J . Org. Chem. 2000, 65, 7235-7239
7235
Ch a r t 1
High ly Regioselective P a lla d iu m -Ca ta lyzed
â-Ar yla tion of N,N-Dia lk yla llyla m in es
Kristofer Olofsson, Mats Larhed, and Anders Hallberg*
Department of Organic Pharmaceutical Chemistry, Uppsala
University, BMC, Box-574,SE-75123 Uppsala, Sweden
palladium acetate, DPPF,7 base (triethylamine, potas-
sium carbonate or pentamethylpiperidine (PMP)) in
acetonitrile as solvent.8 The reactions were conducted at
80 °C and completed after 20 h with more than 99.5%
conversion of 3a -j. The preparative results are sum-
marized in Table 1. For the majority of the couplings,
the internally, â-arylated product 2 was strongly pre-
dominant and isolated in moderate to good yields (35-
81%).9 One notable side-reaction was the deoxygenation
of the triflate to the corresponding arene.10 Large amounts
of arene were produced in some cases in the presence of
triethylamine as base, for example with the naphthalene
triflate 3g and the electron-poor triflates 3h -j. This side-
reaction could be reduced upon changing triethylamine
to the inorganic potassium carbonate, which proved to
be the generally most applicable base, even though
triethylamine (Method C, entries 5 and 6) and PMP
(Method D, entries 8 and 10) were found to deliver higher
yields in a few cases, see Table 1 and Experimental
Section. Increasing the amount of catalyst was also
effective in improving the yields (Method B, entries 4, 7
and 9, Table 1), even though phenyl migration11,12 became
more of a problem with the accompanying larger amounts
Received May 30, 2000
The arylethylamine fragment 1 is common in many
bioactive compounds and molecules with this structural
unit are of importance in the search for effective thera-
peutics. Arylethylamines possessing an exomethylene
group 2 (RdH or alkyl) are similarly often of interest in
medicinal chemistry and serve as building blocks of more
advanced chemical entities (Chart 1). We needed access
to a method for the preparation of structures encompass-
ing 2 in an ongoing medicinal chemistry program.1
A
direct synthesis of 2 by a regiocontrolled Heck-reaction,2
resulting in the addition of an aryl group at the internal
(â-carbon) of N,N-dialkylallylamines, appeared to be an
attractive alternative to the previously reported meth-
ods3,4 due to the simplicity of the experimental procedure
and the easily available starting materials.
We are here reporting a highly regioselective, one-pot,
palladium-catalyzed synthesis of the 2-aryl-3-(N,N-di-
alkylamino)-1-propenes 2. The long reaction times re-
quired for full conversion of the aryl triflates 3 with
standard, thermal heating could in many cases be
shortened considerably with retained, high regioselec-
tivity under single-mode microwave irradiation5,6 (Eq 1).
In addition, performing the standard Heck-coupling
reaction under a carbon monoxide atmosphere allowed
for the synthesis of N,N-dimethylbenzamide.
(5) (a) Neas, E. D.; Collins, M. J . Introduction to Microwave Sample
Preparation; Kingston, H. M.; J assie, L. B. Eds.; American Chemical
Society: Washington, DC 1988, 7-31. (b) Strauss, C. R.; Trainor, R.
W. Aust. J . Chem. 1995, 48, 1665-1692. (c) Majetich, G.; Wheless, K.
In Microwave-Enhanced Chemistry; Kingston, H. M.; Haswell, S. J .,
Eds; American Chemical Society: Washington, DC, 1997; 455-505.
(d) Galema, S. A. Chem. Soc. Rev. 1997, 26, 233-238. (e) Langa, F.;
de la Cruz, P.; de la Hoc, A.; D´ıaz Ortiz, A.; D´ıez Barra, E. Contemp.
Org. Synth. 1997, 373-386. (f) Ha´jek, M. Collect. Czech. Chem.
Commun. 1997, 62, 347-354. (g) Gabriel, C.; Gabriel, S.; Grant, E.
H.; Halstead, B. S. J .; Mingos, D. M. P. Chem. Soc. Rev. 1998, 27, 213-
223. For a discussion on the influence of pressure in microwave-heated
closed vessels, see: (h) Gedye, R. N.; Wei, J . B.; Can. J . Chem. 1998,
76, 525-532.
(6) For examples of microwave irradiation in palladium-catalysed
reactions, see: (a) Larhed, M.; Hallberg, A. J . Org. Chem. 1996, 61,
9582-9584. (b) Larhed, M.; Hoshino, M.; Hadida, S.; Curran, D. P.;
Hallberg, A. J . Org. Chem. 1997, 62, 5583-5587. (c) Olofsson, K.; Kim,
S.-Y.; Larhed, M.; Curran, D. P.; Hallberg, A. J . Org. Chem. 1999, 64,
4539-4541. See also ref 1a.
Resu lts
The aryl triflates 3a -j were in the standard, thermal,
experiments mixed with N,N-dimethylallylamine 4a ,
(7) DPPF ) 1,1’-bis(diphenylphosphino)ferrocene. Although several
other bidentate ligands, including DPPP (1,3-bis(diphenylphosphino)-
propane), have been tried, only DPPF yields high regioselectivities
under the present reaction conditions. (a) Hayashi, T.; Konishi, M.;
Kobori, Y.; Kumada, M.; Higuchi, T.; Hirotsu, K. J . Am. Chem. Soc.
1984, 106, 158-163. (b) Butler, I. R.; Cullen, W. R.; Kim, T. J .; Rettig,
S. J .; Trotter, J . Organometallics 1985, 4, 972-980. (c) Gan, K. S.;
Hor, T. S. A. Ferrocenes; Togni, A.; Hayashi, T., Eds.; VCH: Weinheim
1995; pp 3-104.
(8) DMF and acetonitrile were both found to be suitable solvents,
giving substantially identical yields and regioselectivities.
(9) Couplings with the para-nitro triflate resulted in no notable
product formation and couplings with the meta-aldehyde triflate only
in 13% isolated yield. The 2-pyridyl triflate, which should be capable
of strong palladium coordination, resulted in only trace amounts of
product.
(10) (a) Cabri, W.; DeBernardinis, S.; Francalanci, F.; Penco, S.;
Santi, R. J . Org. Chem. 1990, 55, 350-353. (b) J utand, A.; Mosleh, A.
J . Org. Chem. 1997, 62, 261-274. Deoxygenation of the triflates has
been suggested to be partially brought about through donation of
hydride from organic bases, such as triethylamine, although several
mechanisms may be at hand as deoxygenation occurs in the presence
of inorganic bases without hydrogens as well. (c) Saa´, J . M.; Dopico,
M.; Martorell, G.; Garc´ıa-Raso, A. J . Org. Chem. 1990, 55, 991-995.
(1) (a) Alterman, M.; Andersson, H. O.; Garg, N.; Ahlse´n, G.;
Lo¨vgren, S.; Classon, B.; Danielsson, U. H.; Kvarnstro¨m, I.; Vrang,
L.; Unge, T.; Samuelsson, B.; Hallberg, A. J . Med. Chem. 1999, 42,
3835-3844. (b) Hulte´n, J .; Andersson, H. O.; Schaal, W.; Danielson,
H. U.; Classon, B.; Kvarnstro¨m, I.; Karle´n, A.; Unge, T.; Samuelsson,
B.; Hallberg, A. J . Med. Chem. 1999, 42, 4054-4061.
(2) (a) Heck, R. F. Org. React. 1982, 27, 345-390. (b) de Meijere,
A.; Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994, 33, 2379-2411.
(c) Tsuji, J . Palladium Reagents and Catalysts; J ohn Wiley & Sons:
Chichester 1995; pp 125-168. (d) Cabri, W.; Candiani, I. Acc. Chem.
Res. 1995, 28, 2-7. (e) J effery, T. Advances in Metal-Organic Chem-
istry; Liebeskind, L. S. Ed.; J ai Press Inc: Greenwich 1996, vol 5, pp
153-258. (f) Crisp, G. T. Chem. Soc. Rev. 1998, 27, 427-436. (g)
Amatore, C.; J utand, A. J . Organomet. Chem. 1999, 576, 254-278.
(h) Larhed, M.; Hallberg, A. Handbook of Organo-Palladium Chemistry
for Organic Synthesis; Negishi, E.-I. Ed.; Wiley-Interscience. In press.
(3) For examples of preparations of 2, see: (a) Gupton, J . T.; Andrew,
S. S.; Lizzi, M. J . Synth. Commun. 1982, 12, 361-371. (b) Schwan, A.
L.; Warkentin, J . Can. J . Chem. 1988, 66, 1686-1694.
(4) For the use of 2 in organometallic displacement reactions, see
(a) Gupton, J . T.; Layman, W. J .; Forman, J . T. Synth. Commun. 1986,
16, 1393-1400. (b) Gupton, J . T.; Layman, W. J . J . Org. Chem. 1987,
52, 3683-3686.
10.1021/jo000824z CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/19/2000