Regioselective heck couplings of α,β-unsaturated tosylates and mesylates with electron-rich olefins

Article abstract of DOI:10.1021/ol052136d

(Chemical Equation Presented) Highly regioselective Heck couplings of α,β-unsaturated tosylate and mesylate derivatives with N-acyl N-vinylamines and vinyl ethers were achieved. Several 2-alkoxy-1,3-dienes and 2-acylamino-1,3-butadienes were synthesized i

Full text of DOI:10.1021/ol052136d

ORGANIC
LETTERS
2005
Vol. 7, No. 25
5585-5587
Regioselective Heck Couplings of
-Unsaturated Tosylates and
Mesylates with Electron-Rich Olefins
r,â
Anders Lindhardt Hansen and Troels Skrydstrup*
Department of Chemistry and the Interdisciplinary Nanoscience Center, UniVersity of
Aarhus, Langelandsgade 140, 8000 Aarhus C, Denmark
ts@chem.au.dk
Received September 5, 2005
ABSTRACT
Highly regioselective Heck couplings of
r,â-unsaturated tosylate and mesylate derivatives with N-acyl N-vinylamines and vinyl ethers were
achieved. Several 2-alkoxy-1,3-dienes and 2-acylamino-1,3-butadienes were synthesized in good yields using 1.5 mol % of Pd2(dba)3, 3 mol %
of DPPF, and diisopropylethylamine in dioxane. When working with
alternative to similar couplings using a triflate electrophile.
r,
â
-unsaturated ketones and esters, this method provides a less costly
Formation of new sp2 C-C bonds using the palladium(0)-
catalyzed Heck reaction is a well-known and widely used
technique.1 The degree of regioselectivity in the reaction is
strongly dependent on the substrates and the reaction
conditions used. Electron-deficient olefins, such as acrylates
or acrylamides, usually provide â-substituted products,
whereas with electron-rich olefins (vinyl ethers and amides),
substitution occurs mainly at the R-position. Obtaining ex-
clusive R-substitution on electron-rich alkenes often requires
the use of bidentate ligands, polar solvents, and aryl/alkenyl
triflates as the electrophile.2 Considerable work has been
devoted to the development of new catalytic systems to
facilitate couplings with the less reactive but also less expen-
sive and more readily available aryl chlorides instead of aryl
bromides/iodides.1f,g Aryl/alkenyl electrophiles carrying halo-
gens preferentially follow a neutral Heck mechanism leading
to a higher degree of the â-substituted product. Unfortunately,
this complicates the use of these compounds regarding
couplings with electron-rich alkenes, which often leads to a
mixture of regioisomeric products. Additives such as silver
triflate remove the halogen from the solution and facilitate
pure R-substitution but increase the cost of the reaction.3
Palladium-catalyzed Heck couplings with alkenyl tosylates
(1) For some relevant reviews, see: (a) Heck, R. F. Palladium Reagents
in Organic Syntheses; Academic Press: Orlando, FL, 1985. (b) Tsuji, J.
Palladium Reagents and Catalysts: InnoVation in Organic Synthesis;
Wiley: Chichester, U.K., 1995. (c) Brase, S.; de Meijere, A. In Metal-
Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.;
Wiley-VCH: New York, 1998; Chapter 3. (d) Link, J. T.; Overman, L. E.
In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J.,
Eds.; Wiley-VCH: New York, 1998; Chapter 6. (e) Transition Metal
Catalyzed Reactions; Davis, S. G., Murahashi, S.-I., Eds.; Blackwell
Science: Oxford, 1999. (f) Beletskaya, I.; Cheprakov, A. V. Chem. ReV.
2000, 100, 3009. (g) Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E., Ed.; John Wiley & Sons: New York, 2002. (h)
Whitcombe, N. J.; Hii, K. K.; Gibson, S. E. Tetrahedron 2001, 57, 7449.
(i) Hegedus, L. S. Transition Metals in the Synthesis of Complex Organic
Molecules, 2nd ed.; University Science Books: Sausalito, CA, 1999; Chapter
4.6. (j) Beller, M.; Riermeier, T. H.; Stark, G. In Transition Metals for
Organic Synthesis; Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim,
Germany, 1998; Vol. 1, p 208. (k) Crisp, G. T. Chem. Soc. ReV. 1998, 27,
427.
(2) For a few papers on the topic of insertion and regioselectivity, see:
(a) Ozawa, F.; Kubo, A.; Hayashi, T. J. Am. Chem. Soc. 1991, 113, 1417.
(b) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2. (c) Ludwig, M.;
Stromberg, S.; Svensson, M.; Akermark, B. Organometallics 1999, 18, 970.
(d) Larhed, M.; Hallberg, A. In Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, E., Ed.; John Wiley & Sons: New York,
2002. (e) Mo, J.; Xu, L.; Xiao, J. J. Am. Chem. Soc. 2005, 127, 751. (f)
Cabri, W.; Candiani, I.; Bedeschi, A.; Santi, R. J. Org. Chem. 1992, 57,
3558.
10.1021/ol052136d CCC: $30.25
© 2005 American Chemical Society
Published on Web 11/11/2005

have previously been reported, but all the examples were
performed with electron-deficient alkenes.4,5 Developing new
catalytic systems replacing the toxic and expensive triflate-
substituted electrophiles would be of interest not only from
an academic point of view but also from an industrial one.
Previously, we reported a catalytic system facilitating the
coupling of an R,â-unsaturated tosylate to N-vinyl acetamide
affording 2-acylamino-1,3-butadiene 1 in 55% isolated yield
and with >19:1 R-regioselectivity (Scheme 1).6-8
Table 1. Heck Couplings of R,â-Unsaturated Tosylates with
Enamides and Butyl Vinyl Ethera
Scheme 1. Heck Couplings of R,â-Unsaturated Tosylates with
N-Vinyl Acetamide
Herein, we report general reaction conditions for the
palladium(0)-catalyzed coupling of R,â-unsaturated tosylates
to vinyl ethers and enamides with high regioselectivity and
good yields providing 2-alkoxy-1,3-dienes and 2-acylamino-
1,3-butadienes. Both types are useful compounds in the
synthesis of functionalized cyclohexenes by cycloaddition
reactions.9 Further expansion of this catalytic system to in-
clude R,â-unsaturated mesylates was also successful, provid-
ing similar reactivities and regioselectivities in certain cases.
All tosylate and mesylate derivatives, 2-6 (Table 1) and
16-18 (Table 2), respectively, were synthesized according
to known literature procedures from commercially available
starting materials.10 The Heck reactions were performed with
Pd2dba3 as the palladium source, DPPF as the bidentate
ligand, and DIPEA as the stoichiometric base.8 Cross-
couplings with the tosylate derivatives and N-vinyl aceta-
mide11 generally went to completion within 6 h (Table 1,
entries 1, 3, 5, 7, and 9), but reaction times as short as 1 h
were observed for the synthesis of compound 7 (entry 1).
An excess of the tosyl substrate (1.5 equiv) was applied to
(3) Cabri, W.; Candiani, I,; Bedeschi, A.; Roberto, S. Tetrahedron Lett.
1991, 32, 1753.
(4) Fu, X.; Zhang, S.; Yin, J.; McAllister, T. L.; Jiang, S. A.; Chou-
Hong, T.; Thiruvengadam, K.; Zhang, F. Tetrahedron Lett. 2002, 43, 573.
(5) For examples on the use of vinyl/aryl tosylates in palladium(0)-
catalyzed coupling reactions, as well as oxidative addition studies, see: (a)
Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120, 7369. (b) Fu,
X.; Thiruvengadam, T. K.; Zhang, F. Tetrahedron Lett. 2002, 43, 573. (c)
Roy, A. H.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 8704. (d) Roy, A.
H.; Hartwig, J. F. Organometallics 2004, 23, 194. (e) Klapars, A.; Campos,
K. R.; Chen, C.-y.; Volante, R. P. Org. Lett. 2005, 7, 1185. (f) Fu, X.;
Zhang, S.; Yin, J.; Schumacher, D. P. Tetrahedron Lett. 2002, 43, 6673.
(6) Hansen, A. L.; Skrydstrup, T. J. Org. Chem. 2005, 70, 5997.
(7) For recent Heck coupling with enamides, see: (a) Andappan, M. M.
S.; Nilsson, P.; von Schenck, H.; Larhed, M. J. Org. Chem. 2004, 69, 5212.
(b) Vallin, K. S. A.; Zhang, Q.; Larhed, M.; Curran, D. P.; Hallberg, A. J.
Org. Chem. 2003, 68, 6639. (c) Harrison, P.; Meek, G. Tetrahedron Lett.
2004, 45, 9277.
a Conditions for enamides: Enamide (1 equiv), tosylate (1.5 equiv),
DIPEA (2 equiv). Conditions for vinyl ether: Vinyl butyl ether (4 equiv),
DIPEA (3 equiv), tosylate (1 equiv). For reaction times, see Supporting
Information. Regioselectivity >19:1 branched:linear, measured by 1H NMR.
All yields are isolated yields.
(8) DIPEA ) diisopropylethylamine, DPPF ) 1,1′-bis(diphenylphos-
phino)ferrocene.
(9) (a) Andersson, C.-M.; Hallberg, A. J. Org. Chem. 1989, 54, 1502.
(b) Krohn, K.; Micheel, J.; Zukowski, M. Tetrahedron 2000, 56, 4753.
(10) See Supporting Information.
(11) N-Vinyl acetamide is commercially available.
5586
Org. Lett., Vol. 7, No. 25, 2005

1
Regioselectivities were determined by H NMR spectral
analysis of the crude reaction mixture and, in all cases,
proved better than >19:1 (branched:linear). Compounds
7-15 were purified by column chromatography, affording
yields as high as 91%. Surprisingly, no reaction occurred
when the N-vinyl oxazolidinone was examined (entry 10).
Next we tested the possibility of using the mesylate
derivatives 16-18 (Table 2) as such derivatives represent
an even less expensive class of electrophiles than the
tosylates.12 Subjecting 16 to the reaction conditions used for
the tosylates and N-vinyl acetamide with a reaction time of
5 h resulted in formation of 7 in a similar yield and with a
>19:1 (branched:linear) regioselectivity (entry 1). Other
coupling attempts between mesylates and enamides were also
performed (entries 3, 5, 7, and 8), although the latter two
proved more sluggish and hence led to lower coupling yields.
Butyl vinyl ether was also successfully coupled to the
mesylates (entries 2, 6, and 9), although typically longer
reaction times were required compared to the enamides (from
11 to 24 h). In contrast to the tosylates, no coupling between
the enamides and butyl vinyl ether and the mesylated deriva-
tives of coumarin and 4-hydroxy-6-methyl-2-pyrone were
observed with complete isolation of the starting substrates.
This implies that the mesylate derivatives are less reactive
as electrophiles than the corresponding tosylates, requiring
a strong electron-withdrawing group in the starting materials.
Alternatively, a catalytic system with more electron-donating
ligands that possibly facilitate the oxidative addition step
could be explored. Reacting 16 with N-vinyl pyrrolidone,
an N,N-disubstituted enamide, resulted in no reaction,
suggesting that the monosubstituted amide functionality
might play an important role in the reaction mechanism.
In summary, we have prepared several 2-alkoxy-1,3-dienes
and 2-acylamino-1,3-butadienes starting from inexpensive
tosylate and mesylate derivatives. The couplings proceed in
good yields and with regioselectivities attaining >19:1. This
proves that alternatives to the expensive and toxic triflating
agents exist when working with R,â-unsaturated systems.
The high degree of regioselectivity obtained implies that a
cationic reaction mechanism is operating for these couplings.
Further work is now ongoing to optimize the coupling with
electron-deficient olefins, as well as broadening the perspec-
tive of applying the mesyl electrophiles to other known Pd-
(0)- and Ni(0)-catalyzed reactions.
Table 2. Heck Couplings of R,â-Unsaturated Mesylates with
Enamides and Butyl Vinyl Ethera
Acknowledgment. We are indebted to the Danish Na-
tional Science Research Council and the University of Aarhus
for generous financial support.
a Conditions for enamides: Enamide (1 equiv), tosylate (1.5 equiv),
DIPEA (2 equiv). Conditions for vinyl ether: Vinyl butyl ether (4 equiv),
DIPEA (3 equiv), tosylate (1 equiv). For reaction times, see Supporting
Information. Regioselectivity >19:1 branched:linear, measured by 1H NMR.
All yields are isolated yields.
Supporting Information Available: Experimental pro-
cedures for (a) the synthesis of the tosylate and mesylate
1
derivatives, and (b) the Heck coupling reactions. H NMR
and 13C NMR spectra for the tosylate and mesylate com-
pounds and coupling products. This material is available free
of charge via the Internet at http://pubs.acs.org.
ensure complete conversion of N-vinyl acetamide, which
otherwise complicated purification of the coupling product.
Vinyl butyl ether was less reactive, and longer reaction times
were needed (entries 2, 4, 6, and 8) in most cases ranging
from 2.5 h for 8 (entry 2) to 23 h for 10 (entry 4).
OL052136D
(12) Aldrich prices on reagent grade compounds in euro/mol: mesyl
chloride ) 15.38, tosyl chloride ) 27.16, triflic anhydride ) 460.88.
Org. Lett., Vol. 7, No. 25, 2005
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