Ruthenium-catalyzed arylation of 2-alkenylpyridines with aryl bromides: Alternative E,Z-selectivity to Mizoroki-Heck reaction

Article abstract of DOI:10.1021/ol051654l

(Chemical Equation Presented) Regio- and stereoselective arylation of 2-alkenylpyridines with aryl bromides is catalyzed by specific Ru(II)-phosphine complexes affording β-arylated (Z)-2-alkenylpyridines, in which the aryl moiety is introduced cis to the

Full text of DOI:10.1021/ol051654l

ORGANIC
LETTERS
2005
Vol. 7, No. 18
4009-4011
Ruthenium-Catalyzed Arylation of
2-Alkenylpyridines with Aryl Bromides:
Alternative E,Z-Selectivity to
Mizoroki−Heck Reaction
Shuichi Oi,* Kaori Sakai, and Yoshio Inoue*
Department of Biomolecular Engineering, Graduate School of Engineering, Tohoku
UniVersity, Sendai 980-8579, Japan
oishu@aporg.che.tohoku.ac.jp
Received July 14, 2005
ABSTRACT
Regio- and stereoselective arylation of 2-alkenylpyridines with aryl bromides is catalyzed by specific Ru(II)−phosphine complexes affording
â
-arylated (Z)-2-alkenylpyridines, in which the aryl moiety is introduced cis to the pyridyl group. This geometrical selectivity is in sharp
contrast to the Mizoroki Heck reaction.
−
The palladium-catalyzed reaction of olefins with aryl halides,
referred to as the Mizoroki-Heck reaction, has been
recognized to be of great synthetic value for the substitution
of olefinic hydrogen with aryl groups.1,2 The Mizoroki-Heck
reaction proceeds first via the formation of an arylpalladium
intermediate, which then reacts with an olefinic compound
via syn addition and then finally undergoes syn-â-hydride
elimination of palladium hydride to afford the final product.
This reaction pathway provides an excellent rationalization
for the geometrical chemistry of reactions involving 1,2-
disubstituted olefins, in which the geometry of the two
functional groups R1 and R2 is reversed upon reaction with
an aryl group introduced in the position trans to R1 (Scheme
1).
We previously reported the direct ortho-arylation of
pyridylarenes and aromatic imines using certain aryl halides
in the presence of a catalytic amount of a ruthenium(II)-
phosphine complex.3 In these reactions, coordination of the
pyridyl or imino group to a suitable ruthenium complex
directs metalation to the ortho position of the aromatic
ring. This ruthenium-catalyzed arylation has also been
successfully applied to 2-alkenylpyridines affording Z-
products exclusively (eq 1). It is noteworthy that the
geometrical selectivity of this arylation reaction is in sharp
Scheme 1. Geometrical Chemistry of the Mizoroki-Heck
Reaction
(1) (a) Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn. 1971,
44, 581. (b) Heck, R. F.; Nolley, J. P., Jr. J. Org. Chem. 1972, 37, 2320.
(2) For reviews, see: (a) Heck, R. F. Org. React. 1982, 27, 345. (b)
Heck, R. F. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, U.K., 1991; Vol. 4. (c) Tsuji, J. Palladium
Reagents and Catalysts; InnoVations in Organic Synthesis; Wiley: Chich-
ester, 1996.
10.1021/ol051654l CCC: $30.25
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Published on Web 08/02/2005

contrast to that observed for the above-mentioned Mizoroki-
equiv to 1a) in NMP at 120 °C for 20 h (Mizoroki-Heck
conditions). As expected, in direct contrast to the ruthenium-
catalyzed reaction, the reaction under Mizoroki-Heck condi-
tions resulted in the exclusive formation of (E)-3aa in 60%
yield (eq 3).
Heck reaction.4,5
Initially, the reaction of (E)-2-(1-propenyl)pyridine (1a)
with bromobenzene (2a) was examined using a 2.5 mol %
catalytic amount of [RuCl2(η6-C6H6)]2 in the presence of K2-
CO3 in NMP at 120 °C for 20 h. The reaction afforded the
arylated product 3aa, although the yield was as low as 10%.
The addition of 2 equiv of PPh3 to the ruthenium metal,
however, dramatically increased the 3aa yield to 79%. Here,
arylation occurred exclusively at the â-position of 1a, and
the geometry of the olefinic part was determined to be Z
through NOE experiments. Reactions involving divalent
ruthenium complexes with coordinated triphenylphosphine,
such as RuCl2(η6-C6H6)(PPh3) and RuCl2(PPh3)3, were found
to have lower catalytic activity than the combination of
[RuCl2(η6-C6H6)]2 and PPh3, while the cyclopentadienyl (Cp)
complex CpRuCl(PPh3)2 showed no activity at all. With
regard to other reaction conditions, Cs2CO3 was also found
to act as a good base; however, organic bases such as Pri2-
NEt, and strong bases such as ButOK, failed to afford 3aa.
Polar, aprotic solvents such as NMP and DMF were
determined to be highly suited for this reaction, while the
less polar solvents, such as xylene, afforded the product only
in lower yields. The optimized reaction conditions are thus
shown in eq 2.6
The reactions between various 2-alkenylpyridines and aryl
bromides were then examined under these optimized condi-
tions (Scheme 2, Table 1). The reaction of (E)-2-styrylpy-
Scheme 2
ridine (1b) with bromobenzene (2a) gave the product 3ba
in quantitative yield (entry 1), while (E)-alkenylpyridines,
bearing isopropyl 1c and butyl 1d groups in the â-position,
Table 1. Ruthenium-Catalyzed Arylation of Alkenylpyridines 1
with Aryl Bromides 2a
entry
1
2
product
yield (%)
1
2
3
4
5
6
7
8
9
1b
1c
1d
1e
1f
1g
1d
1d
1d
1d
1d
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
3ba
100
73
88
86
0
59b
85
86
90
75
33
To compare the E,Z-selectivity of the present ruthenium-
catalyzed reaction with that of the Mizoroki-Heck reaction,
1a was reacted with 2a using catalytic amounts of Pd(OAc)2
(5 mol %) and PPh3 (10 mol %) in the presence of Et3N (2
(Z)-3ca
(Z)-3da
3ea
(Z)-3ga
(Z)-3db
(Z)-3dc
(Z)-3dd
(Z)-3de
(Z,E)-3dfc
(3) (a) Oi, S.; Fukita, S.; Hirata, N.; Watanuki, N.; Miyano, S.; Inoue,
Y. Org. Lett. 2001, 3, 2579. (b) Oi, S.; Ogino, Y.; Fukita, S.; Inoue, Y.
Org. Lett. 2002, 4, 1783. (c) Oi, S.; Aizawa, E.; Ogino, Y.; Inoue, Y. J.
Org. Chem. 2005, 70, 3113.
(4) Ruthenium catalyzed Mizoroki-Heck-type olefination and related
reactions: (a) Na, Y.; Park, S.; Han, S.; Han, H.; Ko, S.; Chang, S. J. Am.
Chem. Soc. 2004, 126, 250. (b) Chatterjee, A. K.; Toste, F. D.; Choi, T.;
Grubbs, R. H. AdV. Synth. Catal. 2002, 344, 634.
(5) Although the selectivity is not high, Z-selective Mizoroki-Heck
reaction catalyzed by palladium has been reported. (a) Nilsson, P.; Larhed,
M.; Hallberg, A. J. Am. Chem. Soc. 2001, 123, 8217. (b) Svennebring, A.;
Nilsson, P.; Larhed, M. J. Org. Chem. 2004, 69, 3345.
10
11
a Reactions were carried out using 0.5 mmol of 1, 0.6 mmol of 2, 1.0
mmol of K2CO3, 0.0125 mmol of [RuCl2(η6-C6H6)]2, and 0.05 mmol of
PPh3 in 1 mL of NMP at 120 °C for 20 h under N2 atmosphere. b 0.025
mmol of PPh3 and 1.5 mmol of 2a were used. c Containing 12% of the
E,E-form.
(6) A mixture of 1a (59.6 mg, 0.50 mmol), 2a (94.2 mg, 0.60 mmol),
K2CO3 (138.2 mg, 1.0 mmol), PPh3 (13.1 mg, 0.05 mmol), and [RuCl2-
(η6-C6H6)]2 (6.3 mg, 0.0125 mmol) in 1 mL of dried and degassed NMP
was stirred at 120 °C for 20 h. The reaction mixture was diluted with 10
mL of EtOAc, washed with water (10 mL × 2), and dried over Na2SO4.
After the solvent was removed in vacuo, the residue was purified by silica
gel flash chromatography (hexanes-EtOAc, 5:1) to give (Z)-3aa (77.1 mg,
0.395 mmol). All other reactions were performed using the same procedure.
also reacted well with 2a, affording the products (Z)-3ca and
(Z)-3da, in 73% and 88% yield, respectively (entries 2 and
3). The cycloalkenylpyridine, 2-(1-cyclohexenyl)pyridine
(1e), was found to react with 2a, affording the phenylated
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Org. Lett., Vol. 7, No. 18, 2005

product 3ea with a yield of 86% (entry 4). Interestingly, the
reaction between 2-vinylpyridine (1f) and 2a failed to
undergo arylation (entry 5), while the same reaction between
1.5 mmol of 2a and the R-substituted 1-(2-tolyl)-2-vinylpy-
ridine (1g), in the presence of a sufficient amount of PPh3
(0.025 mmol, Ru/P ) 1:1), afforded (Z)-3ga in 59% yield
(entry 6). The reaction between 1d and certain substituted
bromobenzenes, bearing either electron-donating or -with-
drawing groups in the para position (2b and 2c), gave the
corresponding products (Z)-3db and (Z)-3dc in good yield
(entries 7 and 8). Moreover, 1d also reacted well with
sterically hindered 2-bromotoluene (2d) and 1-bromonaph-
thalene (2e), resulting in the formation of (Z)-3dd and (Z)-
3de, respectively, in good yield (entries 9 and 10). Alkenyl
bromides were also found to react under these conditions.
The reaction between 1d and (E)-â-bromostyrene (2f)
produced 2-[(Z)-2-((E)-styryl)-1-hexenyl]pyridine ((Z,E)-
3df), together with a small amount of E,E-form in this case,
in 33% yield (entry 11).
The reaction between (E)-stilbene and 2a on the other
hand, failed to occur, suggesting that the presence of the
pyridyl group is necessary for the reaction to proceed.
Although there is little experimental evidence at present to
determine the exact reaction mechanism, the following two
steps are believed to be involved in the catalytic pathway:
(i) oxidative addition of the aryl halide to a ruthenium
complex to give an arylruthenium intermediate and (ii) â-cis-
ruthenation of the olefinic moiety, directed by coordination
of the pyridyl group to the ruthenium atom. An outline of
one possible reaction pathway is shown in Scheme 3. Here,
Scheme 4
ruthenacycle 5, followed by oxidative addition of the aryl
halide, affords a tetravalent ruthenacycle 4a (eq a). Alter-
natively, oxidative addition of the aryl halide to a Ru(II)
complex to form a tetravalent arylruthenium complex 6,
followed by â-cis-ruthenation of 1 gives 4a (eq b).7
Moreover, pathways involving zerovalent ruthenium species
present another possible route. The oxidative addition of a
C-H bond at the â-position of 1 to a Ru(0) complex results
in the formation of a ruthenium hydride complex 7,8,9 which
after oxidative addition of the aryl halide, and subsequent
elimination of HX, affords the divalent ruthenacycle 4b (eq
c). Alternatively, oxidative addition of the aryl halide to a
Ru(0) complex to form a divalent arylruthenium complex
8, followed by â-cis-ruthenation of 1, is also expected to
afford 4b (eq d).
In conclusion, we have shown that the ruthenium-catalyzed
arylation of alkenylpyridines with aryl bromides affords the
normally less stable â-arylated (Z)-2-alkenylpyridines, se-
lectively. The geometrical selectivity of this reaction is in
stark contrast to that of the Mizoroki-Heck reaction, which
we attribute to the unprecedented reaction pathway involving
the nitrogen atom-coordinated ruthenacycle 4. Further studies
to expand the scope of the described reaction are now in
progress.
Scheme 3
Acknowledgment. This work was partly supported by a
Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
Supporting Information Available: Experimental details
and analytical and spectral characterization data for all
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
the reaction between a ruthenium complex and an alkenylpy-
ridine 1 and aryl halide 2 results in the formation of a
nitrogen atom-coordinated ruthenacycle 4. Reductive elimi-
nation of 4 affords the arylated product 3, with the
simultaneous regeneration of the initial ruthenium complex.
We believe that the regioselectivity and Z-selectivity of the
reaction is caused by the formation of the key intermediate
4. Several pathways for the formation of 4 are envisaged
(Scheme 4). For example, the â-cis-ruthenation of the olefinic
moiety of 1 by a Ru(II) complex to form a divalent
OL051654L
(7) Heteroatom directed cyclometalation, see: Omae, I. Coord. Chem.
ReV. 2004, 248, 995.
(8) Review: Kakiuchi, F.; Murai, S. In Topics in Organometallic
Chemistry; Murai, S., Ed.; Springer: Berlin, 1999; Vol. 3, pp 47-79.
(9) (a) Chatani, N.; Ishii, Y.; Ie, Y.; Kakiuchi, F.; Murai, S. J. Org. Chem.
1998, 63, 5129. (b) Trost, B. M.; Imi, K.; Davies, I. W. J. Am. Chem. Soc.
1995, 117, 5371. (c) Lim, Y.-G.; Kang, J.-B.; Kim, Y. H. J. Chem. Soc.,
Perkin Trans. 1 1998, 699.
Org. Lett., Vol. 7, No. 18, 2005
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