Cobalt-catalyzed cross-coupling reaction of chloropyridines with grignard reagents

Article abstract of DOI:10.1246/cl.2004.1240

Treatment of 2-chloropyridine with benzylmagnesium chloride in the presence of a catalytic amount of cobalt(II) acetylacetonate in dioxane afforded the corresponding cross-coupling product in excellent yield. Trimethylsilylmethyl and phenyl Grignard reagents also participated in similar cross-coupling reactions.

Full text of DOI:10.1246/cl.2004.1240

1240
Chemistry Letters Vol.33, No.10 (2004)
Cobalt-catalyzed Cross-coupling Reaction of Chloropyridines with Grignard Reagents
Hirohisa Ohmiya, Hideki Yorimitsu, and Koichiro OshimaÃ
Department of Material Chemistry, Graduate School of Engineering, Kyoto University,
Kyoto-daigaku Katsura, Nishikyo-ku, Kyoto 615-8510
(Received July 5, 2004; CL-040793)
Co(acac) (0.10mmol)
2
Treatment of 2-chloropyridine with benzylmagnesium
PhCH MgCl (3.0 mmol)
2
(2)
chloride in the presence of a catalytic amount of cobalt(II)
acetylacetonate in dioxane afforded the corresponding cross-
coupling product in excellent yield. Trimethylsilylmethyl and
phenyl Grignard reagents also participated in similar cross-
coupling reactions.
2
dioxane, 25 °C, 30 min
N
X
X=I, 45%; Br, 40%; OTs, 13%; F, 8%; CN, 0%; OTf, 0%
Trimethylsilylmethyl Grignard reagent also participated in a
similar cross-coupling reaction to yield 2-pyridylmethyltrime-
thylsilane in 68% yield (Table 1, Entry 1). Phenylation at
25 ꢀC resulted in low conversion (Entry 2) and required a higher
temperature to proceed to completion (Entry 3). Installation of
hexyl group was unsuccessful, competing with reduction that
produced pyridine (Entry 4). The reaction with allylmagnesium
chloride, even at À20 ꢀC, failed to isolate 2-allylpyridine and
yielded a complex mixture (Entry 5). Attempted methylation
and vinylation left 1 intact. Reaction with 1-phenylethyl
Grignard reagent afforded no trace of the corresponding
coupling product, instead giving pyridine.
Transition metal-catalyzed cross-coupling reactions are
among the most important carbon–carbon bond forming reac-
tions in organic synthesis.1 Cobalt-catalyzed cross-coupling re-
actions have realized, without suffering from ꢀ-hydride elimina-
tion, the utilization of alkyl halides.2,3 In order to expand the
scope of the cobalt-catalyzed reactions, we examined cross-cou-
pling reactions of aryl halides with several Grignard reagents.
Here we report a cobalt-catalyzed reaction of chloropyridine de-
rivatives with Grignard reagents. Chloropyridines seem unlikely
to undergo cross-coupling reaction, due to the strong carbon–
chlorine bond.4
Table 1. Reaction of 2-chloropyridine (1) with various
Grignard reagents
Treatment of 2-chloropyridine (1, 1.0 mmol) with benzyl-
magnesium chloride (3.0 mmol) in dioxane (3 mL) in the pres-
ence of cobalt(II) acetylacetonate (0.10 mmol) for 30 min at
25 ꢀC afforded 2-benzylpyridine (2) in 81% yield (Eq. 1).5,6
Use of 1.5 mmol of the Grignard reagent and 0.05 mmol of the
cobalt salt led to a slightly lower yet satisfactory yield of 2
(73%). Dioxane is a proper solvent, and reactions in ether or
THF resulted in low conversions. Other cobalt salts such as
CoCl2 and CoCl3 also catalyzed the reaction, although the yields
were lower by ca. 10%. Neither lower nor higher temperatures
improved the yield of 2. The starting material 1 was completely
recovered without any cobalt catalysts.
Co(acac)2 (0.10 mmol)
RMgX (3.0 mmol)
dioxane, 30 min
N
Cl
N
R
1 (1.0mmol)
entry
RMgX
Temp/˚C
Yield/%
(CH3)3SiCH2MgCl
PhMgBr
1
2
3
4
5
25
25
68
17 (33% of 1)
PhMgBr
50 (bath temp.) 73
25
–20
nC6H13MgBr
CH2=CHCH2MgCl
15
complex mixture
Co(acac)2, PhCH2MgCl
(1)
Ph
dioxane, 25 °C, 30 min
N
Cl
1 (1.0 mmol)
Co(acac) (0.05 mmol), PhCH MgCl (1.5 mmol): 73%
N
A variety of combinations of chloropyridine derivatives and
2
Grignard reagents were surveyed (Table 2 and Eqs. 3 and 4).
3-Chloropyridine (3a) was transformed into 3-benzylpyridine
(4a) in moderate yield (Table 2, Entry 1). Unfortunately, the re-
action of 4-chloropyridine yielded no desired product. Benzyla-
tion was so efficient that dibenzylation occurred to yield 4c in
fair yield with contamination by a trace of the monobenzylated
product (Table 2, Entry 3), whereas trimethylsilylmethylation
led to selective conversion of the chlorine at the 2 position
(Table 2, Entries 7 and 8).
Interestingly, benzylation reactions of 3d bearing an alkene
moiety proceeded smoothly (Table 2, Entry 4), albeit the reactiv-
ity of 3d is lower than that of 1. Chloropyridine 3d is a compe-
tent substrate for allylation to obtain 7 in 72% yield (Eq. 4).
These facts stand in sharp contrast to the intramolecular
5-exo-trig cyclization reaction of 2-iodophenyl prenyl ether that
was previously reported.7 The selective cross-coupling without
2
2
Co(acac) (0.10 mmol), PhCH MgCl (3.0 mmol): 81%
2
2
Surprisingly, the reaction of 2-iodopyridine afforded 2 in
only 45% yield, where the starting material was completely
consumed and a significant amount of 1,2-diphenylethane was
obtained (Eq. 2). The bromo analogue was less reactive so that
2 was obtained in 40% yield, along with 19% recovery of the
starting material. Seemingly promising leaving groups such as
p-toluenesulfonate and trifluoromethanesulfonate resisted the
reaction. Attempts to transform 2-fluoropyridine resulted in
failure. Under the cobalt catalysis, 4-iodoanisole and 4-trifluor-
omethyl-1-chlorobenzene failed to react and both remained
unchanged.
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.10 (2004)
1241
Table 2. Cobalt-catalyzed benzylation and trimethylsilylme-
thylation of chloropyridine derivatives
This work was supported by Grant-in-Aid for Scientific
Research and COE research from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
Co(acac) (0.10 mmol)
2
PhCH MgCl (3.0 mmol)
2
Ar−CH Ph
Ar−Cl
2
References and Notes
dioxane, 25 °C, 30 min
1
a) ‘‘Metal-catalyzed Cross-coupling Reactions,’’ ed. by F.
Diederich and P. J. Stang, Wiley-VCH, Weinheim (1998).
b) Special Issue: J. Organomet. Chem., ed. by K. Tamao,
T. Hiyama, and E. Negishi, 653 (2002). c) J. Tsuji,
‘‘Palladium Reagents and Catalysts. Innovations in Organic
Synthesis,’’ Wiley, Chichester (1996). d) ‘‘Comprehensive
Organic Synthesis,’’ ed. by B. M. Trost, I. Fleming, and
C. H. Heathcock, Pergamon Press, New York (1991),
Vol. 3, Chap. 2.1–2.5. e) ‘‘Cross-coupling Reactions. A
Practical Guide,’’ ed. by N. Miyaura, Springer, Berlin
(2002).
Entry ArCl
Product
Yield/%
Cl
Ph
4a
3a
1
2
3
N
N
47
84
42
Ph
3b
Cl
4b
N
N
Ph
Ph
3c
4c
Cl
N
Cl
N
O
O
2
3
a) K. Wakabayashi, H. Yorimitsu, and K. Oshima, J. Am.
Chem. Soc., 123, 5374 (2001). b) T. Tsuji, H. Yorimitsu,
and K. Oshima, Angew. Chem., Int. Ed., 41, 4137 (2002).
c) K. Mizutani, H. Yorimitsu, and K. Oshima, Chem. Lett.,
33, 832 (2004).
For other cobalt-catalyzed cross-coupling reactions: a) P.
´
Gomes, C. Gosmini, and J. Perichon, J. Org. Chem., 68,
1142 (2003). b) G. Cahiez and H. Avedissian, Tetrahedron
N
N
Cl
3d
4d
4
Ph
51
Co(acac) (0.10 mmol)
(CH ) SiCH MgCl (3.0 mmol)
2
3 3
2
Ar−CH Si(CH )
Ar−Cl
2
3 3
dioxane, 25 °C, 30 min
´
Lett., 39, 6159 (1998). c) H. Avedissian, L. Berillon, G.
Cahiez, and P. Knochel, Tetrahedron Lett., 39, 6163
(1998). d) Y. Nishii, K. Wakasugi, and Y. Tanabe, Synlett,
1998, 67. e) L. F. Wlsom, J. D. Hunt, and A. McKillop,
Organomet. Chem. Rev., Sect. A, 8, 135 (1972). f) B. Sezen
and D. Sames, Org. Lett., 5, 3607 (2003). g) M. S. Kharasch
and E. K. Fields, J. Am. Chem. Soc., 63, 2316 (1941).
Entry Ar−Cl
Product
Yield/%
N
N
N
Si(CH )
3 3
5a
3e
N
Cl
N
5
52
70
67
4
5
a) A. Furstner and A. Leitner, Angew. Chem., Int. Ed., 41,
¨
Si(CH )
3 3
3b
5b
Cl
6
N
´
609 (2002). b) A. Furstner, A. Leitner, M. Mendez, and
¨
H. Krause, J. Am. Chem. Soc., 124, 13856 (2002).
Experimental Procedure: Anhydrous cobalt(II) acetylacet-
onate (25.7 mg, 0.10 mmol) was placed in a 20-mL two-
necked flask. Anhydrous dioxane (3 mL) was then added un-
der argon. After the solution became red, benzylmagnesium
chloride (0.98 M ether solution, 3.1 mL, 3.0 mmol) was add-
ed at 0 ꢀC. The mixture was stirred for about 5 min at 25 ꢀC.
2-Chloropyridine (1, 114 mg, 1.0 mmol) was added dropwise
to the reaction mixture. After being stirred for 30 min at
25 ꢀC, the reaction mixture was poured into water. The prod-
ucts were extracted with ethyl acetate (20 mL Â 2). The
combined organic layer was dried over sodium sulfate and
concentrated. Purification of the crude product by silica gel
column chromatography (20% ethyl acetate in hexane)
provided the corresponding benzylated product 2 (137 mg,
0.81 mmol) in 81% yield.
Si(CH )
3 3
3c
5c
7
8
Cl
Cl
N
N
Cl
Cl
Cl
Cl
N
N
Si(CH )
3 3
3f
5d
78
the possible cyclization is suggestive of the absence of the
2-pyridylcobalt or 2-pyridyl radical intermediate. Alternatively,
cobalt-mediated SNAr reaction might be included. Exact
reaction mechanism is not clear at this stage.
Co(acac) (0.10 mmol)
2
PhMgBr (3.0 mmol)
(3)
3b
3d
dioxane, 50 °C (bath temp.)
N
Ph
30 min
6
7
The utility of benzylic pyridines is documented. For
instance, a) M. E. Angiolelli, A. L. Casalnuovo, and T. P.
Selby, Synlett, 2000, 905. b) W. Chai, A. Kwok, V. Wong,
N. I. Carruthers, and J. Wu, Synlett, 2003, 2086. c) F.
Speiser, P. Braunstein, and L. Saussine, Organometallics,
23, 2625 (2004).
6 74%
Co(acac) (0.10 mmol)
CH =CHCH MgBr (3.0 mmol)
2
O
2
2
(4)
dioxane, 25 °C, 30 min
N
T. Fujioka, T. Nakamura, H. Yorimitsu, and K. Oshima,
Org. Lett., 4, 2257 (2002).
7 72%
Published on the web (Advance View) August 28, 2004; DOI 10.1246/cl.2004.1240