Synthesis of unsymmetrical heterobiaryls using palladium-catalyzed cross-coupling reactions of lithium organozincates

Article abstract of DOI:10.1055/s-0028-1087347

Several unsymmetrical heterobiaryls have been synthesized through palladium-catalyzed cross-coupling reactions of lithium triorganozincates. The latter have been prepared by deprotonative lithiation followed by transmetalation using non-hygroscopic ZnCl₂-TMEDA (0.33 equiv). Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087347

LETTER
2955
Synthesis of Unsymmetrical Heterobiaryls Using Palladium-Catalyzed
Cross-Coupling Reactions of Lithium Organozincates
Synthesis of
U
nsym
n
metrical He
n
terobiaryls e Seggio,a Anny Jutand,b Ghislaine Priem,c Florence Mongin*a
a
Chimie et Photonique Moléculaires, UMR CNRS 6510, Université de Rennes 1, Bâtiment 10A, Case 1003, Campus Scientifique de
Beaulieu, 35042 Rennes Cedex, France
Fax +33(2)23236931; E-mail: florence.mongin@univ-rennes1.fr
Ecole Normale Supérieure – CNRS, Département de Chimie, 24 Rue Lhomond, 75231 Paris Cedex 5, France
GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow CM19 5AW, UK
b
c
Received 29 July 2008
dium-catalyzed reactions for which the lithium zincate in-
termediates are generated by transmetalation of the
corresponding lithio compounds using ZnCl2·TMEDA.
Abstract: Several unsymmetrical heterobiaryls have been synthe-
sized through palladium-catalyzed cross-coupling reactions of lith-
ium triorganozincates. The latter have been prepared by
deprotonative lithiation followed by transmetalation using non-
hygroscopic ZnCl2·TMEDA (0.33 equiv).
We first optimized the procedure for the cross-coupling of
zinc compounds obtained from 2-lithiobenzofuran. Ben-
zo[b]furan (1) was lithiated using butyllithium in tetrahy-
drofuran (THF) at –15 °C.13 Transmetalation was
performed using 1:1, 3:1, and 4:1 benzofuryllithium/
ZnCl2·TMEDA stoichiometries in order to generate the
corresponding organozinc, lithium triorganozincate, and
dilithium tetraorganozincate, respectively.
Key words: cross-coupling, heterocycle, metalation, palladium,
zinc
The importance of heterobiaryls in natural products and
pharmaceutical intermediates and their unique photophys-
ical properties have stimulated tremendous efforts for the
development of synthetic methods in the area of aryl–aryl
bond formation.1 Like the Suzuki–Miyaura2 and Stille3 re-
actions, the Negishi4 cross-couplings of organozincs and
aryl halides offer the advantage of stable starting materials
and thus are known to tolerate a large range of functional
groups. Nevertheless, the latter become more attractive
when heteroaryl boronic acids cannot be prepared; in ad-
dition, they do not use highly toxic starting materials.
Nickel-catalyzed cross-couplings of organozinc com-
pounds have been described.14 However, the toxicity of
nickel salts led us to explore alternative routes.15
In 2002 Figadère16 and Fürstner17 separately reported
iron-catalyzed aryl–heteroaryl cross-coupling reactions
starting from aryl Grignard reagents and heteroaryl chlo-
rides. The reactions proceed in good yields when carried
out in THF at –30 °C using iron(III) acetylacetonate
[Fe(acac)3]. A magnesium trialkylzincate, Et3ZnMgBr,
also proved to react with methyl 4-chlorobenzoate when
the reaction was conducted similarly.17 Attempts to per-
form the reaction between benzofurylzinc chloride and
2,4-dichloropyrimidine in the presence of Fe(acac)3 under
the same reaction conditions failed.
The organozincs are in general prepared by treating the
corresponding lithium or magnesium compounds with
zinc halides.5 Alternative methods employ zinc dust or ac-
tive Rieke zinc (direct insertion).5,6 Electrochemical
methods have also been considered.7
A major drawback of the Negishi coupling procedure lies
in obtaining dry zinc chloride or zinc bromide. Mutule and
Suma described in 2005 a sequential microwave-assisted
Grignard formation–transmetalation–Negishi one-pot re-
action using the less hygroscopic TMEDA-chelated zinc
chloride.8 Gauthier and co-workers developed an ap-
proach through lithium zincates using only one third
equivalent of zinc chloride for the synthesis of 5-aryl-2-
furaldehydes from 5-lithio-2-furaldehyde diethyl acetal.9
Miller and Farrell reported the use of a catalytic amount
of zinc chloride to perform nickel- or palladium-catalyzed
couplings of aryl Grignard reagents with aryl halides.10
Other authors completely avoided the use of zinc halide
by generating lithium zincates either by iodine–metal
exchange11 or by deprotonation.12 Herein, we report palla-
We thus turned to palladium-catalyzed reactions
(Scheme 1, Table 1).18 Cross-coupling reactions of all the
benzofurylzincs performed with 2,4-dichloropyrimidine
at 55 °C in THF with catalytic amounts of palladium(II)
chloride and 1,1¢-bis(diphenylphosphino)ferrocene (dppf)19
provided the expected benzofurylpyrimidine 2a.20 Where-
as a lower 44% yield was obtained with the higher order
zincate,21 similar results were shown using the organozinc
SYNLETT 2008, No. 12, pp 2955–2960
x
x
.x
x
.2
0
0
8
Advanced online publication: 12.11.2008
DOI: 10.1055/s-0028-1087347; Art ID: G24108ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 (a) Using PPh3 (4 mol%) instead of dppf; (b) using PCy3
(4 mol%) instead of dppf

2956
A. Seggio et al.
LETTER
Table 1 Coupling Reactions of Lithium Triarylzincates with Heteroaryl Chlorides
1) base, THF, conditions
2) ZnCl2⋅TMEDA (0.33 equiv), r.t., 1 h
3)
Cl
X
N
X
R
Ar
R
ArH
Entry
1
N
PdCl2 (2 mol%), dppf (2 mol%)
55 °C, 12 h
4) hydrolysis
Substrate
Base, conditions
Product
Yield (%)
BuLi, –15 °C, 1 h
56
O
O
N
O
N
1
1
Cl
2
3
BuLi, –15 °C, 1 h
BuLi, –15 °C, 1 h
61, 76a
O
N
N
2b
1
O
61
O
N
4
3
Cl
4
5
BuLi, –75 °C, 1 h
BuLi, –75 °C, 1 h
29b
81
S
N
S
N
8a
5
Cl
S
S
8b
N
N
5
S
6
7
BuLi, –15 °C, 1 h
BuLi, –75 °C, 1 h
56
85
S
N
9a
6
Cl
Cl
Cl
S
S
N
10
7
N
N
8
LiTMP, –75 °C, 1 h
61
N
O
O
12
O
O
11
13
OMe
OMe
9
BuLi, 25 °C, 2 h
64
62
14
N
F
N
N
F
10
LiTMP, –75 °C, 1 h
16
N
15
a Coupling step performed in the presence of DME (5 equiv).
b Since 2,4-dichloropyrimidine reacts rapidly with moisture in air, lower yields can be partly attributed to the presence of pyrimidinone in the
starting heteroaryl chloride.
Synlett 2008, No. 12, 2955–2960 © Thieme Stuttgart · New York

LETTER
Synthesis of Unsymmetrical Heterobiaryls
2957
and lithium triorganozincate (62% and 56% yields, re-
spectively). Other ligands such as triphenylphosphine
(53%), tri(cyclohexyl)phosphine (30%), 1,3-bis(diphenyl-
phosphino)propane (<20%), and 1,4-bis(diphenylphosphino)-
butane (<10%) were tested for the palladium-catalyzed re-
action involving lithium tri(2-benzofuryl)zincate, which
was preferred for stoichiometry efficiency, but proved
less efficient than dppf.22 The pyridylbenzofuran 2b23 was
similarly obtained in 61% yield from 2-chloropyridine
(Table 1, entry 2).
1) BuLi, THF, –75 °C, 1 h
2) ZnCl2⋅TMEDA (0.33 equiv), r.t., 1 h
3)
Br
R
S
PdCl2 (2 mol%), dppf (2 mol%)
55 °C, 12 h
4) hydrolysis
R
S
6
9b R = OMe: 10%
9c R = NO2: 38%, 76% (a)
9d R = CO2Me: 41%
9e R = CN, 79%
Scheme 2 (a) Coupling step performed in the presence of DME (5
equiv)
Having optimized the conditions, various aromatic sub-
strates were used in the deprotonation–transmetalation–
coupling sequence using 2,4-dichloropyrimidine and/or
2-chloropyridine. Furan (3) was similarly lithiated;24 sub-
sequent transmetalation using ZnCl2·TMEDA (0.33
equiv) and coupling with 2,4-dichloropyrimidine afforded
the expected furylpyrimidine 425 (Table 1, entry 3). Ben-
zo[b]thiophene (5), thiophene (6), and 2-chlorothiophene
(7), which were lithiated using butyllithium in THF at –75
°C, –15 °C, and –75 °C,26 respectively, gave the bishetero-
cycles 8a,27 8b,28 9a,29 and 1030 (entries 4–7). N-Boc pyr-
role (11) was deprotonated upon treatment with lithium
2,2,6,6-tetramethylpiperidide (LiTMP) in THF at –75 °C31
to give the 2-pyridyl derivative 1232 (entry 8) after subse-
quent transmetalation–coupling reactions. Anisole (13)
was similarly ortho functionalized33 to afford the 2-py-
ridyl derivative 1434 (entry 9). The reaction also proved
convenient for the functionalization of a p-deficient sub-
strate, 2-fluoropyridine (15), which was converted to the
bipyridine 1635 (entry 10) after lithiation using LiTMP in
THF at –75 °C,36 followed by transmetalation and cross-
coupling steps.
9c,41 9d,42 and 9e43 were isolated in yields ranging from
38% to 79%.
Since 2-chloropyridine and, above all, 2,4-dichloropyrim-
idine are p-deficient chloro substrates, a reaction mecha-
nism involving a nucleophilic aromatic substitution by an
aryl group was suspected (Scheme 3, left). However, this
was discarded since the reaction between lithium tri(2-
benzofuryl)zincate and 2,4-dichloropyrimidine per-
formed without catalyst did not allow the cross-coupling
product 2a to be formed. A mechanism involving an addi-
tion–elimination of an organopalladate as first step can be
proposed alternatively (Scheme 3, right) though this is un-
likely if one considers the poor reactivity of 2,4-dichloro-
pyrimidine towards an arylzincate.44
Cl
ArPd Cl
ArPd–
N
N
Ar–
N
Cl
N
Cl
Ar Cl
N
– Cl–
Since the addition of 1,2-dimethoxyethane (DME) to the
reaction mixture proved to improve yields of Negishi
cross-coupling products,37 the palladium-catalyzed reac-
tion between lithium tri(2-benzofuryl)zincate and 2-chlo-
ropyridine was performed in the presence of five
equivalents of this cosolvent to give the pyridylbenzofu-
ran 2b in a slightly higher yield (76%, Table 1, entry 2).
N
Cl
PdAr
Ar
N
– Cl–
– Pd(0)
N
N
Cl
N
Cl
Scheme 3 Ligands are omitted for clarity
Nevertheless, even using these improved conditions, the
coupling between the N,N-diethylbenzamide lithium zin-
cate and 2-chloropyridine failed, a result probably due to
the size of the diethylamide group.
A more classical pathway is an oxidative addition of 2,4-
dichloropyrimidine to a Pd(0) complex followed by trans-
metalation by the nucleophile (Scheme 4, right). Howev-
er, the oxidative addition could take place either at the 2-
or 4-position. To test the regioselectivity of the oxidative
addition, the reaction of 2,4-dichloropyrimidine (0.01
In addition, when heteroaryl chlorides were replaced by
phenyl chlorides the reactions also failed, even in the pres-
ence of electron-withdrawing groups at the phenyl 4-posi-
tion. We therefore turned to the corresponding bromides38
which have lower carbon–halogen bond-dissociation en-
ergies,39 and investigated the access to functionalized 2-
phenylthiophenes (Scheme 2).
1
mmol) with Pd(PPh3)4 (0.01 mmol) was followed by H
NMR (250 MHz, TMS) and 31P NMR (101 MHz, H3PO4)
in CD2Cl2 at 27 °C. Two 1H signals of equal magnitude at
d = 6.73 (dt, JHH = 5.1 Hz, JPH = 1.2 Hz, H5) and 6.58 (d,
JHH = 5.1 Hz, H6) associated to a 31P singlet at d = 22.0
characterized the formation of complex 17 by oxidative
addition at the 4-position, in agreement with the regiose-
lectivity observed in the catalytic reactions.
The reaction of lithium tri(2-thienyl)zincate with 4-bromo-
anisole afforded the expected coupling product 9b,40 but
in a poor 10% yield due to the competitive formation of
2,2¢-bisthiophene (40–50% yield). With bromobenzenes
containing electron-withdrawing groups at the 4-position,
such as 2-bromo-4-nitrobenzene, methyl 4-bromoben-
zoate, and 4-bromobenzonitrile, the expected derivatives
It should be noted that the presence of a lithium zincate
could also allow the formation of an arylpalladate
– 45
ArPd(0)L2 , which could regioselectively react with 2,4-
Synlett 2008, No. 12, 2955–2960 © Thieme Stuttgart · New York

2958
A. Seggio et al.
LETTER
(2) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58,
9633; and references cited therein.
Cl
N
PdCl
N
Pd(0)
(3) Stille, J. K. Angew. Chem. Int. Ed. Engl. 1986, 25, 508.
(4) (a) Negishi, E.-i.; King, A. O.; Okukado, N. J. Org. Chem.
1977, 42, 1821. (b) Negishi, E.-i. Acc. Chem. Res. 1982, 15,
340. (c) Negishi, E.-i. Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley-VCH:
New York, 1998, Chap. 1.
(5) (a) Erdik, E. Organozinc Reagents in Organic Synthesis;
CRC Press: New York, 1996. (b) Organozinc Reagents;
Knochel, P.; Jones, P., Eds.; Oxford University Press:
Oxford, 1999.
Cl
Ar Pd–
ArPd–
N
Cl
N
Cl
N
Ar– – Cl–
N
Cl
Ar
N
PdAr
N
– Pd(0)
– Pd(0)Cl–
N
Cl
N
Cl
(6) (a) Active Metals; Fürstner, A., Ed.; VCH: Weinheim, 1996.
(b) Majid, T. N.; Knochel, P. Tetrahedron Lett. 1990, 31,
4413. (c) Zhu, L.; Wehmeyer, R. M.; Rieke, R. D. J. Org.
Chem. 1991, 56, 1445.
(7) (a) Gosmini, C.; Lasry, S.; Nédélec, J.-Y.; Périchon, J.
Tetrahedron 1998, 54, 1289. (b) Kazmierski, I.; Gosmini,
C.; Paris, J.-M.; Périchon, J. Tetrahedron Lett. 2003, 44,
6417.
Cl
Ph3P Pd PPh3
5
N
6
N
Cl
(8) Mutule, I.; Suna, E. Tetrahedron 2005, 61, 11168.
(9) Gauthier, D. R. Jr.; Szumigala, R. H. Jr.; Dormer, P. G.;
Armstrong, J. D. III.; Volante, R. P.; Reider, P. J. Org. Lett.
2002, 4, 375.
17
Scheme 4 Ligands are omitted for clarity
(10) Miller, J. A.; Farrell, R. P. Tetrahedron Lett. 1998, 39, 7275.
(11) (a) Kondo, Y.; Takazawa, N.; Yamazaki, C.; Sakamoto, T.
J. Org. Chem. 1994, 59, 4717. (b) Kondo, Y.; Komine, T.;
Fujinami, M.; Uchiyama, M.; Sakamoto, T. J. Comb. Chem.
1999, 1, 123. (c) Uchiyama, M.; Furuyama, T.; Kobayashi,
M.; Matsumoto, Y.; Tanaka, K. J. Am. Chem. Soc. 2006,
128, 8404.
(12) (a) Kondo, Y.; Shilai, M.; Uchiyama, M.; Sakamoto, T.
J. Am. Chem. Soc. 1999, 121, 3539. (b) L’Helgoual’ch,
J. M.; Seggio, A.; Chevallier, F.; Yonehara, M.; Jeanneau,
E.; Uchiyama, M.; Mongin, F. J. Org. Chem. 2008, 73, 177 .
Concerning the generation of(hetero)aryl zincates by
deprotonation, see also: (c) Mulvey, R. E. Organometallics
2006, 25, 1060. (d) Mulvey, R. E.; Mongin, F.; Uchiyama,
M.; Kondo, Y. Angew. Chem. Int. Ed. 2007, 46, 3802.
(13) Benzo[b]furan has previously been metalated using tert-
butyllithium in diethyl ether at –78 °C: Zhang, H.; Larock,
R. C. J. Org. Chem. 2002, 67, 7048.
(14) For nickel-catalyzed cross-couplings of arylzinc compounds
with aryl chlorides, see: (a) House, H. O.; Ghali, N. I.;
Haack, J. L.; VanDerveer, D. J. Org. Chem. 1980, 45, 1807.
(b) Lebedev, S. A.; Sorokina, R. S.; Berestova, S. S.; Petrov,
E. S.; Beletskaya, I. P. Bull. Acad. Sci. USSR, Div. Chem.
Sci. 1986, 35, 620. (c) Miller, J. A.; Farrell, R. P.
Tetrahedron Lett. 1998, 39, 6441. (d) Lipshutz, B. H.;
Blomgren, P. A.; Kim, S.-K. Tetrahedron Lett. 1999, 40,
197. (e) Lipshutz, B. H.; Blomgren, P. A. J. Am. Chem. Soc.
1999, 121, 5819. (f) Walla, P.; Kappe, C. O. Chem.
Commun. 2004, 564. (g) Gavryushin, A.; Kofink, C.;
Manolikakes, G.; Knochel, P. Tetrahedron 2006, 62, 7521.
For nickel-catalyzed cross-couplings of arylzinc compounds
with aryl bromides, see for example: (h) Wu, X.; Rieke,
R. D. J. Org. Chem. 1 995, 60, 6658.
dichloropyrimidine by oxidative addition as depicted in
Scheme 4 (left).
In conclusion, we have described the synthesis of unsym-
metrical heterobiaryls using palladium-catalyzed cross-
coupling reactions of lithium triorganozincates, which
have been prepared through one-pot deprotonative lithiation–
transmetalation using non-hygroscopic ZnCl2·TMEDA.
Typical Procedure: Preparation of 2-(2-benzo[b]thienyl)pyri-
dine (8b)
To a stirred and cooled (–75 °C) solution of benzo[b]thiophene (5,
0.54 g, 4.0 mmol) in dry THF (5 mL) under argon was added
BuLi (about 1.6 M hexanes solution, 4.0 mmol) and, 1 h later,
ZnCl2·TMEDA46 (0.33 g, 1.3 mmol). The mixture was slowly
warmed to r.t. (1 h) before addition of 2-chloropyridine (0.45 g, 4.0
mmol), PdCl2 (14 mg, 80 mmol), and dppf (44 mg, 80 mmol). The
mixture was cooled before addition of H2O (0.5 mL) and EtOAc (50
mL), dried over MgSO4, and the solvents were removed under re-
duced pressure. Compound 8b was isolated by chromatographic pu-
rification on silica gel column (eluent: heptane–CH2Cl2, 50:50 to
30:70) as a white powder (1.0 g, 81%).28
Acknowledgment
We gratefully acknowledge the financial support of Région Breta-
gne, CNRS and GlaxoSmithKline (A.S.). We thank Michel Vaultier
for his contribution to this study.
(15) For discussions on the advantages of palladium over nickel,
see refs. 4c and 5b.
(16) Quintin, J.; Franck, X.; Hocquemiller, R.; Figadère, B.
Tetrahedron Lett. 2002, 43, 3547.
(17) Fürstner, A.; Leitner, A.; Méndez, M.; Krause, H. J. Am.
Chem. Soc. 2002, 124, 13856.
(18) (a) Negishi, E.-i.; Luo, F.-T.; Frisbee, R.; Matsushita, H.
Heterocycles 1982, 18, 117. For palladium-catalyzed cross-
couplings of arylzinc compounds with aryl chlorides, see for
example: (b) Bracher, F.; Hildebrand, D. Tetrahedron 1994,
References and Notes
(1) (a) Stanforth, S. P. Tetrahedron 1998, 54, 263. (b) Hassan,
J.; Sévignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem.
Rev. 2002, 102, 1359. (c) Handbook of Organopalladium
Chemistry for Organic Synthesis, Vol. 1; Negishi, E.-i., Ed.;
Wiley-Interscience: New York, 2002, Chap. 3.
(d) Chinchilla, R.; Nájera, C.; Yus, M. Chem. Rev. 2004,
104, 2667. (e) Chinchilla, R.; Nájera, C.; Yus, M. Arkivoc
2007, (x), 152.
Synlett 2008, No. 12, 2955–2960 © Thieme Stuttgart · New York

LETTER
50, 12329. (c) Amat, M.; Hadida, S.; Pshenichnyi, G.;
Synthesis of Unsymmetrical Heterobiaryls
2959
(30) Compound 10: pale yellow powder; mp 67 °C. The spectral
data were found identical to those previously described.
See: (a) Constable, E. C.; Sousa, L. R. J. Organomet. Chem.
1992, 427, 125. (b) Bayh, O.; Awad, H.; Mongin, F.;
Hoarau, C.; Trécourt, F.; Quéguiner, G.; Marsais, F.; Blanco,
F.; Abarca, B.; Ballesteros, R. Tetrahedron 2005, 61, 4779.
(31) N-Boc pyrrole has previously been metalated using LiTMP
in THF at –75 °C. See: Hasan, I.; Marinelli, E. R.; Lin, L.-C.
C.; Fowler, F. W.; Levy, A. B. J. Org. Chem. 1981, 46, 157.
(32) Compound 12: yellow oil. The spectral data were found
identical to those previously described: Semmelback, M. F.;
Chlenov, A.; Douglas, M. J. Am. Chem. Soc. 2005, 127,
7759.
Bosch, J. J. Org. Chem. 1997, 62, 3158. (d) Herrmann,
W. A.; Bohm, V. P. W.; Reisinger, C.-P. J. Organomet.
Chem. 1999, 576, 23. (e) Dai, C.; Fu, G. C. J. Am. Chem.
Soc. 2001, 123, 2719. (f) Simkovsky, N. M.; Ermann, M.;
Roberts, S. M.; Parry, D. M.; Baxter, A. D. J. Chem. Soc.,
Perkin Trans. 1 2002, 1847. (g) Li, G. Y. J. Org. Chem.
2002, 67, 3643. (h) Lützen, A.; Hapke, M.; Staats, H.;
Bunzen, J. Eur. J. Org. Chem. 2003, 3948. (i) Stanetty, P.;
Schnürch, M.; Mihovilovic, M. D. Synlett 2003, 1862.
(j) Milne, J.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126,
13028. (k) Switzer, C.; Sinha, S.; Kim, P. H.; Heuberger,
B. D. Angew. Chem. Int. Ed. 2005, 44, 1529.
(19) For the use of PdCl2(dppf) as a highly effective catalyst for
the coupling of organozinc reagents, see: Hayashi, T.;
Konishi, M.; Kobri, Y.; Kumada, M.; Higuchi, T.; Hirotsu,
K. J. Am. Chem. Soc. 1984, 106, 158.
(20) (a) Compound 2a: pale yellow powder; mp 186 °C. The
spectral data were found identical to those previously
described, see ref. 20b. 13C NMR (50 MHz, CD3COCD3):
d = 110.9, 112.4, 115.4, 123.5, 124.7, 128.1, 128.7, 152.2,
156.5, 158.6, 161.8, 162.1. (b) Strekowski, L.; Harden,
M. J.; Grubb, W. B. III.; Patterson, S. E.; Czarny, A.;
Mokrosz, M. J.; Cegla, M. T.; Wydra, R. L. J. Heterocycl.
Chem. 1990, 27, 1393.
(33) Concerning the direct lithiation of anisole, see: Shirley,
D. A.; Johnson, J. R.; Hendrix, J. P. J. Organomet. Chem.
1968, 11, 209.
(34) Compound 14: colorless oil. The spectral data were found
identical to those previously described: Mongin, F.;
Mojovic, L.; Guillamet, B.; Trécourt, F.; Quéguiner, G.
J. Org. Chem. 2002, 67, 8991.
(35) Compound 16: beige powder; mp <50 °C. 1H NMR (200
MHz, CDCl3): d = 7.25–7.37 (m, 2 H), 7.72–7.91 (m, 2 H),
8.25 (d, J = 3.2 Hz, 1 H), 8.47–8.58 (m, 1 H), 8.72 (d, J = 4.8
Hz, 1 H). 13C NMR (50 MHz, CDCl3): d = 122.1 (d, J = 4.3
Hz), 122.6, 123.2, 124.3 (d, J = 10.4 Hz), 136.8, 141.6 (d,
J = 3.8 Hz), 147.7 (d, J = 15.1 Hz), 150.0, 151.4 (d, J = 6.8
Hz), 160.9 (d, J = 241 Hz). HRMS: m/z calcd for C10H7N2F
[M+]: 174.0593; found: 174.0595.
(21) Slightly lower cross-coupling yields have been observed
with higher order zincate compared with lithium
triorganozincate, see ref. 9.
(22) No reaction takes place in the absence of transition metal.
Note that product 2a has previously been obtained by
addition of 2-benzofuryllithium at the 4-position of 2-
chloropyrimidine followed by rearomatization using DDQ
in 38% yield, see ref. 20b.
(23) Compound 2b: white powder; mp 88 °C. The spectral data
were found identical to those previously described. See:
Mongin, F.; Bucher, A.; Bazureau, J. P.; Bayh, O.; Awad,
H.; Trécourt, F. Tetrahedron Lett. 2005, 46, 7989.
(24) Ramanathan, V.; Levine, R. J. Org. Chem. 1962, 27, 1216.
(25) Compound 4: white powder; mp 88 °C. The spectral data
were found identical to those previously described, see. ref.
20b. 13C NMR (50 MHz, CDCl3): d = 113.1, 113.1, 114.5,
146.2, 150.4, 158.1, 159.9, 161.7.
(26) Benzo[b]thiophene has previously been metalated using
butyllithium in THF at 0 °C, see: (a) Jen, K.-Y.; Cava, M. P.
J. Org. Chem. 1983, 48, 1449. Thiophene has previously
been metalated using butyllithium in THF at temperatures
between –20 °C and r.t., see: (b) Surry, D. S.; Fox, D. J.;
MacDonald, S. J. F.; Spring, D. R. Chem. Commun. 2005,
2589.
(27) Compound 8a: pale yellow powder; mp 198 °C. The spectral
data were found identical to those previously described, see
ref. 20b. 13C NMR (50 MHz, CDCl3): d = 114.5, 122.9,
125.2, 125.3, 126.3, 126.9, 139.8, 140.1, 141.8, 159.7,
161.9, 162.3.
(36) For the deprotonation of 2-fluoropyridine using a lithium
amide, see: (a) Gribble, G. W.; Saulnier, M. G. Heterocycles
1993, 35, 151. (b) Estel, L.; Marsais, F.; Quéguiner, G.
J. Org. Chem. 1988, 53, 2740.
(37) See, for example: Riguet, E.; Alami, M.; Cahiez, G.
Tetrahedron Lett. 1997, 38, 4397.
(38) For palladium-catalyzed cross-couplings of arylzinc
compounds with aryl bromides, see for example:
(a) Amatore, C.; Jutand, A.; Negri, S.; Fauvarque, J.-F.
J. Organomet. Chem. 1990, 390, 389. (b) Bumagin, N. A.;
Sokolova, A. F.; Beletskaya, I. P. Russ. Chem. Bull. 1993,
42, 1926. (c) Borner, R. C.; Jackson, R. F. W. J. Chem. Soc.,
Chem. Commun. 1994, 845. (d) Goldfinger, M. B.;
Crawford, K. B.; Swager, T. M. J. Am. Chem. Soc. 1997,
119, 4578. (e) Hargreaves, S. L.; Pilkington, B. L.; Russell,
S. E.; Worthington, P. A. Tetrahedron Lett. 2000, 41, 1653.
(f) Loren, J. C.; Siegel, J. S. Angew. Chem. Int. Ed. 2001, 40,
754. (g) Alami, M.; Peyrat, J.-F.; Belachmi, L.; Brion, J.-D.
Eur. J. Org. Chem. 2001, 4207. (h) Karig, G.; Thasana, N.;
Gallagher, T. Synlett 2002, 808. (i) Balle, T.; Andersen, K.;
Vedsø, P. Synthesis 2002, 1509. (j) Kondolff, I.;Doucet, H.;
Santelli, M. Organometallics 2006, 25, 5219. (k) Akao, A.;
Tsuritani, T.; Kii, S.; Sato, K.; Nonoyama, N.; Mase, T.;
Yasuda, N. Synlett 2007, 31.
(39) Legault, C. Y.; Garcia, Y.; Merlic, C. A.; Houk, K. N. J. Am.
Chem. Soc. 2007, 129, 12664.
(28) Compound 8b: white powder; mp 126 °C. The physical and
spectral data were found identical to those of a commercial
sample (Aldrich).
(40) Compound 9b: beige powder; mp 104 °C. The spectral data
were found identical to those previously described:
Takahashi, K.; Suzuki, T.; Akiyama, K.; Ikegami, Y.;
Fukazawa, Y. J. Am. Chem. Soc. 1991, 113, 4576.
(41) Compound 9c: yellow powder; mp 135 °C. The spectral data
were found identical to those previously described: Li, J.-H.;
Zhu, Q.-M.; Xie, Y.-X. Tetrahedron 2006, 62, 10888.
(42) Compound 9d: white powder; mp 134 °C. The spectral data
were found identical to those previously described: Sieber,
F.; Wentworth, P. Jr.; Janda, K. D. J. Comb. Chem. 1999, 1,
540.
(29) (a) Compound 9a: white powder; mp 124 °C. The physical
data were found identical to those previously described in
ref. 29b. 1H NMR (200 MHz, CD3COCD3): d = 7.17 (dd,
J = 7.5, 5.7 Hz, 1 H), 7.46 (d, J = 7.8 Hz, 1 H), 7.59 (dd,
J = 7.5, 1.5 Hz, 1 H), 7.82 (dd, J = 5.7, 1.5 Hz, 1 H), 8.53 (d,
J = 8.1 Hz, 1 H). 13C NMR (50 MHz, CD3COCD3): d =
113.7, 128.8, 129.2, 131.8, 140.5, 159.5, 161.7, 162.0.
(b) Brown, D. J.; Cowden, W. B.; Strekowski, L. Aust. J.
Chem. 1982, 35, 1209–1214.
Synlett 2008, No. 12, 2955–2960 © Thieme Stuttgart · New York

2960
A. Seggio et al.
LETTER
(43) Compound 9e: white solid; mp 88 °C. The spectral data were
found identical to those previously described: Denmark,
S. E.; Baird, J. D. Org. Lett. 2006, 8, 793.
(45) Amatore, C.; Carré, E.; Jutand, A.; Tanaka, H.; Quinghua,
R.; Torii, S. Chem. Eur. J. 1996, 2, 957.
(46) Isobe, M.; Kondo, S.; Nagasawa, N.; Goto, T. Chem. Lett.
1977, 679.
(44) Bonnet, V.; Mongin, F.; Trécourt, F.; Quéguiner, G.;
Knochel, P. Tetrahedron Lett. 2001, 42, 5717.
Synlett 2008, No. 12, 2955–2960 © Thieme Stuttgart · New York