One-pot synthesis of difluorinated ortho -terphenyls by site-selective suzuki-miyaura reactions of 1,2-dibromo-3,5-difluorobenzene

Article abstract of DOI:10.1055/s-0029-1219552

The Suzuki-Miyaura reaction of 1,2-dibromo-3,5-difluorobenzene with two equivalents of arylboronic acids gave difluorinated ortho-terphenyls. The reaction with one equivalent of arylboronic acid resulted in site-selective formation of 2-bromo-3,5-difluoro

Full text of DOI:10.1055/s-0029-1219552

LETTER
913
One-Pot Synthesis of Difluorinated ortho-Terphenyls by Site-Selective
Suzuki–Miyaura Reactions of 1,2-Dibromo-3,5-difluorobenzene
Synthesis of
D
ifluorina
u
ted ortho-T
eh
rphenyls ammad Sharif,a,b Sebastian Reimann,a,b Alexander Villinger,a Peter Langer*a,b
a
Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
Fax +49(381)4986412; E-mail: peter.langer@uni-rostock.de
b
Received 29 December 2009
catalyzed cross-coupling reactions of dibromides, diio-
dides, or bis(triflates) of fluorinated arenes have, to the
best of our knowledge, not been reported to date. Herein,
we report first results of our study related to S–M reac-
Abstract: The Suzuki–Miyaura reaction of 1,2-dibromo-3,5-di-
fluorobenzene with two equivalents of arylboronic acids gave di-
fluorinated ortho-terphenyls. The reaction with one equivalent of
arylboronic acid resulted in site-selective formation of 2-bromo-
3,5-difluoro-biphenyls. The one-pot reaction of 1,2-dibromo-3,5- tions of 1,2-dibromo-3,5-difluorobenzene. The products,
difluorobenzene with two different arylboronic acids afforded di-
fluorinated ortho-terphenyls containing two different terminal aryl
groups.
difluorinated ortho-terphenyls, are not readily available
by other methods.
The S–M reaction of commercially available 1,2-dibro-
mo-3,5-difluorobenzene (1) with two equivalents of aryl-
boronic acids 2a–f afforded the difluorinated ortho-
terphenyls 3a–f in moderate to good yields (Scheme 1,
Key words: catalysis, palladium, Suzuki–Miyaura reaction, site
selectivity, organofluorine compounds
Table 1). The best yields were obtained using 2.2 equiva-
Fluorinated arenes have found widespread applications in
lents of the arylboronic acid, Pd(PPh3)4 (0.03 equiv) as the
medicinal chemistry and crop protection.1 While no fluo-
catalyst, and Cs2CO3 (2.2 equiv) as the base (1,4-dioxane,
rine containing drug had been developed until 1957, more
90 °C, 8 h).11,12
than 150 fluorinated drugs have come to market since then
and now constitute approx. 20% of all pharmaceuticals,2
F
F
with even higher figures for agrochemicals (up to 30%).3
The strategic use of fluorine substitution in drug design
has culminated with the production of some of the key
drugs available on the market.4 The fluorine atom com-
bines a high electronegativity with a small size which
often results in an improvement of drug–receptor interac-
tions. Aryl fluorides are more stable towards undesired
metabolic transformations than the corresponding unsub-
stituted arenes, due to the high biological stability of the
carbon–fluorine bond. In addition, the transport of the
drug 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.5 Last but not the least, or-
ganofluorine compounds are used as ligands6 in catalytic
reactions and as organocatalysts.7
Ar
Ar
Br
Br
ArB(OH)2
2a–f
i
F
F
1
3a–f
Scheme 1 Synthesis of 3a–f. Reagents and conditions: i, 1 (1.0
equiv), 2a–f (2.2 equiv), Cs2CO3 (2.2 equiv), Pd(PPh3)4 (3 mol%),
1,4-dioxane, 90 °C, 8 h.
Table 1 Synthesis of 3a–f
2, 3
a
Ar
Yield of 3 (%)a
4-MeOC6H4
4-EtOC6H4
4-MeC6H4
70
68
45
58
65
60
b
c
In recent years, a number of site-selective palladium(0)-
catalyzed cross-coupling reactions of polyhalogenated
heterocycles have been developed. The site selectivity of
these reactions is generally influenced by electronic and
steric parameters.8 We have reported site-selective
Suzuki–Miyaura (S–M) reactions of tetrabrominated
thiophene, N-methylpyrrole, selenophene, and of other
polyhalogenated heterocycles.9 Site-selective S–M reac-
tions of the bis(triflate) of methyl 2,5-dihydroxybenzoate
have also been studied.10 Site-selective palladium(0)-
d
2,4-(MeO)2C6H3
2,6-(MeO)2C6H3
2-MeOC6H4
e
f
a Yields of isolated products.
The S–M reaction of 1 with arylboronic acids 2a–g (1.0
equiv) afforded the 2-bromo-3,5-difluoro-biphenyls 4a–g
in good yields and with very good site selectivity
(Scheme 2, Table 2).11,13 The formation of the opposite
regioisomers was not observed.
SYNLETT 2010, No. 6, pp 0913–0916
x
x.
x
x.
2
0
1
0
Advanced online publication: 26.02.2010
DOI: 10.1055/s-0029-1219552; Art ID: G41309ST
© Georg Thieme Verlag Stuttgart · New York

914
M. Sharif et al.
LETTER
F
F
Br
Ar
Br
Br
ArB(OH)2
2a–g
i
F
F
1
4a–g
Scheme 2 Synthesis of 4a–g. Reagents and conditions: i, 1 (1.0
equiv), 4a–g (1.0 equiv), Cs2CO3 (1.5 equiv), Pd(PPh3)4 (3 mol%),
1,4-dioxane, 90 °C, 9 h.
Table 2 Synthesis of 4a–g
2, 4
a
Ar
Yield of 4 (%)a
4-MeOC6H4
4-EtOC6H4
60
65
45
67
68
60
60
b
c
4-MeC6H4
d
e
2,4-(MeO)2C6H3
2,6-(MeO)2C6H3
2-MeOC6H4
3,4-(MeO)2C6H3
Figure 1 Crystal structure of 3c
f
g
a Yields of isolated products.
The one-pot reaction of 1,2-dibromo-3,5-difluorobenzene
with two different arylboronic acids afforded the unsym-
metrical difluorinated ortho-terphenyls 5a–d containing
two different terminal aryl groups (Scheme 3,
Table 3).14,15
1) Ar1B(OH)2
F
F
2d–f,i
Ar2
Ar1
Br
Br
2) Ar2B(OH)2
2c,j
i
F
F
1
5a–d
Scheme 3 One-pot synthesis of 5a–d. Reagents and conditions:
1) 1 (1.0 equiv), 2d–f,i (1.0 equiv), Cs2CO3 (1.5 equiv), Pd(PPh3)4 (3
mol%), 1,4-dioxane, 90 °C, 8 h; 2) 2c,j (1.2 equiv), Cs2CO3 (1.5
equiv), 90 °C, 8 h.
Figure 2 Crystal structure of 4e
The site-selective formation of 4a–g and 5a–d can be ex-
plained by steric and by electronic reasons. The first at-
tack of palladium(0)-catalyzed cross-coupling reactions
generally occurs at the more electron-deficient and steri-
cally less hindered position.8,17 Position 1 of 1,2-dibromo-
3,5-difluorobenzene (1) is sterically less hindered because
it is located next to a bromine and to a hydrogen atom
while position 2 is located next to a bromine and to a flu-
orine atom (Figure 3). In addition, position 1 (located
meta to the fluorine atoms) is considerably more electron-
deficient than position 2 (located ortho and para to the
fluorine atoms), due to the p-donating effect of the fluo-
rine atom. In fact, the 1H NMR signals of aromatic protons
located ortho or para to a fluorine atom are generally
shifted to higher field compared to the proton located in
meta position.17
Table 3 Synthesis of 5a–d
2
5
a
b
c
Ar1
Ar2
Yield of 5 (%)a
d,c
e,c
f,c
i,j
2,4-(MeO)2C6H3 4-MeC6H4
2,6-(MeO)2C6H3 4-MeC6H4
48
60
62
45
2-MeOC6H4
4-FC6H4
4-MeC6H4
4-ClC6H4
d
a Yields of isolated products.
The structures of all products were established by 2D
NMR experiments (NOESY, HMBC). The structures of
4e and 3c were independently confirmed by X-ray crystal-
structure analyses (Figure 1 and Figure 2).16
Synlett 2010, No. 6, 913–916 © Thieme Stuttgart · New York

LETTER
Synthesis of Difluorinated ortho-Terphenyls
915
(4) Beller, M.; Neumann, H.; Anbarasan, P. Angew. Chem. Int.
Ed. 2009, 48, 1.
more sterically hindered
less electron-deficient
F
Br
Br
(5) Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A.;
Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004.
(6) (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
F
less sterically hindered
more electron-deficient
Figure 3 Possible explanation for the site selectivity of cross-
coupling reactions of 1
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.
In conclusion, we have reported site-selective Suzuki–
Miyaura reactions of 1,2-dibromo-3,5-difluorobenzene
which provide a convenient approach to difluorinated
ortho-terphenyls and 2-bromo-3,5-difluoro-biphenyls.
The application of the concept outlined herein to other
fluorinated arenes is currently studied in our laboratories.
(7) Reviews: (a) Wittkopp, A.; Schreiner, P. R. The Chemistry
of Dienes and Polyenes, Vol. 2; John Wiley and Sons:
Chichester, 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. Review: (f) Tsogoeva, S. B. Eur. J.
Org. Chem. 2007, 1701.
Acknowledgment
Financial support by the DAAD (scholarship for M.S.) and by the
University of Rostock (scholarship of the interdisciplinary faculty
for S.R.) is gratefully acknowledged.
(8) For reviews of cross-coupling reactions of polyhalogenated
heterocycles, see: (a) Schröter, S.; Stock, C.; Bach, T.
Tetrahedron 2005, 61, 2245. (b) Schnürch, M.; Flasik, R.;
Khan, A. F.; Spina, M.; Mihovilovic, M. D.; Stanetty, P. Eur.
J. Org. Chem. 2006, 3283.
(9) (a) Dang, T. T.; Dang, T. T.; Rasool, N.; Villinger, A.;
Langer, P. Adv. Synth. Catal. 2009, 351, 1595. (b) Dang,
T. T.; Dang, T. T.; Ahmad, R.; Reinke, H.; Langer, P.
Tetrahedron Lett. 2008, 49, 1698. (c) Dang, T. T.;Villinger,
A.; Langer, P. Adv. Synth. Catal. 2008, 350, 2109.
References and Notes
(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; VCH:
Weinheim, 2004. (e) Chambers, R. D. Fluorine in Organic
Chemistry; Blackwell Publishing CRC Press: Boca Raton,
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.; 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. (r) Purser, S.; Moore,
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37, 320.
(d) Hussain, M.; Dang, T. T.; Langer, P. Synlett 2009, 1822.
(10) Nawaz, M.; Farooq, M. I.; Obaid-Ur-Rahman, A.; Khera, R.
A.; Villinger, A.; Langer, P. Synlett 2010, 150.
(11) General Procedure for Suzuki Reactions
A 1,4-dioxane solution (4 mL per 0.3 mmol of 1) of 1,
Cs2CO3, Pd(PPh3)4, and arylboronic acid 2 was stirred at
90 °C for 6 or 8 h. After cooling to r.t. 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.
(12) 1,2-Di(2-Methoxyphenyl)-3,5-difluorobenzene (3f)
Starting with 1 (100 mg, 0.37 mmol), Cs2CO3 (263 mg, 0.81
mmol), Pd(PPh3)4 (3 mol%), 2-methoxyphenylboronic acid
(123 mg, 0.81 mmol), and 1,4-dioxane (4 mL), 3f was
isolated as a colorless solid (72 mg, 60%), mp 111–113 °C.
1H NMR (300 MHz, CDCl3): d = 3.42 (s, 3 H, OCH3), 3.55
(s, 3 H, OCH3), 6.60 (dd, J = 8.3, 0.7 Hz, 1 H, ArH), 6.67–
6.88 (m, 6 H, ArH), 6.94 (dd, J = 7.5, 1.7 Hz, 1 H, ArH),
7.05–7.12 (m, 2 H, ArH). 13C NMR (62.89 MHz, CDCl3):
d = 54.9 (OCH3), 55.2 (OCH3), 102.6 (t, 2JCF = 26.5 Hz,
CH), 110.2 (CH), 110.3 (CH), 113.2 (dd, JCF = 21.2, 3.5 Hz,
CH), 119.7 (CH), 119.9 (CH), 122.1 (dd, J = 17.1, 3.8 Hz,
C), 123.1 (C), 128.6 (t, J = 2.1 Hz, C), 128.90 (CH), 128.92
(CH), 131.0 (CH), 131.7 (CH), 141.9 (t, J = 4.9 Hz, C),
156.0 (C), 157.0 (C), 160.1 (dd, JCF = 247.2, 12.8 Hz, CF),
161.6 (dd, JCF = 247.2, 13.3 Hz, CF). 19F NMR (282.4 MHz,
CDCl3): d = –112.82 (CF), –118.20 (CF). IR (ATR):
n = 3067 (w), 2956 (w), 2926 (w), 2835 (w), 1616 (w), 1596
(w), 1503 (w), 1494 (w), 1455 (w), 1421 (w), 1338 (w), 1287
(w), 1247 (m), 1201 (w), 1180 (w), 1120 (w), 1089 (w), 1024
(m), 928 (w), 877 (w), 865 (w), 800 (w), 755 (w), 744 (m),
701 (w), 635 (w), 586 (m), 537 (w) cm–1. MS (EI, 70 eV):
m/z (%) = 326 (100) [M]+, 295 (12), 251 (21), 238 (10).
(2) Bégué, J. P.; Bonnet-Delpon, D. J. Fluorine Chem. 2006,
127, 992.
(3) Isanbor, C.; O’Hagan, D. J. Fluorine Chem. 2006, 127, 303.
Synlett 2010, No. 6, 913–916 © Thieme Stuttgart · New York

916
M. Sharif et al.
LETTER
(15) 1-(2,4-Dimethoxyphenyl)-2-(4-methylphenyl)-3,5-
HRMS (EI): m/z calcd for C20H16O2F2 [M+]: 326.11129;
found: 326.11090.
difluorobenzene (5a)
(13) 2-Bromo-3,5-difluoro-2¢,4¢-dimethoxybiphenyl (4d)
Starting with 1 (100 mg, 0.37 mmol), Cs2CO3 (119 mg, 0.37
mmol), Pd(PPh3)4 (3 mol%), 2,4-dimethoxyphenylboronic
acid (67 mg, 0.37 mmol), and 1,4-dioxane (4 mL), 4d was
isolated as a colorless solid (81 mg, 67%), mp 64–66 °C. 1H
NMR (300 MHz, CDCl3): d = 3.75 (s, 3 H, OCH3), 3.89 (s,
3 H, OCH3), 6.53–6.57 (m, 2 H, Ar), 6.82–6.88 (m, 2 H, Ar),
7.04 (d, J = 8.9 Hz, 1 H, Ar). 13C NMR (75.46 MHz, CDCl3):
Starting with 1 (200 mg, 0.74 mmol), Cs2CO3 (359 mg, 1.11
mmol), Pd(PPh3)4 (3 mol%), 2,6-dimethoxyphenylboronic
(134 mg, 0.74 mmol), 1,4-dioxane (4 mL), and 4-methyl-
boronic acid (123 mg, 0.89 mmol), 5a was isolated as a
colorless highly viscous oil (120 mg, 48%). 1H NMR (300
MHz, CDCl3): d = 2.19 (s, 3 H, ArH), 3.32 (s, 3 H, OCH3),
3.69 (s, 3 H, OCH3), 6.17 (d, J = 2.3 Hz, 1 H, Ar), 6.32 (dd,
J = 8.3, 2.3 Hz, 1 H, Ar), 6.74–6.83 (m, 2 H, Ar), 6.86–6.91
(m, 5 H, Ar). 13C NMR (62.89 MHz, CDCl3): d = 21.2
(CH3), 55.0 (OCH3), 55.3 (OCH3), 98.4 (CH), 102.5 (t,
2JCF = 26.3 Hz, CH), 104.1 (CH), 113.6 (dd, JCF = 21.9, 3.6
Hz, CH), 121.5 (t, 3J = 2.8 Hz, C), 125.7 (dd, J = 15.3, 3.6
Hz, C), 128.1 (2 CH), 130.0 (2 CH), 131.1 (C), 131.6 (CH),
136.4 (C), 141.2 (dd, J = 9.6, 4.5 Hz, C), 157.0 (C), 159.8
(dd, JCF = 246.8, 13.0 Hz, CF), 160.6 (C), 161.1 (dd,
JCF = 247.1, 13.4 Hz, C). 19F NMR (282.4 MHz, CDCl3):
d = –111.86 (CF), –112.9 (CF). IR (ATR): n = 3080 (w),
2998 (w), 2956 (w), 2836 (w), 1736 (w), 1609 (s), 1586 (s),
1508 (s), 1454 (s), 1425 (m), 1401 (m), 1372 (w), 1303 (s),
1255 (m), 1184 (w), 1158 (s), 1145 (s), 1092 (s), 1032 (s),
996 (s), 925 (m), 861 (w), 834 (m), 818 (s)796 (m), 736 (w),
718 (w), 663 (w), 607 (w), 587 (m) cm–1. MS (EI, 70 eV):
m/z (%) = 340 (100) [M]+, 294 (11), 265 (13), 238 (12). ESI-
HRMS: m/z calcd for C21H19F2O2 [M + H]+: 341.1348;
found: 341.1348.
d = 55.4 (OCH3), 55.6 (OCH3), 98.7 (CH), 103.4 (t, 2JCF
26.6 Hz, CH), 104 (CH), 106.9 (dd, J = 20.4, 4.0 Hz, C),
=
114.5 (dd, J = 22.3, 3.3 Hz, CH), 121.0 (t, J = 2.2, C), 131.1
(CH), 142.9 (d, J = 9.8 Hz, C), 157.4 (C), 159.22 (dd,
J = 248.0, 13.7 Hz, CF), 161.3 (dd, J = 248.6, 13.2 Hz, CF)
161.4 (C). 19F NMR (282.4 MHz, CDCl3): d = –100.5 (CF),
–112.4 (CF). IR (ATR): n = 3079 (w), 3002 (w), 2958 (w),
2937 (w), 2836 (w), 1692 (s), 1785 (s), 1509 (s), 1463 (m),
1447 (m), 1468 (w), 1435 (s), 1345 (w), 1304 (s), 1281 (m),
1256 (m), 1206 (s), 1146 (m), 1127 (s), 1101 (s), 1031 (s),
997 (s), 924 (m), 833 (s), 796 (m), 716 (w), 637 (w), 599 (s),
587 (m) cm–1. MS (EI, 70 eV): m/z (%) = 328 (95) [M]+, 330
(93), 329 (15), 331 (14), 235 (15), 234 (100), 219 (35), 204
(12), 191 (20), 175 (26), 163 (13). ESI-HRMS: m/z calcd for
C14H12BrF2O2 [M + H]+: 328.9983; found: 328.9979.
(14) General Procedure for the Synthesis of 5a–d
The reaction was carried out in a pressure tube. To a dioxane
suspension (4 mL) of 1 (200 mg, 0.74 mmol), Pd(PPh3)4
(3 mol%), and Ar1B(OH)2 (0.74 mmol) was added Cs2CO3
(359 mg, 1.11 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 and Ar2B(OH)2
(0.89 mmol) and Cs2CO3 (359 mg, 1.11 mmol) was added.
The reaction mixtures were heated under Argon atmosphere
for 6 h at 100 °C. They were diluted with H2O and extracted
with CH2Cl2 (3 × 50 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–hexane = 1:4).
(16) CCDC-762919 and 762920 contain all crystallographic
details of this publication and is available free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html or can be
ordered from the following address: Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB21EZ, UK; fax: +44 (1223)336033; or
deposit@ccdc.cam.ac.uk.
(17) For a simple guide for the prediction of the site selectivity of
palladium(0)-catalyzed cross-coupling reactions based on
the 1H NMR chemical shift values, see: Handy, S. T.; Zhang,
Y. Chem. Commun. 2006, 299.
Synlett 2010, No. 6, 913–916 © Thieme Stuttgart · New York