (300 MHz, CDCl3): d = 1.15–1.25 (m, 6 H, 2 ×
Me), 2.61 (q, J = 7.5 Hz, 2 H, CH2), 3.57 (s, 3 H, OMe), 3.78
(s, 3 H, OMe), 3.95 (q, 3J = 7.0 Hz, 2 H, OCH2), 6.87 (d, J =
8.4 Hz, 1 H, ArH), 6.93 (dt, J = 7.5 Hz, 1 H, ArH), 7.14–7.30
(m, 6 H, ArH), 7.98 (d, 4JFH = 6.7 Hz, 1 H, ArH). 13C NMR
(62.90 MHz, CDCl3): d = 14.7 (Me), 15.2 (Me), 28.6 (CH2),
52.3 (OMe), 52.5 (OMe), 64.0 (OCH2), 112.1, 120.5 (2 ×
CH), 123.7 (C), 127.6 (2 × CH), 127.8 (d, 2JFC = 19.0 Hz, C),
128.5 (d, 2J = 20.7 Hz, C), 129.4, 129.5, 130.1 (3 × CH),
131.0 (d, 4J = 1.4 Hz, CH), 133.3 (d, 3JF,C = 5.6 Hz, CH),
136.8 (d, 3JF,C = 4.1 Hz, C), 144.3, 156.3 (2 × C), 159.6 (d,
1JFC = 256 Hz, CF), 165.5 (C=O), 168.1 (d,
4J = 2.7 Hz, C=O). 19F NMR (282 MHz, CDCl3): d =
–106.42 (CF). IR (ATR): 2973 (w), 2944 (w), 2929 (w),
2881 (w), 1724 (br s), 1609 (w), 1580 (w), 1563 (w), 1516
(w), 1497 (m), 1451 (m), 1428 (m), 1390 (m), 1341 (m),
1273 (s), 1249 (s), 1215 (s), 1149 (s), 1123 (m), 1067 (m),
1041 (s), 969 (m), 919 (m), 858 (w), 839 (w), 793 (m), 754
(s), 689 (m), 611 (m), 537 (w) cm–1. GC–MS (70 eV): m/z
(%) = 438 (5) [M+ + 2], 437 (30) [M+ +1], 436 (100) [M+],
405 (19), 376 (30), 361 (16), 348 (20), 317 (20), 289 (9), 271
(9), 244 (5), 171 (3), 151 (2), 128 (2), 59 (2), 29 (4). HRMS
(EI): m/z [M+] calcd for C26H25FO5: 436.16805; found:
436.168135.
Synlett 2010, No. 2, 195–198 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.