The Journal of Organic Chemistry
NOTE
Concomitantly, the addition of an excess of halide salts to the
reaction system was found to retard the reaction, by forming a stable
Pd-halide complex that is inactive in catalysis. As a consequence of
this proposed cationic intermediate, electron deficient boronic acids
are expected to result in poor conversions, which is found by using
dmphen as the ligand.
’ ACKNOWLEDGMENT
The authors gratefully acknowledge Prof. Johannes G. de
Vries and Prof. Ben L. Feringa for useful comments and sugges-
tions. D.H. and S.v.D. thank Abbott Healthcare Products B.V. for
financial assistance.
Also, in our hands, the addition of halide salts resulted in a
dramatic drop in reactivity of the catalyst, irrespective of the
cation (Table 3). A large excess of LiCl inhibited the formation of
6 completely, even at reflux (entry 1). When 1 equiv of LiCl with
respect to the substrate was added, the reaction was retarded at rt
(entry 2), but proceeded with moderate conversion at reflux. Five
mol % (1 equiv with respect to Pd) of LiCl did not hinder the
reaction at all (entry 3). When salts without halides were added,
the catalytic activity was unaffected (entries 6 and 7). It remains
therefore unexplained why on one hand electron poor arylboro-
nic acids react well in the Pd-BIAN catalyzed oxidative Heck
reaction whereas on the other hand a cationic intermediate is
most probably involved.
In summary, Pd(OAc)2/3 is an excellent catalyst for the base-
free oxidative Heck reaction of arylboronic acids at room
temperature. The mild reaction conditions permit the use of a
diverse range of boronic acids and Michael acceptors, including
aldehydes. Kinetic data show the high selectivity and reaction rate
of BIAN ligand 3 compared to commonly used catalysts like 2,9-
dimethylphenanthroline (dmphen). This study represents a
novel and selective route to many of the described compounds,
as most of them have not been synthesized by Heck procedures
previously, and are only observed as side products. Studies to
broaden the scope of this catalyst type are currently underway.
’ REFERENCES
(1) Karimi, B.; Behzadnia, H.; Elhamifar, D.; Akhavan, P. F.; Esfa-
hani, F. K.; Zamani, A. Synthesis (Stuttgart) 2010, 1399.
(2) Heck, R. F. J. Am. Chem. Soc. 1969, 91, 6707.
(3) Cho, C. S.; Uemura, S. J. Organomet. Chem. 1994, 465, 85.
(4) (a) Andappan, M. M. S.; Nilsson, P.; Von Schenck, H.; Larhed,
M. J. Org. Chem. 2004, 69, 5212. (b) Andappan, M. M. S.; Nilsson, P.;
Larhed, M. Chem. Commun. 2004, 218. (c) Enquist, P.-A.; Nilsson, P.;
Sjoeberg, P.; Larhed, M. J. Org. Chem. 2006, 71, 8779. (d) Enquist, P.-A.;
Lindh, J.; Nilsson, P.; Larhed, M. Green Chem. 2006, 8, 338. (e) Lindh, J.;
Enquist, P.-A.; Pilotti, A.; Nilsson, P.; Larhed, M. J. Org. Chem. 2007,
72, 7957.
(5) (a) Jung, Y. C.; Mishra, R. K.; Yoon, C. H.; Jung, K. W. Org. Lett.
2003, 5, 2231. (b) Yoon, M. S.; Ryu, D.; Kim, J.; Ahn, K. H. Organo-
metallics 2006, 25, 2409. (c) Yoo, K. S.; Park, C. P.; Yoon, C. H.;
Sakaguchi, S.; O’Neill, J.; Jung, K. W. Org. Lett. 2007, 9, 3933. (d) Yoo,
K. S.; Yoon, C. H.; Jung, K. W. J. Am. Chem. Soc. 2006, 128, 16384.
(6) Gini, F.; Hessen, B.; Minnaard, A. J. Org. Lett. 2005, 7, 5309.
(7) Gini, F.; Hessen, B.; Feringa, B. L.; Minnaard, A. J. Chem.
Commun. 2007, 710.
(8) For examples of mixtures of products from cyclohex-2-en-1-
one, see: (a) Cho, C. S.; Motofusa, S.-i.; Ohe, K.; Uemura, S.; Shim, S. C.
J. Org. Chem. 1995, 60, 883. (b) Yamamoto, T.; Iizuka, M.; Takenaka, H.;
Ohta, T.; Ito, Y. J. Organomet. Chem. 2009, 694, 1325.
(9) Conley, N. R.; Labios, L. A.; Pearson, D. M.; McCrory, C. C. L.;
Waymouth, R. M. Organometallics 2007, 26, 5447.
’ EXPERIMENTAL SECTION
(10) (a) Tempel, D. J.; Johnson, L. K.; Huff, R. L.; White, P. S.;
Brookhart, M. J. Am. Chem. Soc. 2000, 122, 6686. (b) Svejda, S. A.;
Johnson, L. K.; Brookhart, M. J. Am. Chem. Soc. 1999, 121, 10634.
(11) (a) Kluwer, A. M.; Koblenz, T. S.; Jonischkeit, T.; Woelk, K.;
Elsevier, C. J. J. Am. Chem. Soc. 2005, 127, 15470. (b) Guo, H.; Zheng,
Z.; Yu, F.; Ma, S.; Holuigue, A.; Tromp, D. S.; Elsevier, C. J.; Yu, Y.
Angew. Chem., Int. Ed. 2006, 45, 4997.
(12) Vanasselt, R.; Elsevier, C. J.; Smeets, W. J. J.; Spek, A. L.;
Benedix, R. Recl. Trav. Chim. Pays-Bas 1994, 113, 88.
(13) ten Brink, G. J.; Arends, I.; Hoogenraad, M.; Verspui, G.;
Sheldon, R. A. Adv. Synth. Catal. 2003, 345, 1341.
(14) For examples of side products in the oxidative Heck reaction
and the influence of the ligand on their distribution, see: Yoo, K. S.;
Yoon, C. H.; Jung, K. W. J. Am. Chem. Soc. 2006, 128, 16384.
(15) The yields reported in this article are calculated based on
cyclohex-2-en-1-one, the limiting reagent. These are, therefore, higher
than those reported in ref 5d, where they are calculated based on the
boronic acid.
Representative Procedure:
Synthesis of 3-Phenylcyclohex-2-enone (6) To a Schlenk
tube equipped with a magnetic stirring bar and a septum was added
palladium acetate (11 mg, 5 mol %, 0.05 equiv) and BIAN (28 mg, 7 mol
%, 0.07 equiv). The mixture was dissolved in 2 mL of a solution of
MeOH/H2O (9:1) and stirred for 30 min at 20 °C, followed by the
addition of the cyclohex-2-en-1-one 4 (97 μL, 1.0 mmol, 1.0 equiv) and
phenyl boronic acid 5 (183 mg, 1.5 mmol, 1.5 equiv). The Schlenk tube
was flushed with O2 and connected to an O2 balloon. The reaction
mixture was allowed to stir at 20 °C; when the reaction was judged
complete (by TLC, GC), the reaction was stopped. The reaction
mixture was concentrated in vacuo and loaded directly on the column,
and the desired product, 6 (147 mg, 0.85 mmol, 85%), was isolated as a
off-white solid. 1H NMR (300 MHz, CDCl3) δ 7.54ꢀ7.34 (m, 5H), 6.38
(s, 1H), 2.73 (t, J = 6.0 Hz, 2H), 2.44 (t, J = 6.7 Hz, 2H), 2.10 (t, J = 6.3
Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 199.8, 159.8, 138.8, 130.0,
128.8, 126.1, 125.4, 37.3, 28.1, 22.1. Calcd mass for [M þ H]þ 173.0961,
found [M þ H]þ 173.0960.
(16) For detailed time-profiles of each of the complexes, see the
Supporting Information.
(17) (a) Jagt, R. B. C.; de Vries, J. G.; Feringa, B. L.; Minnaard, A. J.
Org. Lett. 2005, 7, 2433. (b) Fernꢀandez-Ibꢀa~nez, M.; Maciꢀa, B.; Pizzuti,
M.; Minnaard, A.; Feringa, B. Angew. Chem., Int. Ed. 2009, 48, 9339.
(18) Only a few examples of successful MizorokiꢀHeck reaction of
aldehydes are known. For examples with cinnamaldehyde, see: (a)
Aggarwal, V. K.; Staubitz, A. C.; Owen, M. Org. Process Res. Dev. 2006,
10, 64. (b) Amorese, A.; Arcadi, A.; Bernocchi, E.; Cacchi, S.; Cerrini, S.;
Fedeli, W.; Ortar, G. Tetrahedron 1989, 45, 813.
’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proce-
b
dures and spectroscopic and characterization data of all the
synthesized compounds. This material is available free of charge
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: a.j.minnaard@rug.nl.
3501
dx.doi.org/10.1021/jo101942f |J. Org. Chem. 2011, 76, 3498–3501