Cross-coupling reactions of phenylmagnesium halides with fluoroazines and fluorodiazines

Article abstract of DOI:10.1021/jo026136s

The first nickel-catalyzed cross-coupling reactions between fluoroarenes and aryl organometallics using commercially available ligands are described. The nickel-catalyzed cross-coupling reactions between aryl Grignard reagents and fluoroazines and -diazin

Full text of DOI:10.1021/jo026136s

Cr oss-Cou p lin g Rea ction s of P h en ylm a gn esiu m Ha lid es w ith
F lu or oa zin es a n d F lu or od ia zin es
Florence Mongin,* Ljubica Mojovic, Beno ˆı t Guillamet, Fran c¸ ois Tr e´ court, and Guy Qu e´ guiner
Laboratoire de Chimie Organique Fine et H e´ t e´ rocyclique, IRCOF, UMR 6014, Place E. Blondel,
BP 08, 76131 Mont-Saint-Aignan C e´ dex, France
florence.mongin@insa-rouen.fr
Received J uly 3, 2002
The first nickel-catalyzed cross-coupling reactions between fluoroarenes and aryl organometallics
using commercially available ligands are described. The nickel-catalyzed cross-coupling reactions
between aryl Grignard reagents and fluoroazines and -diazines occurred in THF at room
temperature using commercially available 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphos-
phino)propane, or 1,1′-bis(diphenylphosphino)ferrocene as ligand. Various fluoro substrates such
as pyridines, diazines (pyrazine, pyridazine), benzodiazines (quinoxaline), and quinolines were
successfully involved in the reaction with phenylmagnesium halides (phenylmagnesium chloride,
2
-methoxyphenylmagnesium bromide, and 4-methoxyphenylmagnesium bromide). The conditions
used also allowed the cross-coupling of 4-fluorotoluene with arylmagnesium reagents.
In tr od u ction
The activation of carbon-fluorine bonds is of impor-
tance since this reaction contributes to the fundamental
understanding of the reactivity of such very stable
bonds. A variety of methods for the activation of carbon-
We describe here the first nickel-catalyzed cross-
couplings between fluoroarenes and aryl organometallics
using common ligands, such reactions being only known
using N-heterocyclic carbene ligands.1
8
fluorine bonds under mild conditions by stoichiometric
amounts of soluble transition-metal complexes have been
9
Interest in azine and diazine natural products either
for pharmaceuticals or as building blocks for various
applications within materials science and supramolecular
chemistry has led to extensive efforts devoted to a variety
established in the last two decades. However, homogen-
eous stoichiometric or catalytic transformations of aro-
matic fluorides are mainly limited to defluorination
reactions.10 Few examples have been reported in which
carbon-fluorine bond cleavage has been followed by
carbon-carbon bond formation.11 Since the development
2
of synthetic methodologies. Transition-metal-catalyzed
cross-couplings have proven to be an important method
for preparing a number of complex heterocycles. In the
of the nickel-catalyzed cross-coupling of Grignard re-
agents (Kharasch) in the early 1970s,7
c,12
very few reac-
3
,4
3,5
azine and diazine series, several Negishi, Suzuki,
Stille,3
,5b,d,6
and Kharasch cross-coupling reactions have
3,7
(
5) (a) Ishikura, M.; Kamada, M.; Terashima, M. Synthesis 1984,
already been reported. The usefulness of cross-coupling
chemistry to form unsymmetrical biaryls has been driven
by the development of catalyst systems that have suc-
cessively allowed the activation of aryl iodides, bromides,
and chlorides, even at ambient temperature.
9
36. (b) Godard, A.; Turck, A.; Pl e´ , N.; Marsais, F.; Qu e´ guiner, G.
Trends Heterocycl. Chem. 1993, 3, 19. (c) Miyaura, N.; Suzuki, A. Chem.
Rev. 1995, 95, 2457. (d) Godard, A.; Marsais, F.; Pl e´ , N.; Tr e´ court, F.;
Turck, A.; Qu e´ guiner, G. Heterocycles 1995, 40, 1055. (e) Suzuki, A. J .
Organomet. Chem. 1999, 576, 147. (f) Schomaker, J . M.; Thomas, T.
J . J . Org. Chem. 2001, 66, 7125. (g) Bouillon, A.; Lancelot, J .-C.; Collot,
V.; Bovy, P. R.; Rault, S. Tetrahedron 2002, 58, 2885. (h) Bouillon, A.;
Lancelot, J .-C.; Collot, V.; Bovy, P. R.; Rault, S. Tetrahedron 2002, 58,
3323.
(6) (a) Stille, J . K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (b)
Schubert, U. S.; Eschbaumer, C.; Heller, M. Org. Lett. 2000, 2, 3373.
(c) Fallahpour, R.-A. Synthesis 2000, 1138. (d) Mathieu, J .; Gros, Ph.;
Fort, Y. Tetrahedron Lett. 2001, 42, 1879.
*
To whom correspondence should be addressed. Phone: + 33 (0) 2
5 52 24 82. Fax: + 33 (0) 2 35 52 29 62.
1) B o¨ hm, V. P. W.; Gst o¨ ttmayr, C. W. K.; Weskamp, T.; Herrmann,
W. A. Angew. Chem., Int. Ed. 2001, 40, 3387.
2) (a) Katritzky, A. R.; Rees, C. W. Comprehensive Heterocyclic
3
(
(
Chemistry; Pergamon Press: New York, 1984; Vol. 2. (b) Qu e´ guiner,
G.; Marsais, F.; Snieckus, V.; Epsztajn, J . Adv. Heterocycl. Chem. 1991,
(7) (a) Pridgen, L. N. J . Heterocycl. Chem. 1975, 12, 443. (b) Takei,
H.; Miura, M.; Sugimura, H.; Okamura, H. Chem. Lett. 1979, 1447.
(c) Tamao, K.; Kodama, S.; Nakajima, I.; Kumada, M.; Minato, A.;
Suzuki, K. Tetrahedron 1982, 38, 3347. (d) Sengupta, S.; Leite, M.;
Soares Raslan, D.; Quenelle, C.; Snieckus, V. J . Org. Chem. 1992, 57,
4066. (e) Albers, W. M.; Canters, G. W.; Reedijk, J . Tetrahedron 1995,
51, 3895. (f) Meth-Cohn, O.; J iang, H. J . Chem. Soc., Perkin Trans. 1
1998, 3737. (g) Diederich, F.; Stang, P. J . Metal-Catalyzed Cross-
Coupling Reactions; Wiley-VCH: Weinheim, Germany, 1998. (h) B o¨ hm,
V. P. W.; Weskamp, T.; Gst o¨ ttmayr, C. W. K.; Herrmann, W. A. Angew.
Chem., Int. Ed. 2000, 39, 1602. (i) Bonnet, V.; Mongin, F.; Tr e´ court,
F.; Qu e´ guiner, G.; Knochel, P. Tetrahedron Lett. 2001, 42, 5717. (j)
Bonnet, V.; Mongin, F.; Tr e´ court, F.; Qu e´ guiner, G.; Knochel, P.
Tetrahedron 2002, 58, 4429. (k) Bonnet, V.; Mongin, F.; Tr e´ court, F.;
Breton, G.; Marsais, F.; Knochel, P.; Qu e´ guiner, G. Synlett 2002, 1008.
(8) Hudlicky, M. Chemistry of Organic Fluorine Compounds; Pren-
tice-Hall: New York, 1992.
5
2, 187. (c) Mongin, F.; Qu e´ guiner, G. Tetrahedron 2001, 57, 4059. (d)
Turck, A.; Pl e´ , N.; Mongin, F.; Qu e´ guiner, G. Tetrahedron 2001, 57,
489.
3) Stanforth, S. P. Tetrahedron 1998, 54, 263 and references
therein.
4
(
(
4) (a) Negishi, E.-i.; King, A. O.; Okukado, N. J . J . Org. Chem. 1977,
4
2, 1821. (b) Sakamoto, T.; Kondo, Y.; Murata, Y.; Yamanata, H.
Tetrahedron 1993, 43, 9713. (c) Tr e´ court, F.; Gervais, B.; Mallet, M.;
Qu e´ guiner, G. J . Org. Chem. 1996, 61, 1673. (d) Tr e´ court, F.; Gervais,
B.; Mongin, O.; Le Gal, C.; Mongin, F.; Qu e´ guiner, G. J . Org. Chem.
1
998, 63, 2892. (e) Hargreaves, S. L.; Pilkington, B. L.; Russel, S. E.;
Worthington, P. A. Tetrahedron Lett. 2000, 41, 1653. (f) Karig, G.;
Spencer, J . A.; Gallagher, T. Org. Lett. 2001, 3, 835. (g) Loren, J . C.;
Siegel, J . S. Angew. Chem., Int. Ed. 2001, 40, 754. (h) Karig, G.;
Thasana, N.; Gallagher, T. Synlett 2002, 808.
1
0.1021/jo026136s CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/15/2002
J . Org. Chem. 2002, 67, 8991-8994
8991

Mongin et al.
tions with fluoro substrates have been reported. The
nickel-mediated cross-coupling reactions of fluorobenzene
TABLE 1. Cr oss-Cou p lin g of P h en ylm a gn esiu m Ha lid es
w ith F lu or oa zin es a n d F lu or od ia zin es
1
3
with alkylmagnesium chlorides were reported in 1973
and 1999.1 Much more recently, the selective cross-
coupling of aryl fluorides with arylmagnesium halides at
room temperature, mediated by the complex bis[1,3-di-
1h
(
2′,6′-diisopropylphenyl)imidazolin-2-ylidene]nickel(0), has
1
been reported.
Under palladium catalysis, cross-coupling reactions
between arylmagnesium halides and aryl chlorides,
7
f,I-k,14
bromides, or iodides are possible at rt.
Nickel,
which is harder than palladium, was most often chosen
for chlorides7
d,h,k
and fluorides,
1,11h,13
which are harder
than bromides and iodides. So we turned to nickel
catalysis for the reactions between phenylmagnesium
halides and fluoroazines and -diazines. For the activation
of C-F bonds, the low-valent metal must be combined
with a strongly Lewis basic, electron-donating, and
sterically demanding ligand.15 The cross-coupling of
phenylmagnesium halides with fluorobenzenes was found
to be feasible using N-heterocyclic carbene ligands.1
Nevertheless, the use of π-deficient substrates, for which
the oxidative addition step is easier, led us to consider
the use of commercially available ligands such as 1,2-
bis(diphenylphosphino)ethane (dppe), 1,3-bis(diphenylphos-
phino)propane (dppp), and 1,1′-bis(diphenylphosphino)-
ferrocene (dppf). We therefore decided to study the cross-
coupling reaction of phenylmagnesium halides with
fluoroazines and -diazines using these commercially
available ligands.
(
9) (a) Kiplinger, J . L.; Richmond, T. G.; Osterberg, C. E. Chem. Rev.
1
994, 94, 373. (b) Burdeniuc, J .; J edlicka, B.; Crabtree, R. H. Chem.
Ber./ Recl. 1997, 130, 145. (c) Murphy, E. F.; Murugavel, R.; Roesky,
H. W. Chem. Rev. 1997, 97, 3425. (d) Ishii, Y.; Chatani, N.; Yorimitsu,
S.; Murai, S. Chem. Lett. 1998, 157. (e) Richmond, T. G. In Topics in
Organometallic Chemistry; Murai, S., Ed.; Springer: New York, 1999;
Vol. 3, pp 243-269. (f) Braun, T.; Foxon, S. P.; Perutz, R. N.; Walton,
P. H. Angew. Chem., Int. Ed. 1999, 38, 3326. (g) Braun, T.; Cronin, L.;
Higgitt, C. L.; McGrady, J . E.; Perutz, R. N.; Reinhold: M. New J .
Chem. 2001, 25, 19. (h) J akt, M.; J ohannissen, L.; Rzepa, H. S.;
Widdowson, D. A.; Wilhelm, R. J . Chem. Soc., Perkin Trans. 2 2002,
5
76.
10) (a) Aizenberg, M.; Milstein, D. Science 1994, 265, 359. (b)
Deacon, G. B.; Forsyth, C. M.; Sun, J . Tetrahedron Lett. 1994, 35, 1095.
c) Aizenberg, M.; Milstein, D. J . Am. Chem. Soc. 1995, 117, 8674. (d)
(
(
Kiplinger, J . L.; Richmond, T. G. Chem. Commun. 1996, 1115. (e)
Kiplinger, J . L.; Richmond, T. G. J . Am. Chem. Soc. 1996, 118, 1805.
(
(
f) Burdeniuc, J .; Crabtree, R. H. J . Am. Chem. Soc. 1996, 118, 2525.
g) Burdeniuc, J .; Crabtree, R. H. Organometallics 1998, 17, 1582. (h)
Young J r., R. J .; Grushin, V. V. Organometallics 1999, 18, 294. (i) Yang,
H.; Gao, H.; Angelici, R. J . Organometallics 1999, 18, 2285. (j)
Richmond, T. G. Angew. Chem., Int. Ed. 2000, 39, 3241.
(
11) (a) Rieke, R. D.; Bales, S. E. J . Chem. Soc., Chem. Commun.
1
973, 879. (b) Ferraris, D.; Cox, C.; Anand, R.; Lectka, T. J . Am. Chem.
a
Isolated yields based on the fluoro substrate. b Using PhMgCl.
Soc. 1997, 119, 4319. (c) Sung, K.; Lagow, R. J . J . Chem. Soc., Perkin
Trans.1 1998, 637. (d) Atherton, M. J .; Holloway, J . H.; Hope, E. G.;
Saunders: G. C. J . Organomet. Chem. 1998, 558, 209. (e) Fujiwara,
M.; Ichikawa, J .; Okauchi, T.; Minami, T. Tetrahedron Lett. 1999, 40,
c
Using NiCl2(dppe). d The same result was obtained using Ni-
e
(
acac)2 (5 mol %) and dppe (5 mol %). Using 4-MeOPhMgBr.
f
Using 2-MeOPhMgBr. g Using Ni(acac)2 (5 mol %) and dppp (5
7
1
1
1
261. (f) Edelbach, B. L.; Kraft, B. M.; J ones, W. D. J . Am. Chem. Soc.
999, 121, 10327. (g) Widdowson, D. A.; Wilhem, R. Chem. Commun.
999, 2211. (h) Cahiez, G.; Lepifre, F.; Ramiandrasoa, P. Synthesis
999, 2138. (i) Wilhelm, R.; Widdowson, D. A. J . Chem. Soc., Perkin
Trans. 1 2000, 3808. (j) Braun, T.; Perutz, R. N.; Sladek, M. I. Chem.
Commun. 2001, 2254.
mol %). h Using Ni(acac)2 (5 mol %) and dppf (5 mol %).
Resu lts a n d Discu ssion
(
12) (a) Tamao, K.; Sumitani, K.; Kumada, M. J . Am. Chem. Soc.
The reaction of phenylmagnesium chloride with fluo-
ropyridines 1a -c was carried out in THF using [1,2-bis-
2
(diphenylphosphino)ethane]dichloronickel(II) [NiCl (dppe)]
as ligand. Under these conditions, the corresponding
phenylpyridines 2a -c were formed at ambient temper-
ature. Compared to well-defined NiCl (dppe), an in situ
2
1
972, 94, 4374. (b) Corriu, R. P. J .; Masse, J . P. J . Chem. Soc., Chem.
Commun. 1972, 144. (c) Tamao, K.; Sumitani, K.; Kiso, Y.; Zembayashi,
M.; Fujioka, A.; Kodama, S.; Nakajima, I.; Minato, A.; Kumada, M.
Bull. Chem. Soc. J pn. 1976, 49, 1958.
(
13) Kiso, Y.; Tamao, K.; Kumada, M. J . Organomet. Chem. 1973,
5
0, C12.
(
14) (a) Sekiya, A.; Ishikawa, N. J . Organomet. Chem. 1976, 118,
3
(
49. (b) Widdowson, D. A.; Zhang, Y. Z. Tetrahedron 1986, 42, 2111.
c) Huang, J .; Nolan, S. P. J . Am. Chem. Soc. 1999, 121, 9889.
(
catalyst system using bis(acetylacetonate)nickel(II) [Ni-
(acac) ] and dppe gave the same results (Table 1, entries
15) St u¨ rmer, R. Angew. Chem., Int. Ed. 1999, 38, 3307.
2
8
992 J . Org. Chem., Vol. 67, No. 25, 2002

Reactions of PhMgX with Azines and Diazines
TABLE 2. Cr oss-Cou p lin g of P h en ylm a gn esiu m Ha lid es
w ith 8
SCHEME 1
attributed to the poorer electron-donating ability of
phosphine ligands compared to N-heterocyclic car-
benes.18
Since fluoropyridines are known to react directly with
a
19
Isolated yields based on 4-fluorotoluene.
nucleophiles including aryllithiums, a reaction mech-
2
0
anism involving nucleophilic aromatic substitution was
suspected. However, it could be discarded since reactions
of the fluoro derivatives 1a ,b conducted without catalyst
did not allow the cross-coupling products 2a ,b to be
formed. Elimination-addition via azyne or diazyne in-
termediates21 was also unlikely considering the selectivity
of the reaction. Herrmann suggests a polar reaction
through oxidative addition22 instead of radical pathways
for the cross-coupling between arylmagnesium bromides
1
-3). To evaluate the scope of this reaction, experiments
employing different fluorides and phenylmagnesium
halides were conducted. 4-Methoxyphenylmagnesium
bromide was likewise successfully used in the reaction
with 1a ,b to afford compounds 3a ,b in good yields (Table
1
, entries 4 and 5). For more hindered 2-methoxyphen-
23
ylmagnesium bromide, dppp, which usually gives better
results than dppe, was employed and improved the yield
7
1
of the reaction (Table 1, entry 6). Due to their lower
LUMO levels, diazines and quinolines are more prone
to nucleophilic addition than pyridines. Nevertheless,
under the remarkably mild conditions used, no nucleo-
philic addition was observed and the reaction was also
feasible. Fluoropyrazine (4a ), 3-fluoro-6-phenylpyridazine
and fluorobenzenes. Another possibility is an addition-
elimination mechanism to the π-deficient fluoro substrate
(instead of oxidative addition followed by transmetala-
7
i
tion) for the reaction of compounds 1b,c and 4a -c. The
-
+
initial addition step of the “ate” species ArNiL2 ,MgX
(obtained by the reaction of NiL2 with the Grignard
reagent) to the fluoro substrate could lead to the stabil-
ized magnesium amide A, which could furnish the
intermediate B after elimination of magnesium halide
(4b), and 4-fluoro-2-phenylquinazoline (4c) were synthe-
sized from the corresponding chlorides according to
published procedures16 and submitted to cross-coupling
reactions with phenylmagnesium halides. The reactions
proceeded in yields comparable to those obtained in the
pyridine series (Table 1, entries 7-9). 3-Fluoroquinoline
(Scheme 1).
(
6a ) was also prepared17 and shown to react with phen-
Con clu sion
ylmagnesium chloride under the same reaction conditions
in an excellent yield. Concerning 6-fluoro-2-methylquino-
line (6b), the result was largely dependent on the ligand
used: dppe did not afford the coupled product 7b
satisfactorily, whereas dppf allowed the product to be
formed in a high yield (Table 1, entries 10 and 11).
We have described the first cross-coupling reactions of
fluoroazines and -diazines with aryl Grignard reagents.
These nickel-catalyzed reactions were accomplished in
THF at rt using commercially available ligands such as
dppe, dppp, and dppf. The conditions used were suitable
for the reaction of electron-poor fluoro substrates but also,
albeit to a lesser extent, for the reaction of fluoroben-
zenes.
With these efficient conditions in hand for the reaction
with activated, electron-poor fluoro substrates, we then
investigated the reaction with less activated 4-fluoro-
toluene (8). In this case, we have also shown that it is
advantageous to use dppp as ligand instead of dppe; the
reaction performed under these conditions afforded the
coupled products 9a ,b in medium to good yields (Table
(18) (a) Weskamp, T.; B o¨ hm, V. P. W.; Herrmann, W. A. J .
Organomet. Chem. 2000, 600, 12. (b) Bourissou, D.; Guerret, O.;
Gabba ¨ı , F. P.; Bertrand, P. Chem. Rev. 2000, 100, 39.
(19) DuPriest, M. T.; Schmidt, C. L.; Kuzmich, D.; Williams, S. B.
2
). The yields obtained in the benzene series are slightly
J . Org. Chem. 1986, 51, 2021.
(20) Terrier, F. Nucleophilic Aromatic Displacement, VCH: Wein-
heim, Germany, 1991.
1
lower than those reported by Herrmann. This may be
(
21) Hoffmann, R. W. Dehydrobenzene and Cycloalkynes, Academic
(16) (a) Pl e´ , N.; Turck, A.; Heynderickx, A.; Qu e´ guiner, G. Tetra-
Press: New York, 1967.
hedron 1998, 54, 4899. (b) Darabantu, M.; Lequeux, T.; Pommelet, J .-
C.; Pl e´ , N.; Turck, A. Tetrahedron 2001, 57, 739. (c) Svirskaya, P. I.;
Yedidia, V.; Leznoff, C. C. J . Heterocycl. Chem. 1985, 22, 149. (d)
Rutner, H.; Spoerri, P. E. J . Heterocycl. Chem. 1966, 3, 435.
(22) (a) Kumada, M. Pure Appl. Chem. 1980, 52, 669. (b) Herrmann,
W. A. In Applied Homogeneous Catalysis with Organometallic Com-
pounds; Cornils, B., Herrmann, W. A., Eds.; Wiley-VCH: Weinheim,
Germany, 1996; p 764.
(17) Roe, A.; Hawkins, G. F. J . Am. Chem. Soc. 1949, 71, 1785.
(23) Smith, G.; Kochi, J . K. J . Organomet. Chem. 1980, 198, 199.
J . Org. Chem, Vol. 67, No. 25, 2002 8993

Mongin et al.
Exp er im en ta l Section
2-P h en ylp yr a zin e (5a ). The procedure is as described for
a but using fluoropyrazine (98 mg, 1.0 mmol) instead of
2
Gen er a l P r oced u r es. The NMR spectra were recorded in
2 2 2
3-fluoropyridine: yield 81% (eluent CH Cl /Et O, 90:10); mp
1
13
28
CDCl
3
( H at 300 MHz and C at 75 MHz). The main IR
75 °C (lit. mp 73 °C). The physical and spectral data are
analogous to those previously described.2
9,7j
absorptions of the IR spectra are given.
Sta r tin g Ma ter ia ls. THF was distilled from benzophenone/
3
0
3-(4-Meth oxyp h en yl)-6-p h en ylp yr id a zin e (5b). The
procedure is as described for 2a but using 3-fluoro-6-phenylpyr-
idazine (174 mg, 1.0 mmol) instead of 3-fluoropyridine, and
4-methoxyphenylmagnesium bromide (1.2 mmol) in THF (2.4
Na. The water content of the solvents was estimated to be
lower than 45 ppm by the modified Karl Fischer method.24
Reactions were carried out under dry N
2
. Petrol refers to
1
6a
2 2 2
mL) instead of PhMgCl: yield 59% (eluent CH Cl /Et O, 95:
petroleum ether (bp 40-60 °C). Fluoropyrazine (4a), 3-fluoro-
1
6b
16a
5); mp 202-203 °C; H NMR (CDCl ) δ 4.89 (s, 3H), 7.00 (m,
1
6
-phenylpyridazine (4b), 4-fluoro-2-phenylquinazoline (4c),
3
1
7
2H), 7.45 (m, 3H), 7.83 (m, 2H), 8.07 (m, 4H); 13C NMR (CDCl3)
and 3-fluoroquinoline (6a ) have been prepared following
procedures described in the literature.
After the reaction, the organic layer was dried over MgSO ,
4
the solvents were evaporated under reduced pressure, and,
unless otherwise noted, the crude compound was chromato-
graphed on a silica gel (Geduran Si 60, 0.063-0.200 mm)
column (the eluent is given in the product description).
δ 55.8, 114.8, 123.9, 124.5, 127.1, 127.2, 128.7, 129.0, 129.4,
1
1
6
5
30.3, 136.6, 157.4; IR (KBr) ν 3053, 2967, 2936, 2837, 1608,
511, 1428, 1400, 1260, 1248, 1175, 1035, 1024, 821, 791, 749,
-
1
93 cm . Anal. Calcd for C17
.38; N, 10.68. Found: C, 77.69; H, 5.44; N, 10.45.
-(4-Meth oxyp h en yl)-2-qu in a zolin e (5c). The procedure
is as described for 2a but using 4-fluoro-2-phenylquinazoline
224 mg, 1.0 mmol) instead of 3-fluoropyridine, 4-methoxyphen-
ylmagnesium bromide (1.2 mmol) in THF (2.4 mL) instead of
PhMgCl, and Ni(acac) (13 mg, 50 µmol) and dppf (27 mg, 50
µmol) instead of NiCl (dppe): yield 67% (eluent CH Cl /petrol,
0:30). The physical and spectral data are analogous to those
14 2
H N O (262.31): C, 77.84; H,
4
3
2
-P h en ylp yr id in e (2a ). NiCl (dppe) (26 mg, 50 µmol) was
(
suspended in 3 mL of dry and degassed THF under an
atmosphere of dry nitrogen. After addition of 3-fluoropyridine
2
(87 µL, 97 mg, 1.0 mmol) the mixture was stirred for 5 min at
2
2
2
rt until catalysis was commenced by dropwise addition of
PhMgCl (1.2 mmol) in THF (0.60 mL). After 18 h at rt, the
solvent was removed under reduced pressure. The residue was
7
3
1
previously described.
-P h en ylqu in olin e (7a ).32 The procedure is as described
for 2a but using 3-fluoroquinoline (147 mg, 1.0 mmol) instead
of 3-fluoropyridine: yield 97% (eluent CH
NMR (CDCl ) δ 7.5 (m, 7H), 7.83 (dd, 1H, J ) 8.1, 1.0 Hz),
.08 (d, 1H, J ) 8.4 Hz), 8.25 (d, 1H, J ) 2.1 Hz), 9.13 (d, 1H,
J ) 2.3 Hz); C NMR (CDCl
29.6, 129.6, 129.8, 130.0, 133.7, 134.3, 138.2, 147.7, 150.3.
3
dissolved in concd NH
2% 2a (eluent CH Cl
4
OH (0.5 mL) and AcOEt (50 mL) to give
/Et O, 90:10). The physical and spectral
8
2
2
2
1
2 2 2
Cl /Et O, 95:5); H
data are analogous to those obtained for a commercial sample.
-P h en ylp yr id in e (2b). The procedure is as described for
a but using 2-fluoropyridine (87 µL, 97 mg, 1.0 mmol) instead
of 3-fluoropyridine: yield 64% (eluent CH Cl ). The physical
3
2
8
2
13
3
) δ 127.4, 127.8, 128.4, 128.5,
2
2
1
and spectral data are analogous to those obtained for a
commercial sample.
Anal. Calcd for C15H11N (205.26): C, 87.77; H, 5.40; N, 6.82.
Found: C, 87.82; H, 5.41; N, 6.69.
-Meth yl-6-p h en ylqu in olin e (7b). The procedure is as
described for 2a but using 6-fluoro-2-methylquinoline (161 mg,
4
-Meth yl-2-p h en ylp yr id in e (2c). The procedure is as
described for 2a but using 2-fluoro-4-methylpyridine (111 mg,
.0 mmol) instead of 3-fluoropyridine: yield 61% (eluent CH
Cl /Et O, 95:5). The physical and spectral data are analogous
to those obtained for a commercial sample.
-(4-Met h oxyp h en yl)p yr id in e (3a ). The procedure is
2
1
2
-
1
5
.0 mmol) instead of 3-fluoropyridine, and Ni(acac)
0 µmol) and dppf (27 mg, 50 µmol) instead of NiCl
2
(13 mg,
(dppe):
2
2
2
1
yield 91% (eluent CH
(CDCl ) δ 2.77 (s, 3H), 7.32 (d, 1H, J ) 8.4 Hz), 7.35 (m, 3H),
7.64 (m, 2H), 7.87 (m, 2H), 8.02 (d, 2H, J ) 8.8 Hz); C NMR
(CDCl
2 2 2
Cl /Et O, 90:10); mp 90-91 °C; H NMR
3
3
1
3
as described for 2a but using 4-methoxyphenylmagnes-
ium bromide (1.2 mmol) in THF (2.4 mL) instead of PhMgCl:
3
) δ 122.8, 125.6, 127.0, 127.7, 128.0, 129.3, 129.3, 129.5,
yield 80% (eluent CH
2
Cl
2
/Et
2
O, 85:15); mp 57 °C. The physical
136.8, 138.8, 140.7, 147.5, 159.3; IR (KBr) ν 3051, 2989, 2922,
and spectral data are analogous to those previously de-
1596, 1489, 1450, 1371, 1314, 1223, 1126, 892, 842, 815, 782,
2
5
-1
scribed.
-(4-Meth oxyp h en yl)p yr id in e (3b). The procedure is as
764, 701 cm . Anal. Calcd for C16H13N (219.29): C, 87.64; H,
2
5.98; N, 6.39. Found: C, 87.71; H, 6.10; N, 6.14.
described for 2a but using 2-fluoropyridine (87 µL, 97 mg, 1.0
mmol) instead of 3-fluoropyridine, and 4-methoxyphenylmag-
nesium bromide (1.2 mmol) in THF (2.4 mL) instead of
1-Meth yl-4-p h en ylben zen e (9a ). The procedure is as
described for 2a but using 4-fluorotoluene (110 µL, 110 mg,
1.0 mmol) instead of 3-fluoropyridine, and Ni(acac)
50 µmol) and dppp (21 mg, 50 µmol) instead of NiCl
yield 59% (eluent petrol/CH Cl , 90:10). The physical and
2
(13 mg,
PhMgCl: yield 89% (eluent CH
2
Cl
2
/Et
2
O, 95:5); mp 47-49 °C
2
(dppe):
2
6
(
lit. mp 47-50 °C). The physical and spectral data are
2
2
2
7
spectral data are analogous to those obtained for a commercial
sample.
analogous to those previously described.
2
-(2-Meth oxyp h en yl)p yr id in e (3c).26 The procedure is as
4
-Meth oxy-4′-m eth ylbip h en yl (9b). The procedure is as
described for 2a but using 4-fluorotoluene (110 µL, 110 mg,
.0 mmol) instead of 3-fluoropyridine, 4-methoxyphenylmag-
nesium bromide (1.2 mmol) in THF (2.4 mL) instead of
described for 2a but using 2-fluoropyridine (87 µL, 97 mg, 1.0
mmol) instead of 3-fluoropyridine, 2-methoxyphenylmagne-
sium bromide (1.2 mmol) in THF (1.2 mL) instead of PhMgCl,
1
and Ni(acac)
2
(13 mg, 50 µmol) and dppp (21 mg, 50 µmol)
(dppe): yield 79% (eluent CH Cl /Et O, 95:5);
) δ 3.87 (s, 3H), 7.02 (d, 1H, J ) 8.3 Hz), 7.09
t, 1H, J ) 7.5 Hz), 7.2 (m, 1H), 7.37 (td, 1H, J ) 7.8, 1.7 Hz),
PhMgCl, and Ni(acac)
2
(13 mg, 50 µmol) and dppp (21 mg, 50
instead of NiCl
2
2
2
2
1
µmol) instead of NiCl
2
(dppe): yield 59% (eluent petrol/CH -
2
H NMR (CDCl
3
Cl
, 90:10); mp 110-111 °C (lit.33 mp 107 °C). The physical
2
(
7
.7 (m, 3H), 8.71 (dd, 1H, J ) 4.3, 1.2 Hz); 1 C NMR (CDCl
3
and spectral data are analogous to those previously de-
3
)
scribed.33
δ 56.0, 111.7, 121.4, 122.0, 125.5, 129.5, 130.3, 131.5, 136.0,
1
49.8, 156.4, 157.2; IR (KBr) ν 3062, 3005, 2938, 2836, 1602,
586, 1495, 1463, 1438, 1424, 1259, 1242, 1026, 754 cm-1
11NO (185.23): C, 77.81; H, 5.99; N, 7.56.
Found: C, 77.60; H, 6.08; N, 7.41.
1
.
J O026136S
Anal. Calcd for C12
H
(28) Mettey, Y.; Vierfond, J .-M. J . Heterocycl. Chem. 1986, 23, 1051.
(29) Sato, N.; Narita, N. J . Heterocycl. Chem. 1999, 36, 783.
(30) Chen, Y.; Lam, Y.; Lee, S.-Y. Chem. Lett. 2001, 274.
(
(
24) Bizot, J . Bull. Soc. Chim. Fr. 1967, 151.
25) Ishikawa, M.; Kamada, M.; Terashima, M. Heterocycles 1984,
(31) Katritzky, A. R.; Yang, B.; J iang, J .; Steel, P. J . J . Org. Chem.
1995, 60, 246.
2
6
2, 265.
(32) Patterson, J . M.; Mayer, C. F.; Smith, W. T., J r. J . Org. Chem.
1975, 40, 1511.
(33) Lourak, M.; Vanderesse, R.; Fort, Y.; Caub e` re, P. J . Org. Chem.
1989, 54, 4844.
(
(
26) Gilman, H.; Edwards, J . T. Can. J . Chem. 1953, 31, 457.
27) Riggio, G.; Hoffmann, A.; Waster, P. G. Helv. Chim. Acta 1983,
6, 1039.
8
994 J . Org. Chem., Vol. 67, No. 25, 2002