First regioselective ortho-lithiation induced by a 2-chloropyridyl group complexation

Article abstract of DOI:10.1021/jo026788g

It is shown that t-BuLi in Et₂O promotes an exclusive regioselective metalation of 2-aryl-6-chloropyridine compounds at the aromatic ortho position demonstrating that the 2-chloropyridyl moiety may be considered as a directing group. This funct

Full text of DOI:10.1021/jo026788g

F ir st Regioselective Or th o-Lith ia tion In d u ced by a
2-Ch lor op yr id yl Gr ou p Com p lexa tion
Yves Fort* and Alain L. Rodriguez
Synthe`se Organique et Re´activite´, UMR CNRS-UHP 7565, Faculte´ des Sciences,
Universite´ Henri Poincare´-Nancy I, BP 239, 54506, Vandoeuvre-Le`s-Nancy, France
yves.fort@sor.uhp-nancy.fr
Received December 2, 2002
It is shown that t-BuLi in Et2O promotes an exclusive regioselective metalation of 2-aryl-6-
chloropyridine compounds at the aromatic ortho position demonstrating that the 2-chloropyridyl
moiety may be considered as a directing group. This functionally directed metalation group was
successfully used for the selective lithiation of substituted aromatics and for the straightforward
preparation of new N,P ligands.
In tr od u ction
and a strong acidity of hydrogens on the thienyl ring. A
similar DoM effect of the pyridine nitrogen atom in ortho-
lithiation of 2,6-diphenylpyridine and 2-alkyl-6-phenylpy-
ridine compounds has been previously reported.7 How-
ever, such metalations were often not selective and the
absence of functionality on the pyridine ring prevented
all modifications of the pyridinic structure. To the best
of our knowledge, Kauffmann was the only one to report
an example in a heteroaromatic series of a lithiation at
the ortho position of a functional pyridyl group.8 Never-
theless, whatever the basic system used, the metalation
of 2-chloro-6-(2-thienyl)pyridine was still not selective at
the C-γ position on the thienyl ring.
The recognition by Hauser in 19621 that the dimethy-
laminomethyl group could facilitate the direct ortho-
metalation (DoM effect)2a of unreactive aromatics pro-
vided the impetus for a large body of work aimed at
exploiting the synthetic utility of complexing effects. Aryl,
vinyl, and even unactivated alkyl compounds can be
metalated when suitable chelation is provided.2 Chelation
effects have been used to prepare useful lithium com-
pounds but also to provide structural rigidity to control
the stereochemistry of the formation of lithium reagents.3
Despite the importance of these effects, there are rela-
tively few studies on the efficient lithiation of aromatic
and heteroaromatic groups assisted by the intramolecular
pyridine nitrogen atom complexation.4 In fact, nucleo-
philic lithiated reagents generally attack the pyridine
ring even at low temperature.5 Singh has recently
reported that 2-(3-thienyl)pyridine can be easily depro-
tonated at the C-R position of the thienyl ring.6 This
regioselective deprotonation was interpreted as the con-
sequence of an intramolecular pyridyl group coordination
Herein, we describe for the first time the selective and
direct mono-metalation based on the intramolecular
functionalized pyridyl group complexation, thus providing
a convenient access to useful synthons and new electron-
releasing N,P ligands.9
Resu lts a n d Discu ssion
In connection with the study of Kauffmann,8 we
introduced chlorine at the C-6 position of 2-phenylpyri-
dine. Three sites of metalation could be envisioned for
2-chloro-6-phenylpyridine (1,10 Scheme 1). At first, the
2-chloropyridyl group has the potential to act as a
directing metalation group (DMG) by a complex-induced
proximity effect (CIPE)11 thereby directing lithiation to
the ortho-positon of the adjacent phenyl ring. The nitro-
(1) (a) J ones, F. N.; Hauser, C. R. J . Org. Chem. 1962, 27, 701. (b)
J ones, F. N.; Zinn, M. F.; Hauser, C. R. J . Org. Chem. 1963, 28, 663.
(2) (a) Snieckus, V. Chem. Rev. 1990, 90, 879 and references therein.
(b) Slocum, D. W.; J ennings, C. A. J . Org. Chem. 1976, 41, 3653. (c)
Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 19, 356. (d) Beak, P.;
Snieckus, V. Acc. Chem. Res. 1982, 15, 306. (e) Beak, P.; Zajdel, W. J .;
Reitz, D. B. Chem. Rev. 1984, 84, 471. (f) Klump, G. W. Recl. Trav.
Chim. Pays-Bas 1986, 105, 1.
(3) (a) Lamothe, S.; Chan, T. H. Tetrahedron Lett. 1991, 32, 1847.
(b) Hartley, R. C.; Lamothe, S.; Chan, T. H. Tetrahedron Lett. 1993,
34, 1449. (c) Myers, A. G.; McKinstry, L. J . Org. Chem. 1996, 61, 2428.
(d) Rein, K.; Goicoechea-Pappas, M.; Anklekar, T. V.; Hart, G. C.;
Smith, G. A.; Gawley, R. E. J . Am. Chem. Soc. 1989, 111, 2211. (e)
Klein, S.; Marek, I.; Poisson, J .-F.; Normant, J .-F. J . Am. Chem. Soc.
1995, 117, 8853. (f) Riant, O.; Samuel, O.; Flessner, T.; Taudien, S.;
Kagan, H. B. J . Org. Chem. 1997, 62, 6733. (g) Bowles, P.; Clayden,
J .; Tomkinson, M. Tetrahedron Lett. 1995, 36, 9219. (h) Hoppe, D.;
Gonschorrek, C. Tetrahedron Lett. 1987, 28, 785.
(6) (a) Mugesh, G.; Singh, H. B. Acc. Chem. Res. 2002, 35, 226. (b)
Singh, H. B.; Sudha, N. J . Organomet. Chem. 1990, 397, 153. For a
nonselective deprotonation of 2,2′-bipyridine and 2,4′-bipyridine with
one nitrogen atom directing the lithiation, see: Zoltewicz, J . A.; Dill
C. D. Tetrahedron 1996, 52, 14469.
(7) (a) Cornioley-Deuschel, C.; Ward, T.; von Zelewsky, A. Helv.
Chim. Acta 1988, 71, 130. (b) Deuschel-Cornioley, C.; Stoeckli-Evans,
H.; von Zelewsky, A. J . Chem. Soc., Chem. Commun. 1990, 121. (c)
Gschwend, H. W.; Rodriguez, H. R. Org. React. 1979, 26, 1.
(8) Kauffmann, T.; Mitschker, A.; Woltermann, A. Chem. Ber. 1983,
116, 6, 992.
(4) For an intramolecular pyridine nitrogen atom coordination
assisting the deprotonation of a methyl group on silicon, see: Itami,
K.; Kamei, T.; Mitsudo, K.; Nokami, T.; Yoshida, J .-I. J . Org. Chem.
2001, 66, 3970.
(5) Mongin, F.; Que´guiner, G. Tetrahedron 2001, 57, 4059 and
references therein.
(9) For reviews on N,P ligands and related metal complexes see:
(a) Newkome, G. Chem. Rev. 1993, 93, 2067. (b) Helmchen, G.; Pfaltz,
A. Acc. Chem. Res. 2000, 33, 336.
10.1021/jo026788g CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/16/2003
4918
J . Org. Chem. 2003, 68, 4918-4922

Selective Lithiation of Substituted Aromatics
SCHEME 1
F IGURE 1.
TABLE 1. Con d ition s for Selective Dep r oton a tion of 1a
entry
base (equiv)
solvent
conditions
resultb
1
2
3
4
5
6
7
8
LiTMP (3)
n-BuLi (2)
LiTMP (3)
n-BuLi (2)
MeLi (1)
PhLi (1)
s-BuLi (1)
t-BuLi (1)
THF
-78 °C, 3 h
-78 °C, 3 h
-78 °C, 3 h
-78 °C, 3 h
-78 °C, 3 h
-78 °C, 3 h
-78 °C, 3 h
-78 °C, 3 h
3b (78)
3b (72)
n.r.c
THF
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
n.r.c
n.r.c
n.r.c
n.r.c
2b (42)
1 (36)
2b (62)
1 (17)
3b (33)
4b (29)
gen atom should subsequently ensure stabilization of the
formed lithiated intermediate 2a .
9
t-BuLi (1.4)
t-BuLi (1.4)
Et2O/cumened
THF/cumenee
-78 °C, 3 h
-78 °C, 3 h
Nevertheless, competition could result from lithiation
at the position ortho to the chlorine atom conducting to
3a . In addition, as reported by Radinov for chloropyridine
compounds,12 a metalation at the acidic para position of
the pyridinic nitrogen atom also could be considered
providing the lithiated intermediate 4a . Finally, it was
hoped that the nucleophilic substitution of the chlorine
atom could be avoided by use of low reaction temperature
and a nonnucleophilic base.
10
a
b
All reactions performed on 1 mmol of 1. Isolated yields are
given in parentheses. c n.r.: no reaction. Et2O/cumene ratio: 1/1
d
e THF/cumene ratio: 1/1.
chelation of the pyridyl group does not tolerate the
presence of a chlorine atom on the pyridinic substrates.15
In a preliminary study, we examined various basic
reagents for the deprotonation of 1. The selective produc-
tion of the ortho-lithiated intermediate 2a versus 3a
and 4a was evaluated by condensation of MeSSMe as
an electrophile, producing 2b, 3b, and 4b, respectively
(Figure 1). The main results obtained are reported in
Table 1.
As expected with the nonnucleophilic lithium amides,13
a selective metalation at the C-3 position of 1 was
efficiently obtained in the presence of an excess of LiTMP
in THF at -78 °C (entry 1), while no reaction was
detected in Et2O (entry 3). The same behavior was
obtained with 2 equiv of n-BuLi in THF at -78 °C (entry
2). It must be noted that raising the temperature to
only 0 °C produced traces of Cl-Bu nucleophilic sub-
stitution.
On an other hand, whereas n-BuLi, s-BuLi, MeLi, or
PhLi did not work in Et2O (entries 4-7), we were pleased
to observe a selective deprotonation at the ortho position
of the phenyl group with t-BuLi (entry 8).14 This result
is of particular interest since, to the best of our knowl-
edge, even the well-known transition metal-catalyzed
C-H bond activation with the aid of an intramolecular
We next found that the use of 1.4 equiv of t-BuLi in a
mixture of Et2O/cumene gave the single product 2b in
62% yield (entry 9). One portion of cumene in Et2O
increased at -78 °C the solubility of starting material,
without loss of regioselectivity in the metalation. Note
that, whatever the reaction time, the temperature of
lithiation, and the amount of t-BuLi, we were unable to
increase the conversion of 1. A dramatic solvent effect
was also observed in the regioselective lithiation obtained
with t-BuLi. When the metalation was performed in THF
instead of Et2O, the desired deprotonation did not occur
at all. Indeed a mixture of lithiated products at the ortho
and meta position of the chlorine atom (producing 3b and
4b, respectively) was obtained (entry 10). The THF effect
could be subsequently attributed to the inhibition of the
preequilibrium complex A formation by external coordi-
nation (Scheme 2). Consequently, 2-chloro-6-phenylpy-
ridine was deprotonated at the position ortho to the
chlorine atom as a consequence of its DoM effect, and at
the acidic para position of the pyridine ring. It then may
be assumed that the complexation of the nitrogen atom
is crucial for the orientation of the metalation.
To substantiate the importance of the chlorine atom
in the metalation of 1, we replaced this substituent with
methoxy and 1-pyrrolidinyl to afford 2-methoxy-6-phen-
ylpyridine (5) and 2-phenyl-6-(1-pyrrolidinyl)pyridine
(6).16 As a consequence of the methoxy group directing
(10) 2-Chloro-6-phenylpyridine (1) was prepared via a direct lithia-
tion at the C-6 position of the 2-phenylpyridine with 3 equiv of the
n-BuLi-LiDMAE superbase, see: Gros, Ph.; Fort, Y. Eur. J . Org.
Chem. 2002, 3375.
(11) For a review on CIPE, see: Beak, P.; Basu, A.; Gallagher, D.
J .; Park, Y. S.; Thayumanavan, S. Acc. Chem. Res. 1996, 29, 552 and
references 2a and 2c.
(15) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. Rev. 2002, 102, 1731
and references therein.
(12) Radinov, R.; Chanev, C.; Haimova, M. J . Org. Chem. 1991, 56,
4793.
(16) A nucleophilic substitution and a N-arylamination by Nickel
clusters catalyzed by 1 afforded respectively compounds 5 and 6; see:
(a) Desmarets, C.; Schneider, R.; Fort, Y. Tetrahedron Lett. 2000, 41,
2875. (b) Desmarets, C.; Schneider, R.; Fort, Y. Tetrahedron Lett. 2001,
42, 247. (c) Brenner, E.; Schneider, R.; Fort, Y. Tetrahedron Lett. 2000,
41, 2881. (d) Brenner, E.; Schneider, R.; Fort, Y. Tetrahedron 1999,
55, 12829.
(13) (a) Gribble, G. W.; Saulnier, M. G. Tetrahedron Lett. 1980, 21,
4137. (b) Marsais, F.; Que´guiner, G. Tetrahedron 1983, 39, 2009. (c)
Remuzon, P.; Bouzard, D.; J acquet, J .-P. Heterocycles 1993, 36, 431.
(d) Watson, S. E.; Markovich, A. Heterocycles 1998, 48, 2149.
(14) The regioselectivity was determinated by NMR 1H, 13C and
COSY 1H-1H spectroscopies.
J . Org. Chem, Vol. 68, No. 12, 2003 4919

Fort and Rodriguez
TABLE 2. Selective Meta lla tion of Ch lor op yr id in e
SCHEME 2
Com p ou n d s in Et2O/Cu m en e (1/1) a t -78 °C w ith 1.4
equ iv of t-Bu Lia
effect, t-BuLi efficiently accomplished in Et2O/cumene a
lithiation at the C-3 position on the pyridine ring. This
result contrasted with those obtained with 1. An expla-
nation could be a difference of strength in lithium
complexation between Cl and MeO. Since the O-Li
interaction is assumed to be stronger than that of
chlorine, the methoxy group more strongly competes in
lithium complexation with the pyridine nitrogen than the
chlorine atom. The consequence is a delivery of tert-
butyllithium at the ortho position of the methoxy group.
In the case of 2-phenyl-6-(1-pyrrolidinyl)pyridine (6), no
reaction occurred with the addition of t-BuLi. This
pronounced difference between 6 and 1 implies the
governance of the deprotonation not only by the complex
induced proximity effects but also by the acidification of
hydrogens due to the presence of an electron-withdrawing
chlorine atom on the pyridine ring in 1. In addition, the
steric effect could also intervene.
After determining the best conditions for selective
lithiation of 1 at the ortho position of the phenyl group,
we demonstrated the scope of the 2-chloropyridyl DMG
by preparing a series of ortho-substituted 2-chloro-6-
phenylpyridine compounds (Table 2). The versatility of
our methodology was clearly demonstrated by introduc-
ing various functionalities efficiently at the ortho position
(entries 4-9). Compounds 2e-g,i,j were particularly
attractive since they bear potentially reactive functional
groups.
a
b
All reactions performed on 1 mmol of substrate. Isolated
yields after chromatography on silica gel. c 14-21% of 1 recovered.
Deuterium content: 83% (1H NMR). e The lithiation was per-
d
formed at -50 °C. f Deuterium content: 95% (1H NMR).
We also investigated the deprotonation of other related
2-aryl-6-chloropyridines (entries 10-13). As in the case
of 1, 2g, 9, and 11 were exclusively deprotonated at the
position ortho to the 2-chloropyridyl group. This regiose-
lective aromatic metalation involves a stronger ortho-
directing effect of the 2-chloropyridyl group compared to
the DoM effect of the chlorine atom13 or to the ortho- and
sometimes para-directing effects of the trifluoromethyl
group (entries 10-12).17 An additive effect between the
pyridyl group and the chlorine atom can explain the
observed regioselectivity with compound 11 (entry 13).
The total consumption of reagents 2g, 9, and 11 during
the lithiation could result from the acidification of
hydrogens induced by the presence of electron-withdraw-
ing groups on the phenyl ring.
We finally examined structural modifications of the
pyridine ring using the C-Cl bond as a source of further
functionalizations. In this context, the useful synthon 2j
led us to investigate its reactivity for the preparation of
new N,P ligands. As shown in Scheme 3, according to
our previous work on Nickel cluster-catalyzed arylami-
nation,18 the reaction of 2j with pyrrolidine efficiently
gave the new N,P,N ligand 13. Palladium-catalyzed cross-
couplings could also be performed since 2j efficiently
coupled in the presence of CsF19 with naphthylboronic
acid to produce 14 in good yield. Finally, the substitution
reaction with sodium ethanethiolate in DMF afforded the
new mercapto ligand 15 in good yield.
(17) (a) Porwisiak, J .; Dmowski, W. Tetrahedron 1994, 50, 12259.
(b) Schlosser, M.; Mongin, F.; Porwisiak, J .; Dmowski, W.; Bu¨ker, H.
H.; Nibbering, N. H. H. Chem. Eur. J . 1998, 4, 1281. (c) Uchiyama,
M.; Miyoshi, T.; Kajihara, Y.; Sakamoto, T.; Otani, Y.; Ohwada, T.;
Kondo, Y. J . Am. Chem. Soc. 2002, 124, 8514.
(18) (a) Desmarets, C.; Schneider, R.; Fort, Y. J . Org. Chem. 2002,
67, 3029. (b) Brenner, E.; Fort, Y. Tetrahedron Lett. 1998, 39, 5359.
(19) (a) Wright, S.; Hageman, L.; McClure, L. J . Org. Chem. 1994,
59, 6095. (b) Ford, A.; Sinn, E.; Woodward, S. J . Chem. Soc., Perkin
Trans. 1 1997, 24, 927.
4920 J . Org. Chem., Vol. 68, No. 12, 2003

Selective Lithiation of Substituted Aromatics
SCHEME 3 a
(19). Anal. Calcd for C12H10ClNS: C, 61.14; H, 4.28; N, 5.94.
Found: C, 60.89; H, 4.52; N, 6.05.
2-Ch lor o-6-(2-d eu t er iop h en yl)p yr id in e (2c). Column
chromatography (9:1 hexanes/AcOEt) yielded 2c (144 mg, 76%,
1
deuterium content: 83%) as a white solid, mp 36-38 °C; H
NMR δH 7.23 (dd, J ) 7.6 and 1.0 Hz, 1H), 7.41-7.46 (m, 3H),
7.62 (dd, J ) 7.7 and 1.0 Hz, 1H), 7.67 (t, J ) 7.8 Hz, 1H),
7.98 (br d, J ) 7.5 Hz, 1H); 13C NMR δC 118.5, 122.4, 126.8,
128.6, 129.6, 137.5, 139.1, 151.1, 157.9. MS (EI) m/z 192 (34),
191 (44), 190 (100), 155 (49), 128 (29). Anal. Calcd for C11DH7-
ClN: C, 69.30; H, 3.70; N, 7.35. Found: C, 69.14; H, 4.41; N,
7.24.
2-Ch lor o-6-(2-m eth ylph en yl)pyr idin e (2d). Column chro-
matography (9:1 hexanes/AcOEt) yielded 2d (92 mg, 45%) as
1
a pale oil; H NMR δH 2.30 (s, 3H), 7.28-7.34 (m, 4H), 7.35
(d, J ) 7.6 Hz, 1H), 7.41 (br d, J ) 7.2 Hz, 1H), 7.73 (t, J )
7.6 Hz, 1H); 13C NMR δC 20.4, 122.3, 122.6, 126.1, 128.8, 129.8,
131.0, 136.0, 138.9, 139.0, 150.8, 160.7. MS (EI) m/z 205 (14),
204 (36), 203 (46), 202 (100), 168 (21), 167 (26), 166 (22). Anal.
Calcd for C12H10ClN: C, 70.77; H, 4.95; N, 6.88. Found: C,
70.58; H, 4.74; N, 6.73.
a
Reagents and conditions: (i) Pyrrolidine, 10 mol % of Ni(OAc)2,
NaH/t-AmONa, THF, reflux. (ii) Naphthyl-B(OH)2, CsF, 10 mol
% of Pd(PPh3)2Cl2, DME, reflux. (iii) EtSNa, DMF, rt then 50 °C.
[2-(6-Ch lor o-2-pyr idin yl)ph en yl](ph en yl)m eth an ol (2e).
Column chromatography (8:2 hexanes/AcOEt) yielded 2e (157
1
mg, 53%) as a pale oil; H NMR δH 5.86 (br s, 2H), 7.14 (br t,
In conclusion, we have shown that the 2-chloropyridyl
group may be used as a directing ortho-metalation group
in an aromatic series allowing a regioselective lithiation
process. Subsequent functionalization of the C-Cl bond
provided an efficient method for the straightforward
synthesis of useful synthons and new N,P ligands.
Further investigations to extend the scope of this reaction
are currently in progress.
J ) 7.2 Hz, 1H), 7.21 (d, J ) 8.0 Hz, 1H), 7.24, (t, J ) 7.2 Hz,
2H), 7.27 (br d, J ) 7.6 Hz, 2H), 7.32 (d, J ) 7.6 Hz, 1H),
7.35-7.37 (m, 1H), 7.40-7.43 (m, 2H), 7.45-7.47 (m, 1H), 7.65
(t, J ) 7.6 Hz, 1H); 13C NMR δC 74.2, 122.3, 122.4, 126.1, 126.5,
127.6, 127.9, 129.6, 130.4, 130.5, 138.3, 139.7, 143.6, 149.5,
160.2. MS (EI) m/z 297 (33), 296 (33), 295 (100), 260 (5), 241
(52), 218 (32), 216 (32). Anal. Calcd for C18H14ClNO: C, 73.10;
H, 4.77; N, 4.74. Found: C, 73.29; H, 4.61; N, 4.45.
[2-(6-C h lo r o -2-p y r id in y l)p h e n y l](d ic y c lo p r o p y l)-
m eth a n ol (2f). Column chromatography (8:2 hexanes/AcOEt)
yielded 2f (155 mg, 55%) as an orange solid, mp 104-106 °C;
1H NMR δH 0.24-0.29 (m, 2H), 0.30-0.39 (m, 2H), 0.41-0.47
(m, 2H), 0.60-0.66 (m, 2H), 1.04-1.11 (m, 2H), 7.28 (dd, J )
7.6 and 1.2 Hz, 1H), 7.32 (d, J ) 8.0 Hz, 1H), 7.36 (dd, J ) 7.6
and 0.8 Hz, 1H), 7.43 (d, J ) 8.0 Hz, 1H), 7.46 (td, J ) 8.0
and 1.2 Hz, 1H), 7.77 (t, J ) 7.6 Hz, 1H), 8.08 (dd, J ) 8.0
and 0.8 Hz, 1H); 13C NMR δC 1.5, 2.1, 21.2, 73.0, 122.1, 123.0,
126.6, 127.7, 128.6, 132.2, 138.4, 139.6, 147.4, 149.1, 163.9.
MS (EI) m/z 284 (1), 282 (3), 260 (32), 259 (17), 258 (100), 216
(30). Anal. Calcd for C18H18ClNO: C, 72.11; H, 6.05; N, 4.67.
Found: C, 72.15; H, 6.17; N, 4.69.
Exp er im en ta l Section
Gen er a l Meth od s. 1H and 13C NMR spectra were recorded
at 400 and 50 MHz, respectively (excepted for compound 2g,
which was recorded at 200 and 50 MHz, respectively), with
CDCl3 as solvent and TMS as internal standard for 1H NMR.
31P NMR spectra were recorded at 162 MHz. GC/MS (EI)
spectra was recorded on a HP5871 spectrometer.
Ma ter ia ls a n d Solven ts. Et2O, THF, DME, and cumene
were distilled from sodium-benzophenone and stored on
sodium wire before use. DMF was distilled from calcium
hydride immediately prior to use. t-BuLi was used as a 1.5 M
solution in pentane. n-BuLi was used as a 1.6 M solution in
hexanes. Crushed Ni(OAc)2‚4H2O was dried under vaccum (50
mmHg) at 110 °C for 15 h. Sodium hydride (65% in mineral
oil) was used after three washings with THF under nitrogen.
Gen er a l P r oced u r e for Or th o-Lith ia tion of 2-Ar yl-6-
ch lor op yr id in e. A solution of 2-chloro-6-phenylpyridine (191
mg, 1 mmol) in diethyl ether (2 mL) and cumene (2 mL) was
cooled at -78 °C. t-BuLi (0.93 mL, 1.4 mmol) was then added
dropwise under a nitrogen atmosphere. After 3 h of stirring
at -78 °C, the appropriate electrophile (2 mmol) was added
dropwise. The temperature was then allowed to raise to 20
°C. Hydrolysis was performed at this temperature with H2O
(5 mL). The aqueous phase was first extracted with diethyl
ether (10 mL) and then with dichloromethane (10 mL). After
drying (MgSO4), filtration, and evaporation of solvents the
crude product was purified by column chromatography on
silica gel.
2-Ch lor o-6-[2-(m eth ylsu lfan yl)ph en yl]pyr idin e (2b). Col-
umn chromatography (8:2 hexanes/AcOEt) yielded 2b (146 mg,
62%) as a yellow solid, mp 69-72 °C; 1H NMR δH 2.39 (s, 3H),
7.23 (td, J ) 7.6 and 1.2 Hz, 1H), 7.31 (dd, J ) 7.6 and 0.8 Hz,
1H), 7.34 (br d, J ) 7.6 Hz, 1H), 7.39 (td, J ) 7.6 and 1.2 Hz,
1H), 7.44 (dd, J ) 7.6 and 1.2 Hz, 1H), 7.51 (br d, J ) 7.6 Hz,
1H), 7.72 (t, J ) 7.6 Hz, 1H); 13C NMR δC 16.5, 122.6, 122.7,
125.0, 126.3, 129.3, 130.0, 137.4, 138.2, 138.6, 150.6, 158.7.
MS (EI) m/z 237 (2), 235 (55), 222 (34), 220 (100), 200 (4), 184
2-Ch lor o-6-(2-ch lor op h en yl)p yr id in e (2g). Column chro-
matography (8:2 hexanes/CH2Cl2) yielded 2g (99 mg, 44%) as
a yellow oil; 1H NMR δH 7.30 (dd, J ) 8.4 and 2.0 Hz, 1H),
7.32-7.36 (m, 2H), 7.43-7.48 (m, 1H), 7.56-7.63 (m, 2H), 7.70
(t, J ) 8.0 Hz, 1H); 13C NMR δC 122.9, 123.3, 127.0, 129.9,
130.1, 131.6, 132.0, 137.6, 138.4, 150.9, 157.1. MS (EI) m/z 227
(7), 226 (5), 225 (43), 223 (66), 190 (32), 188 (100). Anal. Calcd
for C11H7Cl2N: C, 58.96; H, 3.15; N, 6.25. Found: C, 58.74;
H, 3.42; N, 6.07.
2-Ch lor o-6-[(2-tr im eth ylsilyl)p h en yl]p yr id in e (2h ). Hy-
drolysis was performed with a 2 M aqueous solution of NaOH.
Column chromatography (9:1 hexanes/AcOEt) yielded 2h (157
mg, 60%) as a yellow oil; 1H NMR δH 0.13 (s, 9H), 7.33 (d, J )
7.6 Hz, 1H), 7.46-7.50 (m, 4H), 7.73 (t, J ) 7.6 Hz, 1H), 7.77-
7.79 (m, 1H); 13C NMR δC 0.7, 121.3, 122.4, 127.9, 128.7, 128.8,
135.6, 139.0, 139.8, 145.3, 150.4, 162.1. MS (EI) m/z 262 (1),
248 (36), 247 (20), 246 (100), 216 (2). Anal. Calcd for C14H16
-
ClNSi: C, 64.22; H, 6.16; N, 5.35. Found: C, 64.16; H, 6.12;
N, 5.33.
2-Ch lor o-6-[(2-tr ibu tylstan n yl)ph en yl]pyr idin e (2i). Col-
umn chromatography (9:1 hexanes/AcOEt) yielded 2i (243 mg,
51%) as a pale oil; 1H NMR δH 0.81 (t, J ) 7.2 Hz, 9H), 0.97-
0.99 (m, 6H), 1.22-1.29 (m, 6H), 1.36-1.42 (m, 6H), 7.25 (dd,
J ) 7.8 and 0.6 Hz, 1H), 7.37-7.40 (m, 2H), 7.59 (d, J ) 7.2
and 0.6 Hz, 1H), 7.67-7.71 (m, 3H); 13C NMR δC 11.8, 13.6,
27.4, 29.1, 120.0, 122.4, 127.7, 128.2, 128.3, 137.8, 139.2, 143.4,
J . Org. Chem, Vol. 68, No. 12, 2003 4921

Fort and Rodriguez
144.2, 150.8, 161.1. Anal. Calcd for C23H34ClNSn: C, 57.71;
H, 7.16; N, 2.93. Found: C, 57.38; H, 7.39; N, 2.72.
ether, the mixture was filtered, dried (MgSO4), and concen-
trated. The crude material was purified by chromatography
on silica gel (7:3 benzene/hexanes, then benzene) to yield 13
(320 mg, 81%) as a viscous oil. 1H NMR δH 1.71-1.78 (m, 4H),
3.02-3.08 (m, 4H), 6.21 (d, J ) 8.4 Hz, 1H), 6.66 (d, J ) 8.4
Hz, 1H), 7.07 (ddd, J ) 7.7, 4.0, and 1.2 Hz, 1H), 7.21-7.30
(m, 11H), 7.33 (td, J ) 7.5 and 1.2 Hz, 1H), 7.40 (t, J ) 8.4
Hz, 1H), 7.60 (ddd, J ) 7.5, 4.3, and 1.2 Hz, 1H); 13C NMR δC
25.5, 46.4, 104.7, 111.5, 127.9, 128.0, 128.1, 128.7, 129.6, 133.9,
135.4, 135.5, 136.9, 139.6, 147.8, 148.3, 156.4, 158.2; 31P NMR
δP -14.5. MS (EI) m/z 408 (M•+, 10), 331 (100), 332 (25), 204
(11), 183 (10).
2-Ch lor o-6-[2-(diph en ylph osph in o)ph en yl]pyr idin e (2j).
The reaction was treated with 1.4 mmol of ClPPh2. Column
chromatography (7:3 benzene/hexanes) yielded 2j (157 mg,
1
41%) as a yellow viscous oil; H NMR δH 7.11 (br dd, J ) 7.6
and 4.0 Hz, 1H), 7.15 (d, J ) 7.6 Hz, 1H), 7.25-7.37 (m, 12H),
7.42 (td, J ) 7.6 and 1.2 Hz, 1H), 7.52 (t, J ) 7.6 Hz, 1H),
7.58 (ddd, J ) 7.6, 4.4 and 1.2 Hz, 1H); 13C NMR δC 122.4,
122.5, 128.2, 128.3, 128.4, 128.7, 129.7, 133.9, 134.1, 137.2,
137.6, 138.1, 144.0, 150.3, 159.4; 31P NMR δP -13.4. MS (EI)
m/z 375 (4), 374 (7), 373 (15), 298 (33), 297 (32), 296 (100),
221 (3), 220 (5), 219 (11).
2-[2-(Dip h en ylp h osp h in o)p h en yl]-6-(1-n a p h th yl)p yr i-
d in e (14). A mixture of chloropyridine 2j (185 mg, 0.5 mmol),
Pd(PPh3)2Cl2 (35 mg, 0.05 mmol), and PPh3 (24 mg, 0.1 mmol)
in DME (2 mL)was warmed to form a yellow solution. Naph-
thylboronic acid (130 mg, 0.75 mmol) and CsF (222 mg, 1.5
mmol) were added and the mixture heated under reflux
overnight. After the solution was cooled to room temperature,
water (5 mL) and CH2Cl2 (10 mL) were added, the organic
layer was separated, and the aqueous layer was extracted
twice with CH2Cl2 (20 mL). The combined organic layers were
washed with brine, dried (MgSO4), and evaporated. The crude
product was purified by flash chromotography on silica gel (7:3
benzene/hexanes) to yield 14 (155 mg, 67%) as a viscous oil.
1H NMR δH 7.08 (ddd, J ) 8.0, 4.0, and 0.8 Hz, 1H), 7.17-
7.21 (m, 10H), 7.27 (td, J ) 7.6 and 1.2 Hz, 1H), 7.32-7.37
(m, 1H), 7.40-7.44 (m, 5H), 7.48 (dd, J ) 7.6 and 0.8 Hz, 1H),
7.68 (ddd, J ) 7.6, 4.4, and 1.2 Hz, 1H), 7.71 (t, J ) 8.0 Hz,
1H), 7.82 (dd, J ) 6.8 and 2.0 Hz, 1H), 7.80 (br d, J ) 8.4 Hz,
1H), 7.96 (d, J ) 8.4 Hz, 1H); 13C NMR δC 122.5, 123.3, 125.3,
125.6, 125.8, 126.1, 127.6, 128.1, 128.2, 128.3, 128.4, 128.8,
129.8, 131.2, 133.8, 134.7, 135.8, 135.9, 138.0, 138.4, 146.1,
146.6, 158.1, 159.0; 31P NMR δP -14.0.
2-Ch lor o-6-(2,6-d ich lor op h en yl)p yr id in e (7). Column
chromatography (8:2 hexanes/CH2Cl2) yielded 7 (179 mg, 69%)
as a pale oil; 1H NMR δH 7.17 (d, J ) 8.0 Hz, 1H), 7.18 (t, J )
8.0 Hz, 1H), 7.28 (dd, J ) 8.0 and 0.8 Hz, 1H), 7.29 (br d, J )
8.0 Hz, 2H), 7.68, (t, J ) 8.0 Hz, 1H); 13C NMR δC 123.76,
123.78, 128.2, 130.3, 134.6, 137.1, 139.1, 151.1, 155.7. MS (EI)
m/z 259 (34), 257 (37), 224 (63), 222 (100), 187 (32). Anal. Calcd
for C11H6Cl3N: C, 51.10; H, 2.34; N, 5.42. Found: C, 51.42;
H, 2.57; N, 5.32.
2-Ch lor o-6-[2-ch lor o-6-(t r ib u t ylst a n n yl)p h en yl]p yr i-
din e (8). Column chromatography (8:2 hexanes/CH2Cl2) yielded
8 (389 mg, 76%) as a pale oil; 1H NMR δH 0.74-0.78 (m, 6H),
0.83 (t, J ) 7.2 Hz, 9H), 1.21-1.28 (m, 6H), 1.33-1.41 (m, 6H),
7.27 (dd, J ) 7.6 and 7.2 Hz, 1H), 7.31 (dd, J ) 7.6 and 0.8
Hz, 1H), 7.38 (dd, J ) 7.6 and 1.2 Hz, 1H), 7.48 (br d, J ) 7.2
Hz, 2H), 7.68 (t, J ) 7.6 Hz, 1H); 13C NMR δC 10.9, 13.6, 27.3,
29.0, 123.1, 124.5, 129.1, 129.8, 133.0, 135.4, 138.1, 144.0,
147.1, 151.3, 159.9. Anal. Calcd for C23H33Cl2NSn: C, 53.84;
H, 6.48; N, 2.73.: Found: C, 53.65; H, 6.58; N, 2.82.
2-Ch lor o-6-[2-(m e t h ylsu lfa n yl)-6-(t r iflu or om e t h yl)-
p h en yl]p yr id in e (10). Column chromatography (8:2 hexanes/
CH2Cl2) yielded 10 (271 mg, 89%) as a yellow oil; 1H NMR δH
2.36 (s, 3H), 7.25 (br d, J ) 7.6 Hz, 1H), 7.36 (dd, J ) 8.0 and
0.8 Hz, 1H), 7.46 (d, J ) 2.8 Hz, 1H), 7.47 (d, J ) 6.4 Hz, 1H),
7.52 (br dd, J ) 6.4 and 2.8 Hz, 1H), 7.73 (t, J ) 7.6 Hz, 1H);
13C NMR δC 16.1, 122.3 (CH, J C-F ) 5.3 Hz), 123.6 (CF3, J C-F
) 273.9 Hz), 123.7, 123.8 (CH, J C-F ) 1.5 Hz), 128.6, 129.1,
129.2 (Cq, J C-F ) 30.5 Hz), 131.8, 136.1 (broad signal), 138.8,
141.1, 150.8, 155.9. MS (EI) m/z 303 (2), 290 (35), 288 (100),
268 (18).
2-[2-(Dip h en ylp h osp h in o)p h en yl]-6-(eth ylsu lfa n yl)p y-
r id in e (15). Sodium ethanethiolate (310 mg, 5 mmol) was
added to a stirred solution of chloropyridine 2j (186 mg, 0.5
mmol) in DMF (2 mL) kept under a nitrogen atmosphere. After
48 h of stirring at room temperature, the reaction medium was
heated at 50 °C (1.5 h). After being cooled at room temperature,
the reaction mixture was poured on water and extracted with
CH2Cl2 (20 mL). The combined organic layers were washed
with water, dried (MgSO4), and evaporated. The residue was
chromatographed on silica gel (7:3 benzene/hexanes, then
2-Ch lor o-6-[2-d eu ter io-3-ch lor op h en yl]p yr id in e (12).
Column chromatography (8:2 hexanes/CH2Cl2) yielded 12 (189
mg, 84%, deuterium content: 95%) as a white solid, mp
90-92 °C; 1H NMR δH 7.27 (dd, J ) 7.8 and 0.7 Hz, 1H),
7.38 (d, J ) 3.8 Hz, 1H), 7.39 (d, J ) 5.0 Hz, 1H), 7.60 (dd, J
) 7.8 and 0.8 Hz, 1H), 7.70 (t, J ) 7.8 Hz, 1H), 7.85 (dd, J )
4.9 and 4.0 Hz, 1H); 13C NMR δC 118.7, 123.2, 125.0, 126.9,
129.6, 130.0, 134.9, 139.5, 151.5, 156.4. MS (EI) m/z 226
(63), 224 (100), 191 (28), 189 (57), 154 (31). Anal. Calcd for
1
benzene) to yield 15 (140 mg, 71%) as a viscous oil. H NMR
δH 1.12 (t, J ) 7.2 Hz, 3H), 2.73 (q, J ) 7.2 Hz, 2H), 7.02 (d,
J ) 8.0 Hz, 1H), 7.08 (d, J ) 7.6, Hz, 1H), 7.10 (ddd, J ) 7.6,
4.0, and 0.8 Hz, 1H), 7.23-7.35 (m, 12H), 7.41 (t, J ) 8.0 Hz,
1H), 7.56 (ddd, J ) 7.6, 4.4, and 1.2 Hz, 1H); 13C NMR δC 14.5,
23.9, 119.8, 120.3, 128.2, 128.3, 128.7, 129.7, 133.8, 135.0,
135.6, 146.3, 146.9, 158.4, 159.3; 31P NMR δP -14.6. MS (EI)
m/z 399 (M+., 2), 370 (100), 322 (16), 292 (11), 260 (14), 216
(16).
C
11DH6Cl2N: C, 57.11; H, 7.19; N, 16.65. Found: C, 57.40; H,
7.16; N, 16.26.
2-[2-(Dip h en ylp h osp h in o)p h en yl]-6-(1-p yr r olid in yl)-
p yr id in e (13). A solution of t-AmOH (36 mg, 0.4 mmol) and
pyrrolidine (284 mg, 4 mmol) in THF (1 mL) was added to a
suspension of NaH (62 mg, 2.6 mmol) in THF (3 mL) and the
mixture was heated to 63 °C. 2,2′-Bipyridine (94 mg, 0.6 mmol)
was added followed by dried Ni(OAc)2 (36 mg, 0.2 mmol) and
the reflux was maintained for 1.5 h. To the dark suspension
thus obtained was added a solution of chloropyridine (2j, 374
mg, 1 mmol) and styrene (21 mg, 0.2 mmol) in THF (0.5 mL)
and the mixture was heated for 5 h. After cooling at room
temperature, hydrolysis with water (1 mL), and dilution with
Ack n ow led gm en t. This research was supported by
the CNRS. A.L.R. thanks C. Desmarets, Dr. J . C. Henry,
and Dr. J . Hydrio for helpful discussions.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for all the new compounds 2j, 13, 14, and 15. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O026788G
4922 J . Org. Chem., Vol. 68, No. 12, 2003