Syntheses of substituted pyridines, quinolines and diazines via palladium-catalyzed cross-coupling of aryl Grignard reagents

Article abstract of DOI:10.1016/S0040-4020(02)00411-8

The palladium-catalyzed cross-coupling reactions between arylmagnesium halides (phenylmagnesium chloride, mesitylmagnesium bromide, 4-(methoxycarbonyl)phenylmagnesium chloride and 4-cyanophenylmagnesium chloride) and halopyridines allowed the synthesis of substituted pyridines. Owing to the remarkably mild conditions used (often below 0°C), the reaction could be extended to the use of functionalized halopyridines, haloquinolines and halodiazines.

Full text of DOI:10.1016/S0040-4020(02)00411-8

TETRAHEDRON
Pergamon
Tetrahedron 58 ,2002) 4429±4438
Syntheses of substituted pyridines, quinolines and diazines via
palladium-catalyzed cross-coupling of aryl Grignard reagents
a,b
a
a
a,p
Veronique Bonnet, Florence Mongin, FrancËois Trecourt, Guy Queguiner and Paul Knochel
b
Â
Â
Â
a
 Â
Laboratoire de Chimie Organique Fine et Heterocyclique, UMR 6014, IRCOF, Place E. Blondel, BP 08,
76131 Mont-Saint-Aignan Cedex, France
b
È È
Department Chemie, Ludwig-Maximilians-Universitat Munchen, Butenandtstr, 5-13, Haus F, 81377 Munich, Germany
Received 6February 2002; revised 2 April 2002; accepted 11 April 2002
AbstractÐThe palladium-catalyzed cross-coupling reactions between arylmagnesium halides ,phenylmagnesium chloride, mesitylmag-
nesium bromide, 4-,methoxycarbonyl)phenylmagnesium chloride and 4-cyanophenylmagnesium chloride) and halopyridines allowed the
synthesis of substituted pyridines. Owing to the remarkably mild conditions used ,often below 08C), the reaction could be extended to the use
of functionalized halopyridines, haloquinolines and halodiazines. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
reagents with pyridine, quinoline and diazine halo substrates
,functionalized or not) are recorded.
Interest in azine and diazine natural products and pharma-
ceuticals, or building blocks for various applications such as
material science and supramolecular chemistry, has resulted
in extensive efforts on synthesis methodologies.1 Transition
metal-catalyzed cross-couplings have proven to be an
important method for preparing a number of complex
heterocycles.
2. Results and discussion
Initially, phenylmagnesium chloride ,PhMgCl) was used in
order to optimize reaction conditions for the cross-coupling
reactions with various halopyridines. Under nickel-cataly-
sis, such reactions are possible at room temperature ,rt);6
however, the toxicity of nickel salts led us to explore an
alternative route. So we turned to palladium-catalyzed
cross-coupling reactions.9 Bis,dibenzylideneacetone)pal-
ladium,0) ,Pd,dba)2) and 1,10-bis,diphenylphosphino)ferro-
cene ,dppf) were chosen for this purpose.10 Under these
conditions, 2-, 3- and 4-bromopyridines ,1a±c) reacted
with PhMgCl in tetrahydrofuran ,THF) at rt in excellent
yields ,entries 1±3). Note that both 2-bromo- and 2-chloro-
pyridines could be used. For the halo methylpyridines 1d±e,
no deprotonation of the methyl group was noticed11 and
the coupled products were quantitatively obtained ,entries
4±5). Due to the remarkably mild reaction conditions used
,2408C), the ethyl chloronicotinates 1f±g could also be
involved in the reaction ,entries 6±7). When 3-halopyri-
dines were used, higher temperatures were required for
the cross-coupling. For ethyl 5-bromonicotinate ,1h),
tri,tert-butyl)phosphine ,P,tBu)3) was found to be a
more convenient ligand6b,12 than dppf ,entry 8) ,Scheme 1,
Table 1).
Several Negishi,2,3 Suzuki2,4 and Stille2,4c,d,5 cross-coupling
reactions have already been reported in the azine and
diazine series. The aryl organometallic substrates are
usually prepared via their corresponding lithio derivatives.
More reactive organometallics such as organomagnesium
derivatives suffer from a moderate functional group
tolerance when compared to organozincs, organoboronic
acids or organotin derivatives.6
The strategy developed uses arylmagnesium reagents. We
recently reported an easy access to aryl- and heteroaryl-
magnesium halides,7 starting from the corresponding halo
derivatives. Thus, we decided to involve functionalized
arylmagnesium halides in cross-coupling reactions with
functionalized halopyridines and we found that the reaction
could be catalyzed with palladium under remarkably soft
conditions.8 Herein, details of our investigations concerning
the cross-coupling reactions of various aryl Grignard
Starting from phenyl 6-bromopyridine-2-sulfone ,3), the
cross-coupling reaction could be selectively observed at
C6. The phenylpyridine 4 was indeed given when the
substrate was treated with PhMgCl at rt in THF, in the
presence of catalytic amounts of Pd,dba)2 and dppf. Without
Keywords: palladium catalysis; Grignard reagents; coupling reactions;
azines.
Corresponding author. Tel.: 133-2-35-52-29-00; fax: 133-2-35-52-29-62;
e-mail: guy.queguiner@insa-rouen.fr
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020,02)00411-8

4430
V. Bonnet et al. / Tetrahedron 58 82002) 4429±4438
Scheme 1.
Table 1. Cross-coupling reactions of 1a±h with PhMgCl
Entry
1
Halopyridine
Conditions ,8C, h)
Product
Yield%a
98b,c
25, 5
2
3
4
5
25, 5
95
95d
96
25, 5
25, 7
225, 18
95
6
7
240, 6
240, 6
0, 18
92e
42
8
73f
a
Isolated yields based on 1.
95% at 08C.
97% starting from 2-bromopyridine.
2 equiv. of PhMgCl were used.
95% starting from ethyl 6-bromonicotinate.
Using P,tBu)3, 10 mol%, instead of dppf.
b
c
d
e
f
catalyst, displacement of the phenylsulfonyl group13 by the
phenyl group of the Grignard reagent was selectively
observed to afford the phenylpyridine 5 ,Scheme 2).
Due to their lower LUMO levels, quinolines and diazines
are prone to nucleophilic addition. Nevertheless, under the
conditions used, cross-coupling reactions between PhMgCl
and the commercial haloquinolines 6a,b could be achieved
to give the phenylquinolines 7a,b in good yields ,Scheme 3,
Table 2).
Moreover, the halodiazines 8a±c could also be involved in
the reaction to produce the phenyldiazines 9a±c ,Scheme 4,
Table 3). Remark that when the reaction of 2-chloropyrimi-
dine ,8a) was led without catalyst, the 4-phenyl derivative
Scheme 2.

V. Bonnet et al. / Tetrahedron 58 82002) 4429±4438
4431
Scheme 3.
Table 2. Cross-coupling reactions of 6a,b with PhMgCl
Entry
1
Haloquinoline
Temperature ,8C)
25
Product
Yield%a
80
2
25
75
a
Isolated yields based on 6.
Table 4. Cross-coupling reactions of 1c,d with mesitylmagnesium bromide
Yield%a
Entry
Halopyridine
Product
1
62b
Scheme 4.
Table 3. Cross-coupling reactions of 8a±c with PhMgCl
Entry
1
Halodiazine
Product
Yield%a
80
2
51
a
Isolated yields based on 1.
2 equiv. of mesitylmagnesium bromide were used.
b
2
91
40
10 was obtained after 1,4-addition of the Grignard reagent to
the ring and subsequent oxidation ,Scheme 5).
3
a
This ef®cient procedure in hand, we turned to substituted
arylmagnesium halides. When the halopyridines 1c,d were
treated with commercially available mesitylmagnesium
bromide under the same reaction conditions, the corre-
sponding phenylpyridines 11a,b could also be obtained
,Scheme 6, Table 4).
Isolated yields based on 8.
Next, functionalized arylmagnesium compounds, such
as 4-,methoxycarbonyl)phenylmagnesium chloride14 or
4-cyanophenylmagnesium chloride,14 were used. Treating
2-chloropyridine ,1a) with 4-,methoxycarbonyl)phenyl-
magnesium chloride at 2408C under the same reaction
Scheme 5.
Scheme 6.

4432
V. Bonnet et al. / Tetrahedron 58 82002) 4429±4438
Scheme 7.
Table 5. Cross-coupling reactions of 1a,h, 3, 8, 12±14 with 4-,methoxycarbonyl)phenylmagnesium chloride
Entry
Halo substrate
Conditions ,8C, h)
L
Product
Yield%a
95b
1
240, 5
dppf 5 mol%
2
3
240, 5
240, 5
dppf 5 mol%
dppf 5 mol%
36
32
4
5
6
25,18
215, 7
215, 7
dppf 5 mol%
dppf 5 mol%
dppf 5 mol%
32
32
25
7
8
25, 18
P,tBu)3 10 mol%
62
95
240, 6dppf 5 mol%
9
220, 4
dppf 5 mol%
90
10
240, 6dppf 5 mol%
86
63
11
0, 18
P,tBu)3 10 mol%
a
Isolated yields based on starting halo substrate.
96% starting from 2-bromopyridine.
b

V. Bonnet et al. / Tetrahedron 58 82002) 4429±4438
4433
Scheme 8.
conditions quantitatively afforded the functionalized
phenylpyridine 15a ,entry 1). For the 2-chlorodiazines
8a,b and phenyl 6-bromopyridine-2-sulfone ,3), moderate
yields were observed ,entries 2±4). Starting from 2,5-dibro-
mopyridine ,12a), a good regioselectivity was obtained at
C2 ,entry 5). A single functionalization was observed from
2,6- and 3,5-dibromopyridines ,12b,c), yields being con-
siderably improved using P,tBu)3 instead of dppf ,entries
6±7). From the functionalized 2-bromopyridines 13a,b and
14, addition of the Grignard reagent to the ester or cyano
group could be completely avoided by using lower reaction
temperatures ,240 or 2208C). Excellent yields were
obtained for the synthesis of the bisfunctionalized phenyl-
pyridines 15h±j ,entries 8±10). In the case of the
functionalized 3-bromopyridine 1h, it has also been
advantageous to use P,tBu)3 as ligand instead of dppf
,entry 11) ,Scheme 7, Table 5).
carried out under dry N2. Silica gel ,Geduran Si 60, 0.063±
0.200 mm) was purchased from Merck. iPrMgCl ,2 M) in
THF, PhMgCl ,2 M) in THF, mesitylmagnesium bromide
,1 M) in THF, and BuLi ,2.5 M) in hexane were purchased
from Aldrich. Pd,dba)2 was supplied by Acros, dppf by
Avocado and P,tBu)3 by Aldrich. Petrol refers to petroleum
ether ,bp 40±608C).
After the reaction, the aqueous solution was extracted
several times with CH2Cl2. The organic layer was dried
over MgSO4, the solvents were evaporated under reduced
pressure, and unless otherwise noted, the crude compound
was chromatographed on a silica gel column ,eluent is given
in the product description).
4.2.1. Ethyl 6-chloronicotinate .1f). A mixture of 6-chloro-
nicotinic acid ,6.9 g, 44 mmol), ethanol ,100 mL) and conc.
sulfuric acid ,0.20 mL) was heated at re¯ux for 2 h ,water
was distilled off using a Dean±Stark apparatus) and ethanol
was evaporated. CH2Cl2 ,30 mL) was added to the residue
and the resulting mixture was poured onto an aqueous
saturated solution of Na2CO3 ,40 mL). Yield of 1f ,eluent:
Treating ethyl 6-chloronicotinate ,1f) with 4-cyanophenyl-
magnesium chloride also allowed the synthesis of the
bisfunctionalized phenylpyridine 16 ,Scheme 8).
1
CH2Cl2): 46%; pale yellow oil; the H NMR data are in
accordance with those of the literature;15 13C NMR
,CDCl3) d 14.7, 62.1, 121.4, 123.8, 141.2, 151.4, 152.1,
165.1; IR ,KBr) n 2984, 2938, 1724, 1587, 1457, 1368,
1292, 1274, 1128, 1024, 768 cm21. Anal. Calcd for
C8H8ClNO2 ,185.61): C, 51.77; H, 4.34; N, 7.55. Found:
C, 51.86; H, 4.37; N, 7.87%.
3. Conclusion
Using phenylmagnesium chloride, we could ®nd remark-
ably mild conditions for the cross-coupling reaction with a
large range of halopyridines ,functionalized or not),
haloquinolines or halodiazines. The use of more hindered
or functionalized arylmagnesium halides could lead to more
elaborated azines and diazines, which are of interest for
various pharmaceutical applications.
4.2.2. Ethyl 6-bromonicotinate .13a). Compound 13a was
prepared by bromine-magnesium exchange from 2,5-dibro-
mopyridine,6c using ethyl cyanoformate. Yield of 13a
1
Extension of this strategy to the use of pyridylmagnesium
chlorides is currently under investigation.
,eluent: CH2Cl2/Et2O 80:20): 40%; mp ,508C; H NMR
,CDCl3) d 1.35 ,t, 3H, Jˆ7.9 Hz, CH3), 4.41 ,q, 2H, Jˆ
7.9 Hz, CH2), 7.53 ,d, 1H, Jˆ8.2 Hz, H5), 8.08 ,dd, 1H,
Jˆ8.2, 1.8 Hz, H4), 8.97 ,d, 1H, Jˆ1.8 Hz, H2); 13C NMR
,CDCl3) d 14.4, 61.9, 125.8, 128.2, 139.3, 146.7, 151.2,
164.5; IR ,KBr) n 2983, 2937, 1725, 1581, 1451, 1369,
1290, 1272, 1116, 1022, 764 cm21. Anal. Calcd for
C8H8BrNO2 ,230.06): C, 41.77; H, 3.51; N, 6.09. Found:
C, 41.82; H, 3.57; N, 6.18%.
4. Experimental
4.1. General
Melting points were measured on a Ko¯er apparatus. The
NMR spectra were recorded in CDCl3 or DMSO-d6 with a
Bruker AM 300 spectrometer ,1H at 300 MHz and 13C at
75 MHz). IR spectra were taken on a Perkin±Elmer FT IR
205 spectrometer, and main IR absorptions are given in
cm21. Elemental analyses were performed on a Carlo Erba
1106apparatus.
4.2.3. Ethyl 2-chloronicotinate .1g). A mixture of 2-chloro-
nicotinic acid ,1.6g, 10 mmol) and SOCl 2 ,25 mL) was
heated at re¯ux for 3 h. The excess of SOCl2 was evaporated
and the residue was treated with ethanol ,30 mL) at 08C
with stirring. After 15 h, ethanol was evaporated, CH2Cl2
,30 mL) was added to the residue and the resulting mixture
was poured onto an aqueous saturated solution of Na2CO3
,40 mL). Yield of 1g ,eluent: CH2Cl2): 90%; pale yellow
4.2. Starting materials
1
oil; the H NMR data are in accordance with those of the
THF was distilled from benzophenone/Na. Reactions were

4434
V. Bonnet et al. / Tetrahedron 58 82002) 4429±4438
literature;16 IR ,KBr) n 3416, 2992, 1727, 1580, 1275, 1172,
1022, 763 cm21. Anal. Calcd for C8H8ClNO2 ,185.61): C,
51.77; H, 4.34; N, 7.55. Found: C, 51.96; H, 4.48; N, 7.38%.
,172.03): C, 41.89; H, 3.52; N, 8.14. Found: C, 41.59; H,
3.58; N, 8.25%.
4.4.2. 2-Bromoisonicotinic acid. 2-Bromo-4-methylpyri-
dine ,18 g, 0.11 mol) was dissolved in water ,1 L) and
treated with a solution of KMnO4 ,33 g, 0.22 mol) in
water ,500 mL). After 5 h at re¯ux, the mixture was
®ltrated. The ®ltrate was concentrated to 500 mL and
acidi®ed with conc. HCl to reach pH 3. The precipitate
was ®ltrated and dried under vacuum. Yield: 31%; mp
4.2.4. Ethyl 5-bromonicotinate .1h). A mixture of
5-bromonicotinic acid ,2.1 g, 10 mmol) and SOCl2
,25 mL) was heated at re¯ux for 3 h. The excess of SOCl2
was evaporated and the residue was treated with ethanol
,30 mL) at 08C with stirring. After 15 h, ethanol was evapo-
rated, CH2Cl2 ,30 mL) was added to the residue and the
resulting mixture was poured onto an aqueous saturated
solution of Na2CO3 ,40 mL). Yield of 1h ,eluent:
CH2Cl2): 94%; mp ,508C; the spectral data are in accor-
dance with those of the literature;17 Anal. Calcd for
C8H8BrNO2 ,230.06): C, 41.77; H, 3.51; N, 6.09. Found:
C, 42.51; H, 3.49; N, 6.17%.
1
240±2448C ,lit.19 mp 245±2468C); the H and 13C NMR
data are in accordance with those of the literature;18 IR
,KBr) n 3102, 2774, 2477, 1852, 1714, 1545, 1454, 1366,
1284, 1228, 1008, 765 cm21. Anal. Calcd for C6H4BrNO2
,202.01): C, 35.68; H, 2.00; N, 6.93. Found: C, 35.38; H,
2.03; N, 6.76%.
4.4.3. Ethyl 2-bromoisonicotinate .13b).18 A mixture of
2-bromoisonicotinic acid ,1.5 g, 7.4 mmol), ethanol
,25 mL) and conc. sulfuric acid ,0.20 mL) was heated at
re¯ux for 3 h ,water was distilled off using a Dean±Stark
apparatus) and ethanol was evaporated. CH2Cl2 ,30 mL)
was added to the residue and the resulting mixture was
poured onto an aqueous saturated solution of Na2CO3
,40 mL). Yield of 13b ,eluent: CH2Cl2): 55%; colorless
4.3. Phenyl 6-bromopyridine-2-sulfone .3)
4.3.1. 6-Bromo-2-.phenylthio)pyridine. To a solution of
2,6-dibromopyridine ,2.4 g, 10 mmol) in THF ,20 mL) at
2758C was added a solution of BuLi ,11 mmol) in hexane
,4.4 mL). After 1 h at this temperature, PhSSPh ,2.4 g,
11 mmol) was added and the mixture was stirred for 2 h at
2508C before hydrolysis with water ,10 mL). Yield ,eluent:
CH2Cl2/Et2O 90:10): 54%; mp ,508C; 1H NMR ,CDCl3) d
6.60 ,d, 1H, Jˆ7.9 Hz, H5), 6.72 ,t, 1 H, Jˆ7.9 Hz, H4), 7.13
,d, 1H, Jˆ7.9 Hz, H3), 7.29 ,m, 3H, Ph), 7.41 ,m, 2H, Ph);
13C NMR ,CDCl3) d 117.4, 119.9, 124.1, 130.2 ,2C), 130.4
,2C), 135.6, 141.7, 163.6, 130.7; IR ,KBr) n 3060, 1561,
1536, 1409, 1161, 1142, 776, 751, 610 cm21. Anal. Calcd
for C11H8BrNS ,266.16): C, 49.64; H, 3.03; N, 5.26; S,
12.05. Found: C, 49.69; H, 3.17; N, 5.12; S, 12.16%.
1
oil; H NMR ,CDCl3) d 1.29 ,t, 3H, Jˆ7.2 Hz, CH3), 4.30
,q, 2H, Jˆ7.2 Hz, CH2), 7.68 ,d, 1H, Jˆ4.9 Hz, H5), 7.85 ,s,
1H, H3), 8.38 ,d, 1H, Jˆ4.9 Hz, H6); 13C NMR ,CDCl3) d
14.4, 62.5, 122.2, 127.9, 140.4, 143.0, 151.1, 163.8; IR
,KBr) n 2983, 1731, 1588, 1549, 1362, 1295, 1261, 1141,
1101, 761, 730 cm21. Anal. Calcd for C8H8BrNO2 ,230.06):
C, 41.77; H, 3.51; N, 6.09. Found: C, 41.74; H, 3.69; N,
6.35%.
4.4.4. 2-Bromo-5-cyanopyridine .14). Compound 14
was prepared by bromine±magnesium exchange from
2,5-dibromopyridine,6c using tosyl cyanide. Yield of 14
,eluent: CH2Cl2/Et2O 80:20): 52%; mp 116±1188C ,lit.20
4.3.2. Phenyl 6-bromopyridine-2-sulfone .3). A solution
of 6-bromo-2-,phenylthio)pyridine ,2.4 g, 11 mmol) in THF
,30 mL) was treated at 258C with a solution of 3-chloro-
perbenzoic acid ,7.4 g, 43 mmol) in THF ,40 mL). After
stirring for 6h, Na 2S2O4 ,7.5 g, 43 mmol) was added to the
mixture and the solvent was evaporated. Water ,20 mL) was
added to the residue and the pH of the resulting solution was
adjusted to 7±8 with NaHCO3. Yield of 3 ,eluent: petrol/
1
mp 116±1188C); the H and 13C NMR data are in accor-
dance with those of the literature;20 Anal. Calcd for
C6H3BrN2 ,183.01): C, 39.38; H, 1.65; N, 15.31. Found:
C, 39.22; H, 1.82; N, 15.17%.
1
CH2Cl2 50:50): 42%; mp 129±1318C; H NMR ,CDCl3) d
7.42 ,d, 1H, Jˆ7.5 Hz, H5), 7.51 ,t, 1H, Jˆ7.5 Hz, H4), 7.69
,d, 1H, Jˆ7.5 Hz, H3), 7.92 ,m, 3H, Ph), 8.03 ,m, 2H, Ph);
13C NMR ,CDCl3) d 121.5, 129.4 ,2C), 129.8 ,2C), 132.4,
134.6, 138.6, 140.7, 143.0, 159.3. Anal. Calcd for
C11H8BrNO2S ,298.16): C, 44.31; H, 2.70; N, 4.70; S,
10.75. Found: C, 44.42; H, 2.88; N, 4.74; S, 10.67%.
4.5. General procedure 1: preparation of phenyl
derivatives 2a±h, 4, 5, 7a,b, 9a±c, 10 and 11a,b
Pd,dba)2 ,29 mg, 0.050 mmol), dppf ,27 mg, 0.050 mmol)
and, 10 min later, the halo derivative ,1.0 mmol) were
added to THF ,3 mL). After stirring for 30 min at rt, a solu-
tion of PhMgCl ,1.2 mmol) in THF ,0.60 mL) was added
dropwise at 2408C. After stirring under the conditions
described in the product description, the mixture was
quenched with an aqueous saturated NH4Cl solution ,5 mL).
4.4. Ethyl 2-bromoisonicotinate .13b)
4.4.1. 2-Bromo-4-methylpyridine. To 2-amino-4-methyl-
pyridine ,15 g, 0.14 mol) were successively added dropwise
at 08C a 48% solution of HBr ,120 mL) and Br2 ,21 mL). A
solution of NaNO2 ,24 g) in water ,35 mL) was then intro-
duced dropwise at 08C to the mixture. After 3 h, 50%
aqueous KOH ,200 mL) and Na2SO3 ,18 g) were succes-
sively added. 2-Bromo-4-methylpyridine was distillated
with water. Yield ,eluent: CH2Cl2): 94%; colorless oil; the
1H and 13C NMR data are in accordance with those of the
literature;18 IR ,KBr) n 3053, 2920, 1592, 1464, 1374, 1119,
1079, 986, 849, 823, 700 cm21. Anal. Calcd for C6H6BrN
4.5.1. 2-Phenylpyridine .2a). The general procedure 1 ,5 h
at rt), starting from 1a, gave 2a ,eluent: CH2Cl2/Et2O
90:10). Yield: 98%. The physical and spectral data are
analogous to those obtained for a commercial sample.
4.5.2. 3-Phenylpyridine .2b). The general procedure 1 ,5 h
at rt), starting from 1b, gave 2b ,eluent: CH2Cl2/Et2O
90:10). Yield: 95%. The physical and spectral data are
analogous to those obtained for a commercial sample.

V. Bonnet et al. / Tetrahedron 58 82002) 4429±4438
4435
4.5.3. 4-Phenylpyridine .2c). The general procedure 1 ,5 h
at rt), starting from 1c and using 2.2 mmol of PhMgCl, gave
2c ,eluent: CH2Cl2/Et2O 90:10). Yield: 95%. The physical
and spectral data are analogous to those obtained for a
commercial sample.
4.5.10. 2-Bromo-6-phenylpyridine .5).26 The general
procedure 1 ,12 h at rt and without catalyst), starting from
3, gave 77% ,eluent: CH2Cl2/Et2O 90:10) of 5: mp 50±
1
528C; H NMR ,CDCl3) d 7.29 ,dd, 1H, Jˆ6.0, 1.1 Hz,
H5), 7.38 ,m, 3H, Ph), 7.50 ,t, 1H, Jˆ6.0 Hz, H4), 7.59 ,d,
1H, Jˆ6.0, 1.1 Hz, H3), 7.98 ,m, 2H, Ph); 13C NMR
,CDCl3) d 119.0, 127.4 ,2C), 129.1 ,2C), 129.4, 137.9,
139.9, 140.5, 141.3, 157.2. Anal. Calcd for C11H8BrN
,234.10): C, 56.44; H, 3.44; N, 5.98. Found: C, 56.36; H,
3.61; N, 5.69.
4.5.4. 2-Methyl-6-phenylpyridine .2d). The general pro-
cedure 1 ,7 h at 258C), starting from 1d, gave 2d ,eluent:
1
CH2Cl2/Et2O 90:10). Yield: 96%; pale yellow oil; the H
NMR data are in accordance with those of the literature;21
13C NMR ,CDCl3) d 24.9, 118.7, 122.3, 129.1 ,2C), 129.2,
132.1 ,2C), 137.2, 150.3, 157.4, 158.8; IR ,KBr) n 3061,
2957, 2923, 1592, 1573, 1458, 1239, 757, 694 cm21. Anal.
Calcd for C12H11N ,169.23): C, 85.17; H, 6.55; N, 8.28.
Found: C, 84.79; H, 6.74; N, 8.06%.
4.5.11. 2-Phenylquinoline .7a). The general procedure 1
,5 h at 258C), starting from 6a, gave 80% ,eluent:
CH2Cl2/Et2O 90:10) of 7a. The physical and spectral data
are analogous to those obtained for a commercial sample.
4.5.5. 4-Methyl-2-phenylpyridine .2e). The general pro-
cedure 1 ,18 h at 2258C), starting from 1e, gave 95%
4.5.12. 3-Phenylquinoline .7b). The general procedure 1
,5 h at rt), starting from 6b, gave 75% ,eluent: CH2Cl2/
Et2O 90:10) of 7b. The 1H and 13C NMR data are in
accordance with those of the literature.27
1
,eluent: CH2Cl2/Et2O 90:10) of 2e: mp ,508C; the H and
13C NMR data are in accordance with those of the litera-
ture;22 IR ,KBr) n 3057, 1605, 1558, 1446, 827, 776, 736,
695, 590 cm21. Anal. Calcd for C12H11N ,169.23): C, 85.17;
H, 6.55; N, 8.28. Found: C, 85.48; H, 6.18; N, 8.04%.
4.5.13. 2-Phenylpyrimidine .9a). The general procedure 1
,5 h at rt), starting from 8a, gave 80% ,eluent: CH2Cl2/Et2O
1
90:10) of 9a: mp ,508C; the H and 13C NMR data are in
4.5.6. Ethyl 6-phenylnicotinate .2f). The general pro-
cedure 1 ,6h at 2408C), starting from 1f, gave 92% ,eluent:
CH2Cl2/Et2O 90:10) of 2f: mp 48±508C ,lit.23 mp 51±538C);
the 1H and 13C NMR data are in accordance with those of the
literature;23 IR ,KBr) n 3051, 2982, 1712, 1598, 1284, 1262,
1125, 1017, 748, 691 cm21. Anal. Calcd for C14H13NO2
,227.27): C, 73.99; H, 5.77; N, 6.16. Found: C, 73.54; H,
5.76; N, 6.08%.
accordance with those described in the literature;28 IR ,KBr)
n 3066, 2928, 1567, 1556, 1418, 745, 889 cm21. Anal.
Calcd for C10H8N2 ,156.19): C, 76.90; H, 5.16; N, 17.94.
Found: C, 76.63; H, 5.42; N, 17.58%.
4.5.14. 2-Phenylpyrazine .9b). The general procedure 1
,5 h at rt), starting from 8b, gave 91% ,eluent: CH2Cl2/
1
Et2O 90:10) of 9b: mp 768C ,lit.29 mp 738C); the H and
13C NMR data are in accordance with those of the litera-
ture;30 IR ,KBr) n 3050, 1474, 1447, 1409, 1082, 1010, 772,
744, 692 cm21. Anal. Calcd for C10H8N2 ,156.19): C, 76.90;
H, 5.16; N, 17.94. Found: C, 76.78; H, 5.26; N, 18.02%.
4.5.7. Ethyl 2-phenylnicotinate .2g). The general pro-
cedure 1 ,6h at 2408C), starting from 1g, gave 2g ,eluent:
1
CH2Cl2/Et2O 90:10). Yield: 42%; pale yellow oil; the H
and 13C NMR data are in accordance with those of the
literature;24 IR ,KBr) n 2982, 2937, 1714, 1583, 1562,
1429, 1305, 1283, 1098, 756, 699 cm21. Anal. Calcd for
C14H13NO2 ,227.27): C, 73.99; H, 5.77; N, 6.16. Found:
C, 73.59; H, 5.66; N, 6.19%.
4.5.15. 5-Phenylpyrimidine .9c).31 The general procedure
1 ,5 h at rt), starting from 8c, gave 40% ,eluent: CH2Cl2/
Et2O 90:10) of 9c: mp 39±418C; H NMR ,CDCl3) d 7.08
1
,m, 3H, Ph), 7.17 ,m, 2H, Ph), 7.32 ,s, 1H, H4), 7.41 ,s, 1H,
H6), 7.62 ,s, 1H, H2). Anal. Calcd for C10H8N2 ,156.19): C,
76.90; H, 5.16; N, 17.94. Found: C, 76.75; H, 5.20; N,
17.83%.
4.5.8. Ethyl 5-phenylnicotinate .2h). The general pro-
cedure 1 ,18 h at 08C and P,tBu)3 ,20 mg, 0.10 mmol)
instead of dppf), starting from 1 h, gave 73% ,eluent:
CH2Cl2/Et2O 90:10) of 2 h: mp 68±708C ,lit.25 mp 688C);
the 1H NMR and IR data are in accordance with those of the
literature;25 13C NMR ,CDCl3) d 15.6, 62.0, 128.1 ,2C),
128.2, 129.0, 129.6 ,2C), 135.6, 146.1, 149.4, 149.6,
151.9, 165.6. Anal. Calcd for C14H13NO2 ,227.27): C,
73.99; H, 5.77; N, 6.16. Found: C, 74.13; H, 5.42; N, 6.12%.
4.5.16. 2-Chloro-4-phenylpyrimidine .10). The general
procedure 1 ,8 h at rt, without catalyst and using 5 mmol
of PhMgCl), starting from 8, gave 49% ,eluent: CH2Cl2) of
10: mp 888C ,lit.32 mp 87±898C); the 1H and 13C NMR, and
IR data are in accordance with those of the literature;32 Anal.
Calcd for C10H7ClN2 ,190.63): C, 63.01; H, 3.70; N, 14.69.
Found: C, 63.41; H, 3.55; N, 14.38%.
4.5.9. Phenyl 6-phenylpyridine-2-sulfone .4). The general
procedure 1 ,12 h at rt), starting from 3, gave 71% ,eluent:
CH2Cl2/Et2O 90:10) of 4: mp 172±1748C; 1H NMR ,CDCl3)
d 7.36,m, 2H, H 3,5), 7.48 ,m, 3H, Ph), 7.75 ,t, 1H, Jˆ
7.7 Hz, H4), 7.84 ,m, 4H, Ph), 8.03 ,m, 3H, Ph); 13C NMR
,CDCl3) d 120.2, 123.5, 127.4 ,2C), 129.3 ,2C), 129.4 ,2C),
129.6,2C), 130.4, 134.1, 137.5, 139.1, 139.3, 158.4, 159.1;
IR ,KBr) n 3064, 1582, 1546, 1447, 1322, 1158, 1130,
1087, 765, 729, 692 cm21. Anal. Calcd for C17H13NO2S
,295.36): C, 69.13; H, 4.44; N, 4.74; S, 10.86. Found: C,
68.86; H, 4.36; N, 4.69; S, 10.69%.
4.5.17. 4-.2,4,6-Trimethylphenyl)pyridine .11a).33 The
general procedure 1 ,5 h at rt), using mesitylmagnesium
bromide ,2.2 mmol) instead of PhMgCl and starting
from 1c, gave 62% ,eluent: CH2Cl2/Et2O 90:10) of 11a:
mp 78±808C.
4.5.18. 2-Methyl-6-.2,4,6-trimethylphenyl)pyridine .11b).
The general procedure 1 ,5 h at rt), using mesitylmagnesium
bromide instead of PhMgCl and starting from 1d, gave 51%
1
,eluent: CH2Cl2/Et2O 90:10) of 11b: mp ,508C; H NMR

4436
V. Bonnet et al. / Tetrahedron 58 82002) 4429±4438
,CDCl3) d 1.93 ,s, 6H, 2CH3), 2.20 ,s, 3H, CH3), 2.50 ,s,
3H, CH3), 6.82 ,s, 2H, Ph), 6.94 ,d, 1H, Jˆ7.5 Hz, H3), 7.01
,d, 1H, Jˆ7.5 Hz, H5), 7.54 ,t, 1H, Jˆ7.5 Hz, H4); 13C NMR
,CDCl3) d 19.1 ,2C), 20.0, 23.5, 119.9, 120.5, 127.2 ,2C),
134.6, 135.4 ,2C), 136.2, 136.9, 157.1, 158.3; IR ,KBr) n
2953, 2921, 2857, 1613, 1587, 1574, 1455, 849, 800,
753 cm21. Anal. Calcd for C15H17N ,211.31): C, 85.26; H,
8.11; N, 6.63. Found: C, 84.97; H, 8.21; N, 6.72%.
Ph), 7.98 ,m, 3H, Ph), 8.04 ,m, 2H, Ph); 13C NMR ,CDCl3)
d 51.2, 119.5, 122.6, 126.0, 128.1, 128.2, 129.0, 130.2,
132.9, 137.6, 138.1, 139.9, 155.6, 157.7, 165.5; IR ,KBr)
.
Anal. Calcd for C19H15NO4S ,353.40): C, 64.58; H, 4.28; N,
3.96; S, 9.07. Found: C, 64.89; H, 3.95; N, 3.94; S, 8.80%.
n 3072, 1716, 1585, 1440, 1278, 1120, 771, 688, 594 cm21
4.6.5. Methyl 4-.5-bromo-2-pyridyl)benzoate .15e). The
general procedure 2 ,7 h at 2158C), starting from 12a, gave
32% ,eluent: CH2Cl2/Et2O 90:10) of 15e: mp 1588C; H
1
4.6. General procedure 2: preparation of phenyl
derivatives 15a±k
NMR ,CDCl3) d 3.88 ,s, 3H, CH3), 7.62 ,d, 1H, Jˆ
0
0
8.4 Hz, H3 ), 7.84 ,dd, 1H, Jˆ8.4, 2.5 Hz, H4 ), 8.00 ,2d,
4H, Jˆ6.9 Hz, Ph), 8.66 ,d, 1H, Jˆ2.5 Hz, H6 ); 13C NMR
0
In a ®rst ¯ask, a solution of iPrMgCl ,1.2 mmol) in THF
,0.6mL) was added at 2408C to a solution of methyl
4-iodobenzoate ,0.31 g, 1.2 mmol) in THF ,5 mL). After
40 min at this temperature, 4-,methoxycarbonyl)phenyl-
magnesium chloride is formed. In a second ¯ask, Pd,dba)2
,29 mg, 0.050 mmol), dppf ,27 mg, 0.050 mmol) and,
10 min later, the halo derivative ,1.0 mmol) were added to
THF ,3 mL). After stirring for 30 min at rt, the solution of
4-,methoxycarbonyl)phenylmagnesium chloride was added
dropwise at 2408C. After stirring under the conditions
described in the product description, the mixture was
quenched with an aqueous saturated NH4Cl solution ,5 mL).
,CDCl3) d 25.3, 120.6, 122.4, 127.1 ,2C), 130.5 ,2C), 134.6,
141.4, 142.7, 151.3, 155.0, 167.1; IR ,KBr) n 2943, 1719,
1437, 1281, 1110, 1098, 1004, 828, 779, 741 cm21. Anal.
Calcd for C13H10BrNO2 ,292.13): C, 53.45; H, 3.45; N, 4.79.
Found: C, 53.42; H, 3.44; N, 4.49%.
4.6.6. Methyl 4-.6-bromo-2-pyridyl)benzoate .15f). The
general procedure 2 ,7 h at 2158C), starting from 12b,
gave 25% ,eluent: CH2Cl2/Et2O 90:10) of 15f: mp 145±
1
1508C; H NMR ,CDCl3) d 3.86,s, 3H, CH ), 7.37 ,d,
3
0
0
1H, Jˆ7.5 Hz, H3 ), 7.54 ,t, 1H, Jˆ7.5 Hz, H4 ), 7.65 ,d,
1H, Jˆ7.5 Hz, H5 ), 8.01 ,2d, 4H, Jˆ8.6Hz, Ph); 13C NMR
0
,CDCl3) d 52.6, 119.9, 127.6, 128.6 ,2C), 130.4 ,2C), 131.8,
139.5, 142.0, 142.7, 157.6, 167.1; IR ,KBr) n 2958, 2928,
1722, 1579, 1550, 1431, 1280, 1109, 768 cm21. Anal. Calcd
for C13H10BrNO2 ,292.13): C, 53.45; H, 3.45; N, 4.79.
Found: C, 53.75; H, 3.79; N, 4.49%.
4.6.1. Methyl 4-.2-pyridyl)benzoate .15a). The general
procedure 2 ,5 h at 2408C), starting from 1a, gave 95%
,eluent: CH2Cl2/Et2O 90:10) of 15a: mp 99±1008C ,lit.34
1
mp 988C); the H NMR data are in accordance with those
of the literature;34 13C NMR ,CDCl3) d 52.6, 121.5, 123.3,
126.8 ,2C), 130.4 ,2C), 133.3, 137.4, 143.8, 150.2, 156.6,
167.3. Anal. Calcd for C13H11NO2 ,213.24): C, 73.23; H,
5.20; N, 6.57. Found: C, 73.49; H, 5.46; N, 6.36%.
4.6.7. Methyl 4-.5-bromo-3-pyridyl)benzoate .15g). The
general procedure 2 ,18 h at 258C and P,tBu)3 ,20 mg,
0.10 mmol) instead of dppf), starting from 12c, gave 62%
1
,eluent: CH2Cl2/Et2O 90:10) of 15g: mp 260±2628C; H
4.6.2. Methyl 4-.2-pyrimidyl)benzoate .15b). The general
procedure 2 ,5 h at 2408C), starting from 8a, gave 36%
,eluent: CH2Cl2/Et2O 90:10) of 15b: mp 146±1488C; H
NMR ,CDCl3) d 3.96,s, 3H, CH 3), 7.74 ,d, 2H, Jˆ
1
0
7.9 Hz, Ph), 8.16,s, 1H, H 4 ), 8.25 ,d, 2H, Jˆ7.9 Hz, Ph),
8.96,s, 1H, H 2 ), 8.97 ,s, 1H, H6 ); 13C NMR ,CDCl3) d
52.7, 121.1, 125.7, 128.1 ,2C), 130.1 ,2C), 131.1, 138.8,
142.5, 151.4, 160.0, 166.8; IR ,KBr) n 3015, 2958, 1721,
1608, 1433, 1283, 1192, 1109, 856, 770, 703 cm21. Anal.
Calcd for C13H10BrNO2 ,292.13): C, 53.45; H, 3.45; N, 4.79.
Found: C, 53.48; H, 3.59; N, 4.82%.
0
0
NMR ,CDCl3) d 3.87 ,s, 3H, CH3), 7.16,t, 1H, Jˆ4.9 Hz,
0
H5 ), 8.07 ,d, 2H, Jˆ8.6Hz, H 2,6), 8.44 ,d, 2H, Jˆ8.6Hz,
H3,5), 8.76,d, 2H, Jˆ4.9 Hz, H4 ,6 ); 13C NMR ,CDCl3) d
52.6, 120.1, 128.5 ,2C), 130.2 ,2C), 132.3, 142.0, 157.7
,2C), 164.1, 167.2; IR ,KBr) n 2949, 1723, 1563, 1532,
0
0
1418, 1114, 817, 758, 698 cm21
. Anal. Calcd for
C12H10N2O2 ,214.23): C, 67.28; H, 4.71; N, 13.08. Found:
C, 67.38; H, 4.75; N, 13.14%.
4.6.8. Ethyl 6-.4-.methoxycarbonyl)phenyl)nicotinate
.15h). The general procedure 2 ,6h at 2408C), starting
from 13a, gave 95% ,eluent: CH2Cl2/Et2O 90:10) of 15h:
mp 116±1178C; 1H NMR ,CDCl3) d 1.35 ,t, 3H, Jˆ7.1 Hz,
CH3), 3.91 ,s, 3H, OCH3), 4.40 ,q, 2H, Jˆ7.1 Hz, CH2),
7.79 ,d, 1H, Jˆ7.9 Hz, H5), 8.08 ,s, 4H, Ph), 8.32 ,d, 1H,
Jˆ7.9 Hz, H4), 9.95 ,s, 1H, H2); 13C NMR ,CDCl3) d 14.9,
52.9, 62.1, 121.1, 125.7, 128.1 ,2C), 130.1 ,2C), 131.1,
138.8, 142.5, 151.4, 160.0, 166.8, 167.1; IR ,KBr) n
2982, 2981, 1731, 1710, 1595, 1439, 1371, 1284, 1117,
756cm 21. Anal. Calcd for C16H15NO4 ,285.30): C, 67.36;
H, 5.30; N, 4.91. Found: C, 67.79; H, 5.41; N, 4.86%.
4.6.3. Methyl 4-.2-pyrazyl)benzoate .15c). The general
procedure 2 ,5 h at 2408C), starting from 8b, gave 32%
,eluent: CH2Cl2/Et2O 90:10) of 15c: mp 144±1468C; H
1
NMR ,CDCl3) d 3.88 ,s, 3H, CH3), 8.03 ,d, 2H, Jˆ
8.7 Hz, H2,6), 8.10 ,d, 2H, Jˆ8.7 Hz, H3,5), 8.51 ,dd, 1H,
0
0
Jˆ2.6, 1.5 Hz, H5 ), 8.60 ,d, 1H, Jˆ2.6Hz, H 6 ), 9.01 ,d,
1H, Jˆ1.5 Hz, H3 ); 13C NMR ,CDCl3) d 53.5, 126.9 ,2C),
0
130.3 ,2C), 131.8, 140.4, 142.4, 143.6, 144.4, 151.7, 167.2;
IR ,KBr) n 2963, 1720, 1262, 1099, 1017, 700 cm21. Anal.
Calcd for C12H10N2O2 ,214.23): C, 67.28; H, 4.71; N, 13.08.
Found: C, 67.54; H, 4.47; N, 12.93%.
4.6.9. Ethyl 2-.4-.methoxycarbonyl)phenyl)isonicotinate
.15i). The general procedure 2 ,4 h at 2208C), starting from
13b, gave 90% ,eluent: CH2Cl2/Et2O 90:10) of 15i: mp
4.6.4. Phenyl 6-..4-methoxycarbonyl)phenyl)pyridine-2-
sulfone .15d). The general procedure 2 ,18 h at 258C),
starting from 3, gave 32% ,eluent: CH2Cl2/Et2O 90:10) of
15d: mp 1808C; 1H NMR ,CDCl3) d 3.81 ,s, 3H, CH3), 7.46
,m, 3H, H3,5, Ph), 7.78 ,t, 1H, Jˆ7.9 Hz, H4), 7.87 ,m, 3H,
1
668C; H NMR ,CDCl3) d 1.35 ,t, 3H, Jˆ7.2 Hz, CH3),
3.93 ,s, 3H, OCH3), 4.38 ,q, 2H, Jˆ7.2 Hz, CH2), 7.73 ,d,
1H, Jˆ4.9 Hz, H5), 8.06,s, 4H, Ph), 8.25 ,s, 1H, H ), 8.78
3

V. Bonnet et al. / Tetrahedron 58 82002) 4429±4438
4437
,d, 1H, Jˆ4.9 Hz, H6); 13C NMR ,CDCl3) d 14.6, 52.6, 62.4,
Acknowledgements
120.5, 122.3, 127.3 ,2C), 130.5 ,2C), 131.1, 139.1, 142.9,
150.9, 157.5, 165.4, 167.1; IR ,KBr) n 3063, 1726, 1599,
1390, 1292, 1275, 1111 cm21. Anal. Calcd for C16H15NO4
,285.30): C, 67.36; H, 5.30; N, 4.91. Found: C, 67.33; H,
5.27; N, 4.71%.
We thank the DFG ,Leibniz-Program) and the CNRS for
®nancial support. We thank Chemetall GmbH ,Frankfurt)
and the Degussa ,Hanau) for the generous gift of chemicals.
4.6.10. Methyl 4-.5-cyano-2-pyridyl)benzoate .15j). The
general procedure 2 ,6h at 2408C), starting from 14, gave
86% ,eluent: CH2Cl2/Et2O 90:10) of 15j: mp 16 28C; H
References
1
1. ,a) Katritzky, A. R.; Rees, C. W. Comprehensive Heterocyclic
Chemistry; Vol. 2; Pergamon: New York, 1984.
NMR ,CDCl3) d 3.93 ,s, 3H, CH3), 7.92 ,d, 1H, Jˆ
0
0
7.8 Hz, H3 ), 8.07 ,d, 1H, Jˆ7.8 Hz, H4 ), 8.16,m, 4H,
Â
,b) Queguiner, G.; Marsais, F.; Snieckus, V.; Epsztajn, J.
Adv. Heterocycl. Chem. 1991, 52, 187. ,c) Mongin, F.;
Ph), 9.00 ,s, 1H, H6 ); 13C NMR ,CDCl3) d 52.8, 116.2,
0
120.9, 127.7 ,2C), 128.4, 130.6,2C), 132.7, 138.7, 140.5,
152.9, 157.3, 163.8; IR ,KBr) n 3015, 2959, 2240, 1720,
1438, 1274, 1112, 1108, 835, 749 cm21. Anal. Calcd for
C14H10N2O2 ,238.25): C, 70.58; H, 4.23; N, 11.76. Found:
C, 70.27; H, 4.67; N, 11.49%.
Â
Queguiner, G. Tetrahedron 2001, 57, 4059. ,d) Turck, A.;
Â
Ple, N.; Mongin, F.; Queguiner, G. Tetrahedron 2001, 57,
Â
4489.
2. Stanforth, S. P. Tetrahedron 1998, 54, 263 and references
cited therein.
3. ,a) Negishi, E.-i.; King, A. O.; Okukado, N. J. J. Org. Chem.
1977, 42, 1821. ,b) Sakamoto, T.; Kondo, Y.; Murata, Y.;
4.6.11. Ethyl 5-.4-.methoxycarbonyl)phenyl)nicotinate
.15k). The general procedure 2 ,18 h at 08C and P,tBu)3
,20 mg, 0.10 mmol) instead of dppf), starting from 1h,
gave 63% ,eluent: CH2Cl2/Et2O 90:10) of 15k: mp 98±
Â
Yamanata, H. Tetrahedron 1993, 43, 9713. ,c) Trecourt, F.;
Â
Gervais, B.; Mallet, M.; Queguiner, G. J. Org. Chem. 1996,
Â
61, 1673. ,d) Trecourt, F.; Gervais, B.; Mongin, O.; Le Gal,
1
1008C; H NMR ,CDCl3) d 1.37 ,t, 3H, Jˆ7.2 Hz, CH3),
Â
C.; Mongin, F.; Queguiner, G. J. Org. Chem. 1998, 63, 2892.
3.89 ,s, 3H, OCH3), 4.40 ,q, 2H, Jˆ7.2 Hz, CH2), 7.69 ,m,
2H, Ph), 8.10 ,m, 2H, Ph), 8.44 ,t, 1H, Jˆ1.9 Hz, H4), 8.96
,d, 1H, Jˆ1.9 Hz, H6), 9.17 ,d, 1H, Jˆ1.9 Hz, H2); 13C
NMR ,CDCl3) d 13.3, 51.3, 60.9, 125.4, 126.2 ,2C),
129.2, 129.4 ,2C), 134.4, 140.0, 142.3, 149.1, 150.7,
164.1, 165.6; IR ,KBr) n 3036, 2956, 1933, 1720,1718,
1439, 1276, 1255, 1171, 854, 762 cm21. Anal. Calcd for
C16H15NO4 ,285.30): C, 67.36; H, 5.30; N, 4.91. Found:
C, 67.77; H, 5.67; N, 4.81%.
,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.
4. ,a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
,b) Suzuki, A. J. Organomet. Chem. 1999, 576, 147.
 Â
,c) Godard, A.; Turck, A.; Ple, N.; Marsais, F.; Queguiner,
G. Trends Heterocycl. Chem. 1993, 3, 19. ,d) Godard, A.;
Â
Â
Â
Marsais, F.; Ple, N.; Trecourt, F.; Turck, A.; Queguiner, G.
Heterocycles 1995, 40, 1055. ,e) Ishikura, M.; Kamada, M.;
Terashima, M. Synthesis 1984, 936. ,f) Schomaker, J. M.;
Thomas, T. J. J. Org. Chem. 2001, 66, 7125.
4.7. General procedure 3: preparation of phenyl
derivatives 16
5. ,a) Stille, J. K. Angew. Chem. Int. Ed. 1986, 25, 508.
,b) Mathieu, J.; Gros, Ph.; Fort, Y. Tetrahedron Lett. 2001,
42, 1879.
In a ®rst ¯ask, a solution of iPrMgCl ,1.2 mmol) in THF
,0.6mL) was added at 2408C to a solution of 1-cyano-4-
iodobenzene ,0.27 g, 1.2 mmol) in THF ,5 mL). After 1 h at
this temperature, 4-cyanophenylmagnesium chloride is
formed. In a second ¯ask, Pd,dba)2 ,29 mg, 0.050 mmol),
dppf ,27 mg, 0.050 mmol) and, 10 min later, the halo
derivative ,1.0 mmol) were added to THF ,3 mL). After
stirring for 30 min at rt, the solution of 4-cyanophenyl-
magnesium chloride was added dropwise at 2408C. After
6 h at 2408C, the mixture was quenched with an aqueous
saturated NH4Cl solution ,5 mL).
6. To our knowledge, organomagnesium reagents have been only
involved in cross-couplings with not functionalized substrates,
for examples in the pyridine series, see: ,a) Pridgen, L. N.
È
J. Heterocycl. Chem. 1975, 12, 443. ,b) Bohm, V. P. W.;
Weskamp, T.; Gstottmayr, C. W. K.; Herrmann, W. A.
Ã
Angew. Chem. Int. Ed. 2000, 39, 1602. See also: Metal-
catalyzed Cross-coupling Reactions; Diederich, F., Stang,
P. J., Eds.; Wiley±VCH: Weinheim, 1998.
È
7. ,a) For a short review, see: Rottlander, M.; Boymond, L.;
Berillon, L.; Lepretre, A.; Varchi, G.; Avolio, S.; Laaziri,
Â
Ã
4.7.1. Ethyl 6-.4-cyanophenyl)nicotinate .16). The
general procedure 3, starting from 1f, gave 87% ,eluent:
CH2Cl2/Et2O 90:10) of 16: mp 120±1248C; 1H NMR
,CDCl3) d 1.37 ,t, 3H, Jˆ7.2 Hz, CH3), 4.38 ,q, 2H,
Â
H.; Queguiner, G.; Ricci, A.; Cahiez, G.; Knochel, P. Chem.
Â
Eur. J. 2000, 6, 767. ,b) Trecourt, F.; Breton, G.; Bonnet, V.;
Â
Mongin, F.; Marsais, F.; Queguiner, G. Tetrahedron Lett.
Â
1999, 40, 4339. ,c) Trecourt, F.; Breton, G.; Bonnet, V.;
Â
Mongin, F.; Marsais, F.; Queguiner, G. Tetrahedron 2000,
0
0
Jˆ7.2 Hz, CH2), 7.73 ,d, 2H, Jˆ6.1 Hz, H2 ,6 ), 7.79 ,d,
0
0
1H, Jˆ7.4 Hz, H5), 8.12 ,d, 2H, Jˆ6.1 Hz, H3 ,5 ), 8.33
,dd, 1H, Jˆ7.4, 2.1 Hz, H4), 9.24 ,d, 1H, Jˆ2.1 Hz, H2);
13C NMR ,CDCl3) d 13.3, 60.6, 112.3, 117.3, 119.3, 124.6,
126.9 ,2C), 131.7 ,2C), 137.2, 141.3, 150.2, 157.4, 164.0;
IR ,KBr) n 2963, 2223, 1713, 1593, 1287, 1264, 1120,
1023, 782 cm21. Anal. Calcd for C15H12N2O2 ,252.28): C,
71.42; H, 4.79; N, 11.10. Found: C, 71.25; H, 4.88; N,
10.98%.
56, 1349. ,d) Bolm, C.; Pupowicz, D. Tetrahedron Lett.
1997, 38, 7349.
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